The genetic control of meiosis.

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THE GENETIC CONTROL

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OF MEIOSIS Bruce S. Baker! Department of Zoology, University of North Carolina, Chapel Hill, North Carolina 27514

Adelaide T. C. Carpenterl Department of Anatomy, Duke University Medical Center, Durham, North Carolina 27710

Michael S. Esposito Department of Biology, University of Chicago, Chicago, Illinois 60637

Rochelle E. Esposito Department of Biology, University of Chicago, Chicago, Illinois 60637

L.

Sandler

Department of Genetics, University of Washington, Seattle, Washington 98195

CONTENTS

INTRODUCTION

.................................................................... . .. . .... . .......................... . .. . . Cross-Specific Comparisons ........................................................................................

LOWER EUCARYOTES

........................................................ . ... ...................................... Criteria for Mutant Isolation .................................................................................. Fertility ........................................................................... .......................................

Effects on specific meiotic events

54 55 57

57 57

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Mitotic disturbances ................................................................................................ Yeasts ........................................................................................................................ Fertility mutants .................................................................................................... Mutants with altered meiotic exchange .. ...... .............................................................. Defective mating-type control of sporulation ..............................................................

58 59 60 62 63

IPresent address: Department of Biology, University of California at San Diego, La . Jolla, California 92093.

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BAKER, CARPENTER, ESPOSITO, ESPOSITO

SANDLER

. . . . . . .... ... .. ................................... . . ................. .... ............ . ........ . .. .. . . . .... Radiation-sensitive mutants .... . ....... . .... . .. . ... .. .. . . .. .... ..... ..... ..... ... .. .. .. .. .. . .... .. ..... ...... . ...

Sporulation derepressed mutants

.

&

.

.. ...... .... .. .. .. .. .. ....

Induced-mitotic-recombination-defective mutants

Mutation and meiosis ............. . .... ....... ... ... ..... . ........ .... ....... ....... . .. .............. . .... ...... .... Cell division cycle mutants

.

. .

.

.

. . . .. ......... ... .... ..... .. ..... ...... ...

............... .... .. ... ..... .... .. .. ..

Schizosaccharomyces .. .. ..... .. . .... . .... . ...... .........:..........................................................


Neurospora ................ ....... ..... ..... ......... . ........ ...... . ..... . .. . ... .. ........... . .... ........................ Fertility mutants ... . ... . ...... .. .. . . .... . . .. .. ... .. ................................................................. Region-specific efficts on exchange ............................................................................ Mutation and meiosis ... . ...... .. ............ . .. . .. . ... . ...... ... .. .... . .. . .. .... .... . .. .. .. . .. . . . .. ..... ......... . Ascus and spore morphology mutants .. ...... ... .... ... .... ...... ... ... ........ .... ... .... .......... ...... ... Radiation-sensitive mutants . ... . .. ..... .. .. ... ... .... ... . . ............ .. . .. . . ... ........ . .. . .. . .. ............. . . . Nuclease mutants

....................................................................................................

Podospora ....... ... ... ... .. ..... .. ... ........ ....... ............... ... ....... ... ... .... ... .... .... .... ... ..... ... ... . ..... . Schizophyllum ............... ..... ............... ...... ... ... .... ... ... ... . ... .. . ........ .. . . ..... . . .. .. ... .. .... ...... . Aspergillus . ...... ..... . .. ..... ............... ........ ........................................... .... ...................... Ustilago ..................... .. ..... ...... ..... ....... ... .......... .... ... ... ...... ....... .. ........ .............. ... ... ... . Ascobolus ..... ... ... ............ . .. ... .. . .. . .. ....... . ... .. . .... .. ..... ..... . .. .... .. ....... .. .. . ... ... ... .. ...... ... .. .. .. Other Lower Eucaryotes ... ... .. ... ....... .. ... ... .... ... . .... ..... .. .... . .. ..... ... .... ... ... ... ........ ... ......

64 65 65 66 67 67 68 68 69 71 71 72 72 72 73 74 75 76 76

DROSOPHILA ..................................................................................................................

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Analytic Methods ...................................................................................................... Sex Differences in Meiosis .... ... ..... .. .. ... ... ... ....... .... ... ... ... . .... ...... .... .... . .. ... ........ ... ... ... . Recombination-Defective Meiotic Mutants .............................................................. Exchange in recombination-defective meiotic mutants ... ................. . ...........................

78 78 78 79 82 84 85 86 86 86 87 87 89 90 90 93 94

Disjunction in recombination-defective meiotic mutants

..............................................

Meiotic ultrastructure in recombination-defective meiotic mutants

. .

.... .. .......................

.

The complexity of genic effects

Recombination-defective mutants in other Drosophila species . ....... .... .......................... Recombination and DNA Metabolism ..... ........ ... . ..... . ............. .... ....... ... ..... ..... ... .... . Mutagen sensitivity ....... ... ................... ...... .... ... .... ...... ... ........................................... Repair . .. ... . ... . . . ... .. ....... .......................... ....... ... .... . .. . ..... . . ...... ... .... ....... .................... Mitotic chromosome behavior ......................... ......................................................... Mutagenicity ........ . .... .. .... .. ... .. ... .. ..... .... .. . .. . ............................................................ Recombination in males ........ ... .. .......... . ..................... .......... . . ... . .... ......................... Disjunction-Defective Meiotic Mutants .. . ... ... . ......... . ... .. . .. . . .. . ........... ... ........ . ..... . . .... . Mutants A ffecting Meiosis II ............. ........... .... .... ... ... ...... ........ . .................. .. ... ... .... . Male-Specific Meiotic Mutants ..................... .... ......... ....... . ........... .............. ........ .....

HIGHER PLANTS

............................................................................................................

Premeiotic Mitosis and Commitment to Meiosis . ... . ............ . ... .... .......................... .. Prophase I ........ ........................................................................................................ Asyndetic mutants .. .............. ..... . ............... ............. . .. . .. . ...... ... . .. .. ........................... The consequences of asyndesis .................................................................................. Mutants affecting chromosome integrity ..... . . . ... . ... ... ......... ........ . .. . .. .. . .. . ........ .. . .......... Meiosis I Spindle ........................ .. ... ........... ... ................ . .. . .... ... . ....... . .. ... . ...... . .. . .. . .. .. Entry into Meiosis II . .......... ........ .... .. . .. . .. . .......... ... ... ... ... .......... ............................. ... Second Division ... . ....................... ..... .... . .............. . ... ............ ..................................... Postmeiotic Mutants ................................................................................................

MAN

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96 97 97 98 103 104 106 107 107 108 108

INTRODUCTION Although the descriptive cytology of the meiotic divisions has been actively and successfully pursued for more than a century, and although the properties of meiosis


THE GENETIC CONTROL OF MEIOSIS

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as the physical basis of transmission genetics in eucaryotes has been a major field of investigation since the rediscovery of Mendel's principles, only relatively recently has the genetic control of meiosis received systematic attention. In this review we examine the genetic control of meiosis by considering the consequences of mutations that interrupt the normal sequence of meiotic events. Many such meiotic mutants, analyzed to varying extents, are known in the fungi and other lower eucaryotes, in Drosophila, and in higher plants. We intend to make a systematic survey of these mutants; to the extent that the data permit, we infer how the wild-type allele of each meiotic mutant insures a normal meiosis. Since the discovery by Gowen & Gowen (1) of the first meiotic mutant, c(3)Gin Drosophila, and the recognition that mutations of this kind can be used to study the meiotic process (2, 3), the genetic control of meiosis has been examined in several reviews. Among these are discussions of meiotic mutants in general (4, 5), in lower eucaryotes (6-24), in higher plants (25-29), and in Drosophila (30-35). Subjects excluded from this article, except where directly relevant to the analysis of a meiotic mutant, but reviewed elsewhere are: fungal incompatibility systems, reviewed by Koltin et al (36); biochemical controls of meiosis, reviewed by Stern & Hotta (37); the phenomenon of meiotic drive, dealt with by Zimmering et al (38) and by Hartl & Hiraizumi (39); meiotic cytology, reviewed by Rhoades (40), includ ing the synaptonemal complex, reveiwed by Gillies (41 ); the very extensive work on the genetic control of synapsis by chromosome 58 In wheat, considered elsewhere in this volume (42); anomalous meioses that characterize a species, considered in animals by White (43) and in plants by Darlington (44) and by John & Lewis (4); and meiotic effects of external agents, chromosomal aberrations, aneuploidy, super numerary chromosomes, and interspecific hybridizations.

Cross-Specific Comparisons In the sections of this review to follow, we present reasonably detailed descriptions of the effects of meiotic mutants as they have been studied in a variety of individual species. Here, we very briefly examine some of the more general properties of meiosis that are revealed by considering the genetic control of meiosis across species lines. Experimental details and references are found in appropriate sections in the body of the text. We begin by noting that meiosis can be distinguished from the mitotic cell cycle beginning with the initiation of premeiotic DNA synthesis. That this synthesis is unique is suggested by differences in the timing and extent of premeiotic replication, and by mutants uniquely incapable of premeiotic DNA synthesis. That the entry into meiosis in higher plants is genetically controlled is shown by mutants that alter commitment to meiosis. In addition, in some plants there appear to be mutants in loci affecting the transition from meiosis I to meiosis II. Other mutants affect the return to mitotic cell division after meiosis, thus providing an endpoint to meiosis. In this review we use the term meiotic mutant to mean a mutation that drastically modifies the normal pattern of chromosome behavior beginning with the initiation of premeiotic DNA synthesis and before the reinitiation of mitosis after the comple tion of the second meiotic division.


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BAKER, CARPENTER, ESPOSITO, ESPOSITO & SANDLER

By this definition, there are many meiotic loci in all forms in which they have been looked for. Exactly how many meiotic loci there are in any given species, however, cannot be computed because of the limited criteria applied to detect mutants in any one system, and because mutants obtained thus far are not recovered according to Poisson expectations. While the map positions of meiotic loci have not in general revealed any striking overall patterns, there are several apparent cases of clustering of meiotic mutants with similar phenotypes in Drosophila. Although clustering of meiotic loci has been observed only in Drosophila, in no other form· is there a collection of meiotic mutants large enough and sufficiently well mapped to make the observation. If this clustering is not casual, it might imply an evolutionary history of gene duplication followed by divergence, or an organization of the chromosome at a supragenic level. Among the most important generalizations to emerge from the study of meiotic mutants is that some, but not all, of the metabolic processes involved in meiotic development and recombination are also used in somatic cells in processes involved in DNA metabolism necessary to insure chromosome stability both spontaneously and after irradiation. This relationship is evidenced by the many reciprocal observa tions, in all species in which it has been examined, that meiotic mutants often exhibit mitotic chromsome instability, while mutants recovered because they are sensitive to irradiation or radiomimetic drugs often prove to have meiotic effects, particularly on recombination. Another generalization to emerge from the study of meiotic mutants is that an exchange is necessary for normal disjunction in organisms in which recombination normally occurs. In all recombination-defective meiotic mutants in which the mat ter has been examined, abnormal segregation of nonexchange homologues obtains. However, while necessary, an exchange is not sufficient to insure normal meiotic segregation. This is shown by the existence of disjunction-defective meiotic mutants in which exchange is normal, but disjunction nevertheless abnormal. Furthermore, that an exchange does not determine reductional (versus equational) separation of centromeres is shown by observations of equational segregation following meiotic exchange in organisms with interruptable meioses. With regard to the genetic control of exchange itself, it appears that there are at least two levels of control-one that is region-specific and one that acts on the chromosome as a whole. With respect to the latter, two types of mutant that alter recombination are found. One type produces an alteration in the distribution of exchanges among and along chromosome arms, often, but not invariably, accom panied by a change in the overall frequency of exchange. The properties of such mutants suggest that the distribution of exchanges within and among cells, as well as the distribution of exchanges along the length of the chromosome, are all under resolvable genetic control. A second type of mutant alters the frequency, but not the spatial distribution, of recombinants. Finally, for reasons that are still speculative, it is a common observation that while many meiotic mutants are recovered that affect the first meiotic division, meiotic mutants affecting the second division are relatively rare in all forms that have been studied.


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LOWER EUCARYOTES Lower eucaryotes, particularly the fungi, have for many years played an important role in the study of meiosis. This is due in part to the diversity of their life cycles and in part to certain topological aspects of meiosis that make it particularly amenable to study in these organisms. The flexibility of life cycles frequently permits vegetative propagation of haploid, diploid, higher euploid, and aneuploid meiotic products. In some cases, such cells can be stimulated to enter meiosis without further hybridization. This facilitates the isolation of both recessive and dominant meiotic mutants and allows ready examination of the relationship between distur bances in meiosis and the mitotic cell cycle. Of particular advantage in studies with lower eucaryotes is the recovery of all four products of meiosis in physical association. The presence of tetrads has been most useful in discerning the properties of intergenic and intragenic exchange and their relation to one another (16). Although tetrad analysis has also been employed to study chromosome behavior, only recently has the utility ofthis approach been fully appreciated. The patterns of gametic death among the products of meiosis owing to chromosomal aberrations, aneuploidy, and mutations affecting exchange and segregation have been extensively studied in Neurospora by Perkins and his col laborators (45, 46), and should become an increasingly useful probe into meiosis in other systems as well (47, 48). The simple cultivation procedures that can be applied to initiate meiosis, and in some instances to harvest large quantities of meiocytes relatively free of vegetative cells, offer additional advantages for cytological and biochemical investigations of meiotic mutants. Criteria for Mutant Isolation

Three criteria have been used to screen for meiotic mutants: (a ) decreased produc tion of functional gametes; (b) abnormalities in specific meiotic events such as the initiation of meiotic development, genetic recombination, and chromosome segrega tion; and (c) anomalies in aspects of mitotic cell division, as, for example, the regulation of the cell division cycle and the repair of radiation-induced damage. Reduced fertility is detected either by the failure to produce mature meiotic products or by gametic abortion once such products have formed (49-61). The rationale is to obtain mutations, affecting any stage in meiosis, that alter the ability of the final products of meiotic development to be formed or to be viable in either asexual or sexual reproduction. Strains exhibiting reduced fertility often do so, however, for reasons other than the presence of meiotic mutants. Variants that disturb gamete formation in general, that possess chromosomal aberrations (45), or that have become polyploid (62) are also recovered by this method. The use of fertility as the criterion has, as its limitation, the failure to detect mutations that disturb meiosis but permit functional gametes to develop. Studies in higher plants and animals, as described below, suggest that mutations resulting in general defects in recombination and chromosome segregation result in the formaFERTILITY

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tion of aneuploid gametes, and will be detected by reduced fertility. However, subtle alterations in recombination in specific regions of the genome can be overlooked by exclusive use of this criterion (18). Nearly all of the procedures for detect ing mutations affecting specific meiotic events have been directed towards the isola tion of mutants exhibiting enhanced or depressed recombination. In most cases, one or two loci are marked by heteroalleles and several additional intervals by heterozy gous markers. When this criterion is employed in conjunction with selective sys tems, the method is to monitor the level of intragenic recombination as a preliminary screen by determining the frequency of prototrophic recombinants produced at the completion of meiosis. Mutants that exhibit enhanced or depressed prototroph production are then examined for intergenic exchange. Since the initial selection is generally for variants that modify intragenic exchange, mutations in gene functions that govern only intergenic crossing-over are likely to be excluded. Caution must also be exercised in restricting analysis of intragenic recombination to prototroph production. Since prototrophs represent primarily one (single-site conversion to wild type) of several types of recombinants that arise by intragenic exchange,


EFFECTS ON SPECIFIC MEIOTIC EVENTS

modification in the mode or distribution of recombinant classes may lead to an

enhanced or depressed frequency of prototrophs without substantial alteration in the overall frequency of gene conversion (63). Altered patterns of recombination exhibited by variants in mitosis as well as meiosis are frequently associated with reduced fertility for reasons that are not always understood but perhaps result from increased chromosome breakage, chromosome loss, or nondisjunction. Meiotic mutants that perturb chromosome segregation but not recombination have not yet been sought by selective means; they may, however, be recovered indirectly by procedures that detect a reduction in fertility. The preceding methods have the common feature that they reveal lesions in meiosis once meiotic development has been initiated. Recently several systems have also been developed to isolate mutations affecting the initiation of meiosis by screen ing for mutants that promote precocious meiosis or that permit meiosis to occur under culture conditions that generally do not stimulate meiotic development (64, 65). A number of different criteria have been used thus far to detect mutations that disturb aspects of vegetative growth and, in some cases, meiosis. These are enhancement or depression of (a) mutagen sensitivity as evi denced by increased mutagen-induced lethality, (b) spontaneous and/or induced mutation, (c) spontaneous and/or induced recombination, (d) nuclease activity, and (e) disturbances in the mitotic cell cycle. The first four criteria detect mutations that alter DNA metabolism. The rationale is the expectation that aspects of the genetic control of recombination will be uncovered. This expectation derives from the many data collected in procaryotic systems that relate the processes of genetic recombina tion, gene mutation, and the repair of radiation-induced damage (66). The last

MITOTIC DISTURBANCES


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criterion allows the detection of mutations in functions required for mitosis that lead to termination of cell division at specific points in the cell cycle (67); these mutants can then be examined to see if they also affect meiosis. It is evident from the studies described below that mutants selected on the basis of mitotic defects frequently express meiotic abnormalities and vice versa. The joint genic control of mitosis and meiosis, as well as evidence for independent functions, is manifested in several species of both lower and higher organisms.


Yeasts

Among lower eucaryotes, the genetic control of meiosis has been most extensively studied in Saccharomyces cerevisiae. Biochemical and cytological events during meiosis and spore development (collectively termed sporulation), the properties of genetic exchange during meiosis, and the methodologies employed in studies of sporulation have been previously reviewed (to, 12, 14, 19-22) and are discussed only briefly here. Several criteria have been used to detect mutations affecting sporulation in Sac charomyces. Mutations have been sought that alter (a) the production of mature spores (spo); (b) the recovery of intragenic prototrophic recombinants during meio sis (me;, con ); (c) the control of sporulation by the mating type alleles (esp, sea, and rme); and (d) the initiation of meiosis (spd). Mutations affecting meiosis and spore formation have also been recovered by initial selection for mitotic abnormalities detected by (a) altered production of radiation-induced intragenic prototrophic recombinants (ree); (b) altered sensitivity to radiation (rad) and chemical mutagens (mms); (c) enhanced or depressed gene mutation (rev, umr, mut, rem); and (d) altered control of the cell division cycle (cdc). In yeast, two special genetic systems have been developed that permit the recov ery, without extensive breeding programs, of both recessive and dominant mutations that can be directly assayed for effects on sporulation. One approach takes advan tage of the life cycle of homothallic strains to obtain mutations in homozygous condition in diploid cells (58-60); the other employs disomic, heterothallic strains (n+ 1), which begin, but do not complete, sporulation (68). In heterothallic forms of Saccharomyces, haploid cells of a and a mating-type copulate with one another and give rise to diploids heterozygous at the mating-type locus; the diploids are stable and reproduce by budding. In sporulation-inducing medium, they cease growth and undergo meiosis. The presence of both mating-types is generally required for sporulation. Individual ascospores of a or a mating-type give rise to stable haploid progeny. Strains disomic for chromosome III and hete rozygous for the mating-type locus (n+l a/a) undergo premeiotic DNA synthesis and become committed to genetic recombination during meiosis. Spore development is not completed in these strains. In homothallic forms, individual 0 or a ascospores give rise to daughter cells of opposite mating-type (0 ascospores form a daughter cells and vice versa). Within a few divisions of germination, the a and a daughter cells derived from a single spore then copulate to form diploid progeny homozygous for all loci except the mating-type locus. These diploids are stable and reproduce by budding in a manner similar to heterothallic forms.


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Wild-type yeast, both heterothallic and homothallic, undergo a series of commit ment stages during sporulation. In Saccharomyces, as in other systems where this has been examined (69), cells removed from a meiosis-inducing environment early in development retain the capacity to revert to mitotic division when placed in growth medium. At later times, cells become committed to complete the meiotic divisions before resuming mitotic division (70-73) . Studies of genetic exchange indicate that sporulating cells become committed to both intragenic and intergenic recombination before they become committed to the meiotic divisions and ascos porogenesis (7 1, 73, 74); that is, cells that revert to mitotic division nevertheless exhibit the enhanced levels of genetic exchange characteristic of meiosis. The en hanced recombination exhibited by cells exposed to sporulation medium has been termed commitment to recombination (73 , 74) . Recent evidence indicates that commitment to exchange is a reversible cellular stage achieved during premeiotic DNA synthesis and therefore represents the establishment of conditions during DNA replication favoring recombination, rather than the completion of exchange events at that time (75). Examination of commitment to exchange in several regions of the genome suggests that different intervals become conditioned for exchange at different times (73) . Finally, cytological studies have established the presence of a classical meiotic prophase during yeast meiosis (76, 77) . Sporulation-defective mutants have been systematically recovered in homothallic strains by Esposito & Esposito (59) on the basis of a reduced production of mature, refractile ascospores. Among 75 spo mutants initally selected, many exhibited temperature-sensitive defects; all were capable of vegeta tive cell division. Complementation tests revealed recessive mutations at 1 1 loci (spo 1-spo 1 1), as well as three dominant mutations whose allelism to the other loci has not been determined. From the frequency of repeat mutations within a locus it has been estimated that approximately 50 genetic loci are specifically required for the production of mature ascospores (78) . Several hundred additional conditional spa variants have been recently isolated, as well an additional mutant class selected on the basis of depressed ascospore viability (79) . This latter includes variants that exhibit depressed ascospore production as well as those that form near normal levels of asci containing inviable spores. The spo mutants characterized thus far exhibit defects throughout the sporulation process with most of the mutations being pleiotropic. Among twelve mutant strains studied, spa 1, 6, 7, 8, 9, to, 1 1, and SPO 98 affect meiosis and exhibit cytological defects prior to metaphase I; the remaining four mutants, spa2, 3, 4, and 5, express defects following chromosome segregation at meiosis I and/or II (47, 80-82) . Two of the latter, spo2 and spa3, express temperature-sensitive functions leading to an irreversible inhibition of spore formation prior to spindle pole body (spindle plaque) duplication at meoisis I and the time at which their cytological defect is detected, indicating that gene functions may be expressed substantially earlier than the final stage of arrest or abnormal behavior (80, 83). Among spo mutants that affect meiosis, spo8, 9, and to are defective in the completion of mitosis by budded cells in sporulation medium, as well as spore formation of the entire cell population (budded and unbudded cells). The functions FERTILITY MUTANTS



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specified by these loci are therefore indispensable for both mitosis under sporulation conditions and sporulation by G 1 cells (S4). Mutants carrying spa7, 8, 9, 1 1 , and the dominant mutant SP098 are deficient in premeiotic DNA synthesis (84). They are capable of mitotic cell division in vegetative growth medium and thus govern gene products that are probably not essential for mitotic DNA synthesis. The spa8-bearing strain is among those most extensively studied. In addition to its defects in the completion of mitosis (bud growth and cell separation) and premei otic DNA synthesis, spa8 does not undergo commitment to meiotic recombination and terminates before spindle plaque duplication (62, 82, 84). While spaS cells are capable of vegetative cell division under nonsporulation conditions, they are slightly UV-sensitive and defective in UV-induced conversion leading to prototroph produc tion. Homozygotes for spa8 are unstable in mitosis as evidenced by frequent segrega tion of genetic markers originally present in heterozygous condition (62). The behavior of spaS suggests that it is defective in a function required not only for the repair of radiation damage and UV-induced recombination during mitosis, but also for normal premeiotic DNA synthesis and subsequent meiotic development. The phenotype of this mutation is similar to ree 1 in Ustilago described in a later section. The spa7 mutation, like spa8, affects meiosis and mitosis. During sporulation, spa7 cells complete mitosis but fail to undergo premeiotic DNA synthesis and are defective in commitment to intragenic recombination. During mitotic cell division they exhibit normal UV-sensitivity and UV-induced heteroallelic recombination. The presence of spa7, however, has an antimutagenic effect during mitosis resulting in a lOO-fold depression in the recovery of spontaneous suppressor mutations (85). The phenotype of spa7 indicates that it is defective in a function of DNA metabolism normally associated with the production of spontaneous mutations, but only slightly, if at all, involved in UV-induced DNA repair mechanisms. As this function is dispensable for mitotic replication but indispensable for premeiotic replication, it may represent the activity of a DNA polymerase or an associated enzyme that plays a minor role in vegetative replication and repair, and a major role in meiotic replication. The spa 1 1 mutation allows completion of mitosis in sporulation medium, and, as in spaS and spa7, results in less than a 10% increase in DNA during premeiotic synthesis. Despite the absence of a major round of premeiotic DNA replication, however, spal l strains, unlike the other mutants, progress through the cytological stages associated with meiotic development, exhibiting a near normal meiotic index, although mature spores are not formed (S l , S4). Recently it has been shown that spa 1 1 forms axial cores but fails to develop sy,naptonemal complexes (8 1, 82). It is concluded that premeiotic DNA synthesis is not required for axial core formation and that normal synaptonemal complex development is not essential for the progres sion of the meiotic divisions. The results also indicate that premeiotic DNA synthe sis is either required for central element assembly into synaptonemal complexes or that both of these events are subject to common genetic control. Failure to complete mitotic cell separation in sporulation medium is exhibited by spa 10 which nevertheless initiates meiosis and undergoes premeiotic DNA synthe sis, illustrating that these two events are independently controlled (84). The spa 1


62


mutant completes mitotic division in sporulation medium, undergoes premeiotic DNA synthesis, forms synaptonemal complexes, and initiates commitment to ex change (62, 73). The wild-type allele of spo 1 is apparently required for the transition from prophase I to metaphase I since spindle plaque duplication is not completed in this mutant. Several other mutations that disrupt sporulation have been discovered among existing heterothallic laboratory strains. A diploid variant producing only two spored asci containing diploid spores has been described (8 1 , 86, 87). One nuclear division is observed which initially resembles meiosis I and then takes on the appearance of meiosis II, particularly in the structure of the spindle plaque. Premei otic DNA synthesis occurs, synaptonemal complexes develop, and preliminary findings suggest that commitment to exchange and equational chromatid separation take place. The apparent function of the wild-type allele of this locus is to prevent equational centromere division immediately following prophase I of meiosis. Another diploid variant has been detected that exhibits chromosomal loss and enhanced exchange in mitosis (88). This phenotype is due to the presence of a recessive gene mutation, chi (formerly her). The effect of chi on mitotic chromo some loss appears to be primarily confined to loss of linkage group III. Meiosis in chi/chi homozygotes is associated with an approximately twofold decrease in ex change in three intergenic intervals tested on chromosome III, and with reduced ascospore viability (88a). The reduction in viability could be a consequence of increases in the formation of nondisjunctional products, but this has not yet been documented. The behavior of chi-bearing strains represents another example of a mutation that affects both chromosomal stability in mitosis and meiotic develop ment. Suppressor mutations in tRNA genes also interfere with meiosis and ascus pro duction (89, 90). The SUP3 mutation, which causes tyrosine to be inserted at ochre nonsense codons, has among the most severe effects on sporulation (89). In SUP3 strains, ochre suppression, rather than the absence of wild-type function, is responsi ble for disruption of events from premeiotic DNA synthesis to spore maturation. Faulty protein termination may be the basis of this effect. Respiratory-deficient strains do not form asci (9 1-94). These strains probably owe their defect in sporulation to an inability to metabolize acetate, the carbon source most effective in promoting sporulation (95). Finally, a cytoplasmic condition, AM (abnormal meiosis), has been described that causes an extra round of DNA syn thesis in meiosis resulting in spores that exhibit tetraploid segregation patterns (96, 97). Mutants specifically defec tive in meiotic intragenic exchange resulting in prototroph production and prior events required for exchange have been selected by Roth & Fogel (68), and Roth (98). Variants were detected in an n + 1 strain which was disomic for chromosome III, heterozygous for the a and a mating-type alleles, and heteroallelic at the leu2 locus. Survivors of mutagenesis were screened for the presence of intragenic prototrophic recombinants at leu2 following incubation under sporulation condiMUTANTS WITH ALTERED MEIOTIC EXCHANGE



63

tions. Fifteen strains were recovered that produced less than 10% of the wild-type level of prototrophs and retained the a and a mating-type alleles as well as the leu2 heteroalleles. These strains were preselected for wild-type behavior with re spect to radiation-induced mitotic gene conversion and are therefore most likely different from the rec mutants that are described in a later section. Five variants have been studied in detail. Two are defective in premeiotic DNA synthesis, intragenic exchange leading to prototrophy, and ascus production (99). This phenotype is due to a single recessive mutation, meil, in one strain, and two recessive mutations, men and mei3, in the other. In these mutants, the absence of intragenic exchange is thought to result from the failure of premeiotic DNA synthe sis. The remaining three strains, carrying recessive mutations at con 1, con2, and con 3, are capable of premeiotic DNA synthesis but not gene conversion events leading to prototrophy. Diploids homozygous for these mutations exhibit reduced ascus production (100). The behavior of these mutants has been interpreted as being due to a change in the distribution of gene conversion events, e.g. increased cocon version, resulting from an extension of heteroduplex regions of DNA during the process of exchange. Recently, 48 additional temperature-sensitive mutants defec tive in intragenic prototroph production have been isolated by similar procedures (98). Ten are defective in premeiotic DNA synthesis and the remainder deficient in prototroph production alone. Thus far, the study of these variants indicates that premeiotic DNA synthesis per se is not sufficient to commit cells to intragenic recombination during sporulation. Furthermore, certain gene functions that modulate genetic recombination during meiosis are not required for radiation-induced mitotic exchange or repair of radia tion damage. Evidence for modifiers that alter exchange in specific regions of the genome has also been reported in Saccharomyces (100, 101; see also 1 1 8a). Recombination between his4 and leu2 on chromosome III varies approximately eightfold indepen dently of exchange in a nearby region. This variation is thought to be under the control of two genetic loci (100). Gene conversion at the SUP6 locus has been found to vary from 25% to 2% in different crosses. Similar evidence for heterogeneity of exchange frequencies has been noted in the his 1 arg6 interval (4.7 to 10. 1 map units) without effects on adjacent intervals (101). -

In Saccharomyces, the presence of both a and a mating-type alleles is required for sporulation. Diploids of ala or ala mating-type do not undergo premeiotic DNA synthesis (102), fail to exhibit the enhanced levels of exchange observed in a/a cells (103, 104), and usually do not form spores (105). Some metabolic activities associated with sporula tion, however, can be detected (104, 106). Gene mutations that modify the behavior of both a/a and a/a diploids permit ting sporulation have been recovered in an extensive mutant hunt by Hopper & Hall (64), as well as among existing laboratory strains (1 1 1, 1 12). In the study by Hopper & Hall, mutants capable of sporulation were selected from mutagen-treated a/a and a/a strains, heterozygous for two recessive, unlinked, drug-resistance markers.

DEFECTIVE MATING-TYPE CONTROL OF SPORULATION


64


Variants were detected by screening for drug-resistant meiotic segregants following sporulation of surviving clones. The properties of the dominant CSPI mutation have been studied most exten sively ( 107). a/a strains carrying CSPI differ from a/a sporulation-competent cells in two respects: (a) in vegetative culture they are a/a-like in behavior (1081 10), in that they are more sensitive to UV and are deficient in UV-induced mitotic recombination; and (b) during sporulation, although DNA synthesis occurs at wild-type levels, intragenic recombination and ascus production are depressed (among the 20% asci observed intergenic exchange values are normal). It has been postulated that the CSPI mutation in an a/a diploid results in a specific meiotic defect in genetic recombination, which in tum causes depressed spore production because subsequent sporulation events depend upon normal exchange-a result similar to that seen in Drosophila and higher plants. Since CSPl, a/a strains exhibit altered behavior in their response to UV compared to a/a strains, it was suggested that the defective function is involved in UV repair processes as well (107). The mutations sea and rme, studied by Gerlach (I I I) and Kassir & Simchen (112), are both recessive and probably located in different cistrons, based upon preliminary mapping data. The rme mutation has been shown to permit DNA replication in sporulation medium in a and a haploid strains in a manner similar to the CSPI mutation (1 12). A strain designated 132, carrying a dominant mutation preventing sporulation, has been described by Simchen et al (72). Strain 132 is defective in premeiotic DNA replication (113). The sporulation defect appears to involve an alteration at the mating-type locus resulting in a defective a allele (a* ). Although mating of a* to a strains occurs at low frequency, diploids bearing the a* allele do not sporulate and mate as a cells (112). MacKay & Manney (114, 115) have reported similar observations in a detailed study of mutations of the mating-type locus. SPORULAnON DEREPRESSED MUTANTS Vegetative cultures of Saccharomyces

generally do not enter meiotic development in the presence of fresh or spent growth medium because of repression by glucose or nitrogen. Dawes (65) has devised an approach based upon this observation to detect sporulation mutants that were specifically altered in events governing the initiation of sporulation. Homothallic haploid ascospores were mutagenized, plated on rich medium, and clones that sporulate in stationary phase were detected by replica plating following selective killing of unsporulated clones by ether treatment ( 1 1 6). Two heteroallelic, recessive mutations, spdl-1 and spdl-2 (sporulation derepressed), were recovered. Both of these result in insensitivity to nitrogen repression but still permit glucose repression of sporulation. Of particular interest is the observation that among revertants of this phenotype are recovered additional sporulation-deficient mutants (some of them temperature-sensitive) that prevent meiosis and spore formation in spent growth medium as wen as in sporulation medium. It has not yet been determined whether these represent a select class of sporulation mutants concerned with initiation func tions or a collection similar to the spo mutants (59).


65

Mutants defec tive in X-ray- and UV-induced mitotic heteroallelic recombination resulting in prototroph production at the arg4 locus have been selected in an n + 1 strain disomic for chromosome VIII by Rodarte-Ramon & Mortimer ( l17-11Sa). Reces sive mutations in at least four genes, ree l , 2, 3, and 4, were uncovered among seven mutants studied in detail. Both rec3 and 4 abolish spontaneous, X-ray-, and UV induced heteroallelic reversion (prototroph production), although neither mutation has any effect on radiation-induced intergenic exchange or the amount of radiation induced lethality. Mutations in ree I abolish radiation-induced intragenic recombi nation alone. Thus, the pathways leading to spontaneous and radiation-induced intragenic exchange include shared as well as independent gene products. Further more, these can be distinguished from gene products required for the repair of radiation-induced lethality and radiation-induced intergenic crossing-over in mito sis (1 l7, l lS). Since ree2 strains exhibit wild-type behavior following UV irradia tion, but are X-ray-sensitive and defective in X-ray-induced heteroallelic reversion, the lesions induced by UV and X rays must also be metabolized independently. Among the variants, ree2, 3, and 4 have sporulation effects. Homozygous ree2 diploids exhibit only 1-2% asci and 10% spore viability while rec3 homozygotes are completely sterile. The ree4 mutation permits normal spore formation and ascospore viability, but specifically suppresses heteroallelic reversion (prototroph production) during meiosis without detectable effects on intergenic exchange. In ree4, gene conversion occurs at normal rates but specific modulation in the distribu tion of conversion events occurs resulting in increased coconversion. This effect is specific to the arg4 locus and does not alter the pattern of exchanges at six other loci tested. The behavior of ree4 has been interpreted as being due to fewer heterodu plex regions being initiated at the arg4 locus as well as an increase in the length of such regions during exchange (1 1 8a; see also 63). The ree4 mutation may be similar to the ree mutations in Neurospora in that it exhibits specific effects in restricted regions of the genome. In any case, it is evident that gene functions required for spontaneous and radiation-induced mitotic heteroallelic reversion are also expressed during meiosis (1 1 7, 1 1 8) and likely play a role in meiotic recombination.


INDUCED-MITOTIC-RECOMBINATION-DEFECTIVE MUTANTS

RADIATION-SENSITIVE MUTANTS UV and/or X-ray sensitivity is controlled by over 30 independent loci in Saccharomyces. The behavior of variants carrying mutations at two or more loci can result in epistatic, additive, or synergistic interac tions, suggesting the existence of at least three pathways for the repair of UV and X-ray damage (1 19-123). One pathway, involving the RADl , 2, 3, 4, and possibly. 22 loci, is concerned with UV excision repair ( 1 l9, 120, 124- 1 3 1). Recessive muta tions in these genes result in UV sensitivity and higher frequencies of UV-induced mutation per unit dose than wild type (130-1 38). A second pathway, involving "error-prone" repair, includes the RADS, 6, 8, 9, and 1 8 and the REVI and 3 loci ( 1 3 1 , 1 3 8-140). Variants carrying recessive mutations in these genes are UV-sensi tive and X-ray-sensitive to varying degrees, and exhibit depressed levels of UV mutagenesis (127, 1 3 1 , 1 3S, 140- 147). A third pathway, thought to play a minor


66


&

SANDLER

role in the repair of UV damage, includes loci that are primarily concerned with X-ray repair; e.g. RAD50 and 5 1 , and likely some or all of RAD52-57 (1 21-23, 145). A number of these mutants have been examined for mitotic and meiotic recombi nation and meiotic fertility. Four variants defective in excision repair, rad l , 2, 3, and 4, exhibit increases in UV-induced intragenic mitotic recombination upon direct plating after irradiation; all but rad2 clearly enhance UV-induced intergenic ex change as well (1 19, 148, 149). Enhanced mitotic recombination among putative excision-defective mutants has also been observed in Aspergillus and Neurospora ·and may reflect the involvement of one or more of the remaining functional repair systems (the error-prone and/or minor UV pathways) in the recombination process. Three variants in the UV error-prone pathway also exhibit increased UV- and X-ray-induced intragenic and intergenic eXChange, rev 1, rev2 ( rad5), and rev3 (142), while one mutant, rad9-4, has been reported to be almost totally deficient in UV-induced recombination (149). The decrease in recombination in rad9-4 would suggest that the error-prone pathway is also involved in radiation:induced exchange. The increases observed in the other mutants (rad5, rev I and 3) may reflect altered gene products involved in recombination or enhanced activity of the third pathway in the presence of these lesions (1 19). None of these mutants has been found to significantly alter spontaneous mitotic recombination or meiotic exchange among viable meiotic products. There is evidence, however; that some of the functions required for the repair of UV and X-ray damage are required for sporulation. In particular, rad6, involved in UV error-prone repair, and many of the mutants associated with the third pathway, concerned primarily with X-ray repair, rad50, 52, 53, 55, and 57, either abolish or reduce ascus formation and/or ascospore viability (145). Mutations in RAD9 have also been found to reduce ascospore viability (149a). Many radiation-sensitive mutants are also sensitive to chemical mutagens (14 1 , 1 50-1 53). Studies of mutants selected o n the basis o f MMS sensitivity indicate that more than 25 complementation groups control this phenotype. Some of these also significantly reduce sporulation and enhance mitotic recombination (1 54). One enhances spontaneous mitotic gene conversion only and has been found to be allelic to radl 8 (ISS). In summary, the properties of radiation-sensitive mutants in Saccharomyces indicate that certain gene functions concerned with the repair of radiation-damaged DNA are also involved in the process of radiation-induced genetic recombination in mitosis and in normal meiotic development. The nature of the meiotic lesions in these strains has not yet been determined. =

MUTATION AND MEIOSIS Meiosis was first shown to be associated with en hanced spontaneous mutation in yeast by Magni & von Horstel (156); this has since been observed in several other organisms (1 57-1 59). The "meiotic effect" on muta tion appears to be allele specific and has been correlated with outside marker exchange ( 1 60); it has been demonstrated for reversion to prototrophy as well as for forward mutation to suppressors (161). It was initially proposed that the increase



67

in spontaneous mutation rate at meiosis was due to addition or deletion mutations resulting from unequal crossing-over (1 62-164), in part because certain base substi tution mutants failed to show this response, and also because 5-amino acridine enhanced the effect (165). An alternative view is that enhanced spontaneous mutation during meiosis is due to a process normally assoeiated with recombination (85). If so, it should be possible to isolate meiotic mutants that affect both spontaneous mutation and spontaneous recombination. A candidate for this type of mutation, spo7 , is defective in spontane ous mitotic mutation and in sporulation (85). Another, rem 1, enhances spontaneous mitotic mutation, spontaneous mitotic heteroallelic recombination resulting in. prototroph production, and leads to reduced ascospore survival (1 66). Other mu tants, designated mut (1 67-169), alter the rate of spontaneous mutation during mitosis but have not yet been examined for their effects on meiosis. Approximately 1 50 conditional mutations that terminate cell division under restrictive conditions at particular stages in the mitotic cell cycle have been detected among 1 500 temperature-sensitive mutants isolated by Hartwell and collaborators (67). Complementation tests indicate the presence of 32 cdc complementation groups. Strains containing mutations in 20 of the cdc genes were examined by Simchen for their meiotic behavior under condi tions restrictive for mitotic division ( 1 70). Most of the mitotic nuclear division and DNA synthesis functions appeared to be required for meiosis as well as mitosis. Among mutants that exhibit ascus production, cdc24, cdc6, and cdc 1 5 show reduced segregation of a recessive drug resistance marker, can 1 , determined by the recovery of canavanine-resistant clones following sporulation, suggesting that spore development does not require normal reductional segregation. The cdc6 and cdc1 5 mutants also exhibit reduced levels of intragenic recombination leading to a de creased frequency of prototrophs per cells plated. It has not been reported whether ascospore survival is normal in these cases. It is important to note that cells must complete mitosis in a meiosis-inducing medium before they enter the meiotic cycle. Since conditional cell cycle defects frequently lead to lethality under restrictive conditions, evaluation of the progress of meiotic landmark events can be complicated by the presence of inviable cells resulting from the completion of the final mitosis under restrictive conditions. A careful assessment of viability and completion of mitosis during sporulation is required to interpret the meiotic defects exhibited by these strains. The data col lected thus far, nevertheless, suggest that a number of functions are likely to be shared between the two modes of cell division. CELL DIVISION CYCLE MUTANTS

SCHIZOSACCHAROMYCES In S. pombe, sporulating clones containing ascos pores stain a dark blue-black color in the presence of iodine vapors. Mutant clones defective in meiosis and spore production have been selected by Bresch et al by their failure to give an iodine-positive reaction during cultivation under conditions that permit sporulation (58). Spontaneous, UV-induced, and nitrous-aeid-induced mu tants were isolated in a homothallic strain to facilitate the recovery of recessive


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mutations in homozygous condition in diploid cells. Twenty-six complementation groups were identified by recessive mutants incapable of sporulation. Since three of these were tightly linked, it was concluded that the mutant collection contained 24 unique complementation groups. These strains exhibit defects in cell fusion required for zygote production ((us 1), meiosis I (meil - mei4), meiosis II (mes l), and postmeiotic spore formation (spo 1 - spo 1 8). Mutants of mei 1, 2, and 3 terminate at the mononucleate stage and do not become committed to meiosis; however, they do remain capable of resuming mitotic cell division ( 1 7 1). Premeiotic DNA synthesis is absent in mei l and mei3 (1 72). The mei4 mutant, on the other hand, undergoes premeiotic DNA synthesis, becomes committed to meiosis, and terminates at the mononucleate stage (58, 1 7 1 , 1 72). Several variants affecting aspects of mitotic growth have also been recovered which may be useful in the study of the genetic control of meiosis (173, 174). A dominant mutation designated REC l , which reduces UV-induced intragenic hete roallelic recombination (prototrophs) at the ade6 locus during mitosis, has been recovered by Goldman & Gutz (1 74). This mutation permits sporulation and does not affect heteroallelic exchange at ade6 during meiosis. The genetic control of radiation sensitivity in S. pombe has been extensively studied. Mutations in over 20 rad loci are known (175-1 77). These have been examined for thymine dimer excision (178, 1 79), spontaneous and UV-induced mutation ( 1 80-- 1 83), caffeine sensitivity (1 82, 1 84--1 86), and so on. UV-induced genetic recombination is reduced in rad l , thought to be defective in recombinational repair (1 87); it has been suggested that more than one pathway exists for both excision and recombinational repair ( 1 79, 1 88). Neurospora

In Neurospora, the following criteria have been employed to detect mutations that affect the sexual cycle: (a) reduction in fertility, (b) altered intragenic and intergenic exchange in meiosis, (c) effects on mutation during meiosis, (d) alteration of ascus or ascospore morphology, ( e ) radiation-sensitivity, and (j) nuclease-deficiency. Variants affecting meiotic exchange and mutation, and some of those exhibiting reduced fertility, were discovered among existing laboratory strains, among strains collected from nature, and in vegetative conidia following mutagenesis ( 1 8, 1 89, 190). Fertility mutants have been recovered by selection for male or female sterile strains (55, 56, 19 1), and for strains that yield enhanced levels of immature unpigmented ascospores (45, 46). Most male and/or female sterile strains recovered thus far have not been examined specifically for meiotic defects (55, 56, 1 9 1-198). Among the mutants recognized by the production of immature unpigmented ascospores, four have been shown to affect meiosis itself. One, mei-l, identical with a previously described genetic determinant designated the Abbot factor (199), has been studied extensively by Smith ( 46). mei-] is recessive, affects all linkage groups, drastically reduces exchange, causes extensive nondisjunction, and results in 90%

FERTILITY MUTANTS



69

aborted ascospores. Crossing-over is reduced uniformly among suriving ascospores on one linkage group tested. Cytological studies indicate that synapsis consists of only occasional paired regions, normal synaptonemal complex is absent, and chromosome disjunction is abnormal (200). The function specified by mei-I+ is thus required for exchange and thereby the maintenance of bivalents. A dominant meiotic mutant, Mei-2, also drastically reduces recombination and enhances nondisjunction (46). There is only partial pairing at zygotene with most chromosomes univalent at metaphase I (200). A recessive on linkage group I, mei-3, was recognized because it causes the elimination of terminally duplicated chromosome segments both somatically and after fertilization (20 1). In addition, the meiotic mutant blocks an early stage of ascus development resulting in barren perithecia. The mei-3 mutant appears to be a mutator; among the mutants recovered from mei-3 was mei-4, an unlinked meiotic mutant whose expression varies drastically among different isolates. Cyto logically (200), the first meiotic division in mei-4 is normal, but the second and third divisions resemble those of mei-I. REGION-SPECIFIC EFFECTS ON EXCHANGE Heterogeneity in crossover fre quencies in N. erassa and related species (199, 202-2 1 5) suggests that the various laboratory strains of Neurospora differ with respect to genetic factors governing exchange. During the last decade, a significant body of data has been gathered, primarily by D. G. Catcheside and his collaborators (7, 1 8, 2 1 6, 2 1 7), providing unambiguous evidence that a major part of this heterogeneity is caused by gene functions that regulate exchange in specific regions of the genome. Two classes of regulatory elements governing exchange in restricted regions have been defined: ree+, genetic elements that repress exchange and are not generally linked to the affected intervals, and eog+, genetic regions that promote exchange and are linked to their site of action. A third element, con, has been postulated as the recognition site for the action of the ree+ gene product (21 7, 2 1 8). These elements were recognized by the discovery of ree- alleles that enhance exchange among existing laboratory strains (2 19-226). In ree- strains, eog+ and eog- can be distin guished because cog+ promotes a higher level of recombination than does cog- (2 1 8, 227). Thus far, three rec genes have been extensively characterized, rec-I (2 19, 220, 226, 228, 229), rec-2 (221 , 222, 224, 230-232), and ree-3 (223, 225, 231-236). One cog element has been described that modifies the expression of ree-2 (2 1 8, 227), and indirect evidence has been provided for different eon-3 sites that modify the behavior of ree-3 in different genetic intervals (2 17). Mutations in ree-I cause a 10- to 25-fold increase in heteroallelic recombination (prototroph production) at his-I (linkage group V) and nit-2 (linkage group I). The pattern of flanking markers recovered among prototrophs indicates enhanced con version of the proximal allele in the presence of ree-I. There is no effect of ree-I on 19 other regions tested. Mutations in ree-2 enhance prototroph production at his-3 (linkage group I), as well as intergenic exchange in the intervals between his-3 and ad-3, arg-3 and sn (linkage group I), and pyr and his-5 (linkage group IV). The


70


enhancement is approximately fivefold in homozygous eog- and an additional three to sixfold when cog+ is present. When ree-2+ is present, proximal alleles are con verted more frequently. In a ree-2, eog- background, there is no apparent polarity. There is no effect of ree-2 on 13 other regions tested. Mutations in ree-3 enhance prototroph production at his-2 (linkage group I), and am-I (linkage group V), 1 0 t o 25-fold. Intergenic exchange i n the intervals between his-2 and sn, and arg-I and aer-3 (linkage group I) is also increased. Studies of conversion at the am-I locus indicate enhanced conversion of proximal alleles, as in ree-I. No effect on 12 other tested regions has been observed. The eog+ factor, located on linkage group I, increases prototroph production at the linked proximal locus his-3 approximately sixfold, and intergenic exchange between his-3 and ad-3 about threefold. Its major effect is observed in the absence of ree-2+ repression of exchange, e.g. in a ree-2 background. In eog+ X cog- crosses, the his-3 allele linked to cog+ is preferentially converted indicating that eog+ is a cis-acting regulatory element. This property has been confirmed in a study by Catcheside & Angel (227), who employed a translocation with one break in the his-3 region. In the interchange strain, the distal portion of chromosome I containing cog+ and part of the his-3 gene is translocated to chromosome VII. It was shown that rec-2 has no effect on conversion of proximal alleles unless cog+ is also present in the nontranslocation parent (Le. physically linked to the proximal his-3 muta tion). This can be interpreted as evidence that the initial events leading to exchange originate distally to cog and promote conversion of cis alleles under derepressed conditions. The evidence for can elements is based on the presence of ree-3 alleles that can be distinguished by differences in the degree to which intragenic exchange is re pressed at two unlinked loci, his-2 and am-I, suggesting a difference in recognition (can) sites associated with am-I and his-2 (2 1 7). The ree alleles present in various wild-type strains have recently been determined (2 1 7). Each of the strains tested carries one of two alleles at rec-I and rec-2, and one of three alleles at ree-3. Some strains exhibit unexpected ree phenotypes based on the behavior of their ancestral strains, casting doubt on the origin of these strains. Before. this can be completely evaluated, however, it is necessary to determine the mei alleles present in these strains because mei genes can cause a general depression in exchange; they may, therefore, modify the behavior of ree genes, which enhance exchange in specific regions of the genome, leading to spurious ree + phenotypes. It is particularly important to examine, for example, the ree assignments of the Abbott 4A and St. Lawrence 79a strains since the former is known to carry mei-I (46) and the latter yields approximately 50% spores that fail to pigment and ripen ( 2 17 ).

The regulation of genetic exchange in Neurospora has been likened to the operon model of regulation in procaryotes (2 1 8). In the analogy, ree genes are compared to repressor genes, cog elements to promotors, and can regions to operators. Two alternatives have been considered. In one, the ree+ gene product complexes with can sites to repress the activity of closely linked genetic regions that specify recombi nase enzymes required for exchange. These enzymes, in turn, interact with cis-



71

acting eog+ sites (which may be unlinked) that act to promote exchange in nearby regions. This model requires a limited number of ree+ genes but recombinase enzymes with some specificity for the regions they affect. Alternatively, ree+ gene products may interact with con sites to repress exchange in intervals near con. The recombinase enzymes interact with cog+ to initiate exchange which can proceed to completion only under derepressed conditions. This notion requires many ree genes but only one set of recombinase enzymes. At the present time there is not enough information to distinguish between these possibilities. Other instances of variation in recombination frequencies owing to mutations similar to, if not identical with, those described above have been reported. Griffiths & Threlkeld (237) and Griffiths (238) have described the complementation of factors that reduce exchange on linkage group VI between cys-2 and pan-2 in a hetero karyon when the heterokaryon is used as a protoperithecial or conidial parent. These results may be interpreted as complementation of recessive ree mutations present in each strain that enhance exchange. Dominant factors, similar to cog+, that elevate exchange have also been found (239, 240). They were first detected by differences in crossover frequencies on linkage group I between N. sitophila and N. crassa (202). When the proximal portion of linkage group I of N. sitophila is transferred into N. crassa, exchange is enhanced owing to the transfer of two closely linked regions located between his-2 and ad-3. Because cog+ maps in this region, it may be identical with one of these factors. Finally, a mutation affecting meiotic exchange has been discovered in studies of the effect of ediene, an antibiotic produced by Bacillus brevis, on Neurospora (24 1). The antibiotic inhibits DNA, RNA, and protein synthesis and appears to increase the frequency of intergenic exchange. A mutation to edeine resistance, ed'-2, also causes an apparent increase in exchange by one third in the absence of the drug. The basis of this effect is not understood. MUTATION AND MEIOSIS Bausum & Wagner (242) and Bausum (243) have reported enhanced homoallelic reversion of an isoleucine-valine mutation ( TIV 318) following meiosis. The enhanced meiotic reversion of this mutation is governed by a Mendelian factor located on linkage group V. This observation is of interest in view of reports in yeast, Schizophyllum, and higher plants of enhanced mutation during meiosis. Further study of these factors may illuminate a possible relationship between gene functions governing spontaneous mutation and recombination.

A number of mutations have ' been described, primarily by Srb and his collaborators, in N. crassa and N. tetra sperma that alter vegetative mycelial morphology, and ascus and ascospore mor phology, resulting in abnormal numbers and nonlinear arrangements of ascospores (244-254). While these abnormalities appear to result from alterations associated with cell shape and not from meiotic defects, they can have profound consequences on the fertility and the genetic content of meiotic products and are therefore noted here. ASCUS AND SPORE MORPHOLOGY MUTANTS

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RADIATION-SENSITIVE MUTANTS Mutations in seven genes have been detected

in N. crassa that confer ultraviolet sensitivity (190, 256-261 ); several of these, uvs-l, 3. 4. and 5. also result in various levels of ascus and ascospore abortion. No effect on meiotic intragenic or intergenic exchange among surviving spores has been detected. The mitotic behavior of uvs-3, 4. and 5 has been examined in haploid strains bearing duplications for the mating-type locus (258, 259). The duplication strains grow slowly vegetatively and are sterile in meiosis. They are released from slow growth by losing the duplication owing to either somatic crossing-over or deletion. uvs-3 is released earlier than uvs+, uvs-4, or uvs-5. It is thought that the release is due to enhanced spontaneous exchange in uvs-3, since the isolates recovered still retain other properties characteristic of duplications (Le. a substantial fraction of barren perithecia). In addition, uvs-3 is X-ray-sensitive and exhibits a higher muta tion rate than wild type. The behavior of uvs-3 is similar to reel in Ustilago, and in some respects to rem 1 in Saccharomyces, in exhibiting enhanced levels of spontaneous exchange and muta tion in mitosis, and reduced fertility in meiosis. As in other systems, the study of radiation-sensitive mutants in Neurospora indicates that some of the functions involved in the repair of radiation-damaged DNA play an as yet undefined role in spontaneous mutation and recombination in mitosis and in meiotic development. Two nuclease mutants have been isolated in Neurospora, nuc-] and nuc-2 (262, 263). The nuc-2 mutation causes radiation sensitivity as well, but thus far there is no evidence that either of these affects meiosis, as in Ustilago.

NUCLEASE MUTANTS

Podospora

In Podospora anserina, the criteria of reduced fertility and abnormal spore mor phology have been used to select for meiotic mutants by Simonet & Zickler (264). Meiosis in Podospora results in the production of linear four-spored asci. Complete chiasma interference occurs, each chromosome arm having a maximum of one exchange. The mating-type locus exhibits nearly 1 00% second division segregation. As a consequence of the spindle geometry during meiosis and the postmeiotic mitosis, and complete chiasma interference, each ascospore is binucleate and hetero karyotic for mating-type. The vegetative mycelia derived from single spores are capable of forming self-compatible prototoperithecia and conidia, and are therefore pseudohomothallic. Mutants affecting meiosis in Podospora were obtained by mutagenesis of microco nidia which were then used to fertilize protoperithecia. Spores were picked from independent perithecia, allowed to "self," and the effects on the subsequent meiosis were examined. This procedure allows the detection of induced mutations in genes near the centromere that affect ascospore development because such mutations will be present in homokaryotic condition in the binucleate spores from the initial cross. Mutations in eleven genes, resulting in either the absence of asci, few or no spores within asci, or abnormal spore formation were recovered. Cytological characteri zations of mutant strains indicate disturbances in fertilization and nuclear fusion


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(car-I), prophase I of meiosis (mei-l, 2, and 3), components of the spindle ap paratus (mei-4 and 5; kin-I, 2, and 3), and the third (mitotic) division (spo-l and 2). Both mei-l and mei-2 have reduced chromosome pairing. A leaky mei-2 allele, mei-2-2, that partially complements other mei-2 alleles has allowed analysis of meiotic exchange in strains bearing this mutation (265). In mei-2-2/mei-2-2, mei-2-2/mei-2-1, and mei-2-2/mei-2-3 diploids, intergenic exchange increases near

the centromere and decreases distally on three linkage groups tested. The mating type locus, as well as other markers that generally segregate at the second meiotic division owing to complete chiasma interference, exhibits second division segrega tion values closer to, but still above, the theoretical limit of 66% expected on the basis of no interference. The mutation frequency in mei-2/mei-2 during meiosis was reported to be tenfold higher than wild type. The phenotype expressed by mei-2bearing strains of Podospora is similar to the phenotypes of many recombination defective mutants in Drosophila, suggesting that the wild-type allele governs a precondition for exchange. Strains carrying mei-3 develop enlarged croziers and nuclei. Chromosomes retain their individualized appearance even in interphase of meiosis I, and appear to coalesce early in diplotene when the cells arrest. Pleiotrophic effects are also ob served in mutants that exhibit disturbances in the spindle apparatus and associated structures. In mei-4, for example, meiosis I spindle plaques, meiosis II plaques, and the third mitotic division plaques are all abnormal in appearance and position. Several other mutations have been described that affect perithecial development and spore viability. The precise defects are less well known; they include, among others, nutritional requirements, suppression, mycelial morphology and pigmenta tion abnormalities, and others (266). Schizophyllum

Mutations that perturb meiosis in S. commune have been largely restricted to mutants discovered in natural and laboratory populations that modify exchange in specific regions of the genome governing genetic incompatibility (267-275). Schizophyllum possesses a bifactorial incompatibility system consisting of A and B incompatibility factors. The genetic loci controlling these factors are unlinked and reside on the A and B linkage groups respectively. Each factor is specified by two linked loci designated A a and A/3, and Ba and B/3; the A factor loci are approxi mately 25 map units apart and the B factor loci nearly 10 map units apart. Many alleles have been recovered at each locus. Sexual reproduction occurs between strains with different A and B factors. Variation in recombination frequency has been observed between A a and A /3, and Ba and B{3 (1 to 23% for the A factors and 0. 1 to 8% for the B factors). This variation, as well as variation in other intervals, has been demonstrated primarily by Simchen, Stamberg and their collaborators to be under genic control. Recombi nation in A a-A {3, Ba-B{3, and a distal interval on linkage group B, nic-2-uro-l, are each controlled by different genetic factors (269-271). Two such factors have been given gene symbols: rec-l controls exchange between A a and A {3 (273) and


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is located about 20 units from A/3, while B ree-l controls exchange between Ba and B/3 and is located about 9 map units distal to B/3 (274). There are probably at least two genes controlling A factor recombination, at least two genes controlling B factor exchange, and perhaps three genes influencing ex change between nie-2 and ura-l, but these have not yet been well defined or given gene symbols except for the two previously mentioned. It is clear that the effects of these genes are highly localized as they do not affect exchange in adjacent regions. Recently, evidence for dominant alleles that enhance exchange between Ba and B/3 that are located between these markers has been reported. These may be analogous to eog+ in Neurospora. Stamberg & Koltin (275) have suggested that several sites with additive effects are present between B a and B/3 controlling exchange in this region; too few data are yet available to evaluate this hypothesis. Aspergillus

Selection of mutants with reduced fertility, altered radiation sensitivity, and mitotic recombination has led to the recovery of several mutations affecting meiotic develop ment in Aspergillus nidulans. Strains exhibiting reduced fertility (sgp 1-sgp5) were detected on the basis of slow growth on glUcose-containing medium (49). As they cannot utilize TCA cycle intermediates, these variants are probably analogous to petite strains of Saccharomyces which are unable to undergo meiotic development owing to respiratory deficiency. Of greater interest in the present context are the radiation-sensitive strains and other variants selected for their effects on mitotic recombination. Recessive muta tions in five genes governing UV sensitivity (uvsl or A, uvsB, C, D, and E) have been isolated (276-279); these affect mitotic recombination in diploid cells and in addition cause partial or complete sterility in meiosis. The uvsB and uvsD loci are thought to govern excision repair and uvsC and uvs E, recombination repair (278-284). Mutations of uvsB and uvsD enhance spontane ous mitotic intragenic recombination measured by prototroph production (280, 282-284); in uvsB there is also an increase in mitotic intergenic exchange (279). Mutations at both loci result in the recovery of many diploid progeny following sexual reproduction. In uvsD53, the diploids recovered after meiosis exhibit a high frequency of marker segregation suggesting that. they may have initiated events required for meiotic exchange and then returned to mitosis. When ascospores are formed, germination is often poor, spore morphology is abnormal, and genetic recombination is normal or reduced among survivors. Mutations of uvsC and uvsE decrease spontaneous mitotic intragenic exchange measured by prototrophs (280, 282-284). The uvsE mutant is X-ray sensitive and increases spontaneous mutation in mitosis (282). In both mutants, partial or com plete sterility is observed in meiosis. Recently, Parag & Parag (285) have obtained mutations affecting mitotic ex change by mutagenesis of a haploid heteroallelic and heterozygous for diagnostic markers contained in a duplication for a portion of the right arm of chromosome I. Six ree strains were recovered which exhibited tenfold or greater reductions in the frequency of spontaneous mitotic recombination. One UV -sensitive strain, pop,



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was iso.lated which exhibited a loo-fo.ld increase in proto.tro.ph productio.n and an increase in the frequency o.f secto.rs fo.r heterozygo.us markers. The duplicatio.n was repo.rted to. be highly unstable in the pop strain. The p op mutatio.n is allelic to. uvs B 1 3. In additio.n to. these mutants, TJpshall & Kafer (286) repo.rt a variant strain that appears to. be free o.f chro.mo.so.mal aberratio.ns but exhibits a tenfo.ld increase in no.ndisjunctio.n fo.r all chromo.so.mes. The studies o.f uvs mutants in Aspergillus again indicate an asso.ciatio.n between radiatio.n sensitivity and spo.ntaneo.us alteratio.ns in mito.tic reco.mbinatio.n and re duced fertility in meio.sis. The increase in spo.ntaneo.us mito.tic exchange in uvsB and D may be due to. the accumulatio.n o.f lesio.ns that stimulate reco.mbinatio.n, while the decrease in exchange in uvsC and E reflects a defect in the reco.mbinatio.n pathway in bo.th mito.sis and meio.sis.

Usti/ago The recovery of mutants in Ustilago maydis by Holliday and his collabo.rators has invo.lved selectio.n fo.r strains exhibiting UV sensitivity (287, 288), nuclease defi ciency (289, 290), and DNA synthesis defects during mito.tic divisio.n (8, 1 6, 29 1293). Three recessive mutatio.ns conferring UV sensitivity, iso.lated by mutagenic treat ment o.f a haplo.id strain (287, 294), were examined fo.r their effects o.n mito.tic intragenic reco.mbinatio.n (proto.tro.ph pro.ductio.n), mito.tic intergenic exchange, and meio.tic develo.pment. The pro.perties o.f two. o.f these mutatio.ns are in so.me respects similar to. tho.se o.f the uvs strains o.f o.ther fungi in that bo.th enhancement and depressio.n o.f spo.ntaneo.us reco.mbinatio.n in mito.sis are co.rrelated with reduced fertility in meio.sis. The uvs l mutatio.n, renamed ree l , enhances sPo.ntaneo.us mito.tic intragenic reco.mbinatio.n at least tenfo.ld at three lo.ci studied. Mito.tic intergenic reco.mbina tio.n is also. elevated in ree 1 strains, as o.bserved by an increase in flanking marker recombination amo.ng selected prototrophs and by mito.tic segregation. UV only slightly stimulates intragenic reco.mbinatio.n (pro.to.tro.ph pro.ductio.n) abo.ve spo.nta neo.us levels but do.es enhance reciprocal exchange and mutatio.n. In additio.n reel! ree 1 diplo.ids exhibit a high degree o.f mo.rpho.lo.gical and co.lo.r variatio.n during vegetative growth, altho.ugh haplo.id ree l strains appear no.rmal. In either 2n o.r 1 n c1o.nes, 10-20% of the cells are inviable, suggesting chromo.so.me breakage and lo.ss. In meio.sis, the ree 1 mutatio.n leads to. partial sterility (10% spo.re viability) and causes abno.rmal spo.re mo.rpho.lo.gy. There is no. effect o.n reco.mbinatio.n amo.ng viable spo.res (8, 288, 294). The uvs2 mutation, renamed ree2, causes a reductio.n of UV-induced mito.tic intragenic and intergenic reco.mbinatio.n. In co.njunctio.n with ree l , ree2 eliminates spo.ntaneo.us intragenic reco.mbinatio.n. Cell inviability and co.lo.ny variatio.n are mo.re pro.no.unced than in ree 1 alo.ne indicating synergism between the two. muta tio.ns. ree2 strains are X-ray sensitive and sterile in meio.sis. The third uvs mutatio.n, uvs3, is ·defective in rapid excisio.n o.f thymine dimers, although slo.W excisio.n do.es o.ccur (293). This strain exhibits no.rmal sPo.ntaneo.us mito.tic reco.mbinatio.n, has little effect o.n UV-induced exchange, and no. effect on meio.sis.


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Nuclease-defective mutants have also been sought in Ustilago in an effort to recover variants that disturb exchange. Two mutants, one deficient in extracellular (nuc l) and one in intracellular (nuc2) nuclease activity, have been obtained (289). The double mutant, nuc 1 nuc2, is deficient in both nuclease activities, in spontane ous and UV-induced mitotic intragenic exchange, and meiotic intragenic exchange. Spontaneous intergenic exchange is normal in mitosis and meiosis, although UV irradiation induces multiple exchanges. Recently, Ahmad et al (295) have shown that the nuclease that is deficient in these mutants preferentially inactivates trans fecting DNA containing mismatched bases and is thereby implicated in repair of heteroduplexes. In addition to these variants, Unrau & Holliday (29 1 , 292) have examined mitotic exchange in a temperature-sensitive mutant defective in DNA synthesis. Incubation of this strain at temperatures that prevent DNA replication increases both intra genic and intergenic mitotic exchange. The authors suggest that the inhibition of DNA replication stimulates the recombination and repair processes, or perhaps puts the cells in a meiotic-like state (see also 296). Ascobolus

In Ascobolus immersus, four modifiers that control the frequency of meiotic intra genic recombination in restricted regions of the genome have been found segregating in wild-type laboratory strains (297, 298). The modifiers, designated cvI, 2, 4, and 6, control the level of gene conversion of nearby alleles at the bI, 2, 4, and 6 spore color loci respectively. The cv factors are similar to those described by Catcheside ( 1 8) and by Simchen & Stamberg (299) which specifically modify the pattern of exchange in localized regions of the genome. They differ from these elements, however, in two respects: (a) genetic alterations at cv sites depress exchange only when present in heterozy gous condition; crosses that are homozygous for a given cv factor exhibit enhanced exchange at diagnostic b sites; and (b) the modifiers in heterozygous state depress exchange several hundredfold leading to almost total suppression of gene conver sion. In contrast, the rec+ genes in Neurospora depress exchange in heterozygous or homozygous condition and are not always linked to the regions they control, while the cog+ factor in Neurospora, which is closely linked to its site of action, enhances exchange in heterozygous or homozygous condition. In both cases the magnitude of the effect is maximally about thirtyfold. It has been suggested that the various wild-type strains of Ascobolus differ from one another by the presence of small structural alterations spanning the cv regions which are thought to include sites where recombination events are initiated. Accord ing to this view, structural heterozygosity in these regions would depress gene conversion by preventing pairing or hybrid DNA formation (298). Other Lower Eucaryotes

Esser & Straub (61) obtained recessive mutations at fifteen loci controlling sexual development of Sordaria macrospora by X-ray mutagenesis. Mutations at two loci, min and pa, prevent meiosis following karyogamy, while the remainder exert their effects at other stages.



77

Sterile mutants of Sordaria fimicola (300, 301) and Cochliobolus heterostrophus (5 1-53), and nonmating mutants of the green alga, Chlamydomonas reinhardi (302-304), have also been reported. A fertile, radiation-sensitive strain of C rein hardi has been described that exhibits enhanced spontaneous and radiation-induced intragenic recombination during meiosis (305). Several mutations affecting sexual reproduction of the octad ascomycete Glome rella cingulata have been described (54, 306, 307). One recessive mutation dw l (dwarf), recovered after growth of the fungus on medium containing radiocarbon, partially blocks meiosis and results in the formation of viable ascospores of reduced size and a high frequency of asci containing reduced numbers of ascospores (306). In dw l homozygotes, the fusion nucleus is localized in the tip of the ascus rather than at the center of the cell as in wild type. Nuclear and chromosomal disintegra tion is observed at prometaphase of the first meiotic division. Disintegration of chromosomes during the second meiotic division and the postmeiotic mitoses is less frequently observed. Nevertheless, the disintegration seen in the postmeiotic mitoses indicates that the mutant affects both meiotic and mitotic chromosome behavior. DROSOPHILA Meiotic mutants in Drosophila have been recovered as mutations that cause genet ically detectable anomalies in meiotic chromosome behavior. Because gametic aneu ploidy has no influence on gamete function in Drosophila (308, 309), meiotic mutants that result in the formation of gametes containing abnormal numbers of chromosomes (owing to nondisjunction, loss, or chromosome breakage), as well as mutants that alter quantitative parameters of meiotic chromosome behavior (e.g. recombination frequencies, interference) can be detected in appropriate crosses. A fly bearing such a mutant, however, must be viable and fertile in order for the mutant to be recovered. Consequently, mutations in certain classes of genes will not be detected: those that are essential for both meiotic and mitotic cell division, those whose product is required for the'completion of meiosis or gametogenesis, and those controlling meiotic events unrelated to chromosome behavior. Despite these limitations, screens of mutagenized chromosomes (32, 3 1 0-3 1 5) and of chromosomes collected from natural populations (30) have resulted in the isolation of 32 meiotic mutants representing 29 loci In addition, about 50 mutants ' (representing approximately 10 loci) hypersensitive to killing by the radiomimetic compound, methyl methanesulfonate (MMS) have been isolated; some of these MMS-sensitive mutants are meiotic mutants by the criterion of abnormal meiotic chromosome segregation (3 1 8-320). One mutant was recovered in a recombination selection experiment (3 1 6). Finally, six meiotic mutants have been fortuitously discovered over the years (1, 321-325). In addition, a few meiotic mutants have been reported in other Drosophila species (326-329). Instances of polygenic effects on meiotic recombination (330-343), mi totic recombination (344), radiation sensitivity (345-3 5 1 ), and single gene effects too weak to be conveniently genetically analyzed (30, 32, 352) are not considered further here. .

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Analytic Methods To date, meiotic mutants in Drosophila have been analyzed primarily genetically. By appropriate crosses, it can be determined at which of the genetically detectable landmarks of meiosis (recombination, disjunction at meiosis I, distributive disjunc tion, disjunction at meiosis II) chromosome behavior is abnormal and the nature of the abnormality can be characterized (e.g. increased or decreased recombination, nondisjunction of all chromosomes or only certain chromosomes, nondisjunction independent of exchange or of only nonexchange chromosomes). Such an analysis, together with the assumption that the sequence in which meiotic landmarks occur is the same in mutants as in wild type, (a) makes it possible to infer the first stage of meiosis at which the product of the wild type allele of a locus is required for normal chromosome behavior, and (b) allows an examination of whether the regular occurrence of subsequent stages of meiosis is dependent on the normal occurrence of the initially affected step. Sex DifJerences in Meiosis

The process of meiosis has long been known to differ in the two sexes in D. melanogaster (353). Crossing-over, distributive pairing (354), interchromosomal effects of rearrangements (355), and the formation of synaptonemal complex (41) occur only in females. The sexual dimorphism of the meiotic events in wild type is also manifested by meiotic mutants; with only four exceptions, all mutants affect meiotic chromosome behavior in only one sex. Because most extant mutants are sex specific, we consider the sexes separately in this discussion; females are examined first. Of the 24 loci identified by meiotic mutants in females, in all but two cases 'the mutants disrupt the normal behavior of all chromosome pairs. Thus, these mutants must represent defects in the general cellular control of recombination and segrega tion. Mutants defective in region-specific controls of recombination, such as those reported in the fungi, would almost certainly have been undetected by most screen ing procedures employed to date in Drosophila, although possible cases of this type have been reported (3 16, 356, 357). Female meiotic mutants, with only one exception, fall into two classes: (a) recom bination-defective mutants-mutants at loci controlling pachytene or prepachytene processes required for a normal frequency and/or distribution of exchanges along the chromosome, and (b) disjunction-defective mutants-mutants at loci that func tion to effect regular segregation. There is one mutant (ord) that is both recombina tion and disjunction defective (3 1 2). We consider recombination-defective mutants first, followed by those that are either disjunction-defective or both recombination defective and disjunction-defective.

Recombination-Defective Meiotic Mutants There are 2 1 loci known in D. melanogaster at which mutants affect recombination in females; because the major autosomes have not been extensively screened, many more remain to be discovered. The large number of recombination-defective loci



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raises the question of whether all of these are directly involved in mediating meiotic recombination. Recombination frequencies are sensitive to alterations in both the external environment [e.g. temperature (358-360)] and internal physiology [e.g. maternal age (32 1, 361, 362)] and thus it is likely that physiological changes not directly related to the process of exchange could elicit changes in the frequency or distribution of exchanges. In fact, at least two of the recombination-defective mu tants may well act on meiosis indirectly (see discussions of abo and mei-l, below). There are three lines of evidence that suggest that most of the known recombina tion-defective loci are directly involved in mediating meiotic recombination. These are: (a) several mutant alleles abolish or greatly reduce meiotic crossing-over, strongly suggesting that the wild-type alleles at these loci are directly involved in recombination; (b) several mutants have been directly demonstrated to be defective in the repair of radiation-induced DNA damage, and the involvement of these, as well as additional loci, in some aspect of DNA metabolism is strongly suggested by observations that flies bearing mutant alleles are hypersensitive to killing by radia tion and radiomimetic chemicals and exhibit elevated frequencies of spontaneous somatic crossing-over and chromosome breakage; and (c) abnormalities have been observed by electron microscopy at pachytene in structures thought to be associated with the process of exchange. Mutants at eight loci [mei-9, mei-41, mei-S282, mei-352, mei-218, mei- W68, mei-B, c(3)G] fit one or more of these criteria. Moreover, the meiotic effects of mutants at these loci are sufficiently similar to one another, and to those of mutants at three other loci [mei-S51, mei-251. abo], to warrant considering these eleven together. Investigation of these mutants has been aimed at four major questions: (a) How are the frequency and distribution of crossing-over along the chromosome deter mined? (b) What are the disjunctional consequences of reduced exchange? (c) Are DNA repair/replication and meiotic recombination under common genetic control? And (d) how are the cytologically detectable events of zygotene and pachytene related to exchange? These questions are considered separately. Recombi nation-defective mutants at these loci are recessive; when homozygous in females they result in decreased levels of recombination and/or an altered distribution of recombination. A useful subdivision of these mutants can be made on the basis of how they affect the distribution of exchanges along a chromosome arm. In wild type, there are at least two ways in which the distribution of exchanges is nonrandom. First, exchanges are nonrandomly distributed with respect to one another (chiasma interference). Second, the frequency of exchange is not constant per unit of physical length. There is little or no crossing-over in the basal hetero chromatin, whereas in the euchromatin the frequency of crossing-over is approxi mately constant for all regions except those adjacent to the basal heterochromatin and the telomere where crossing-over per unit of physical length is decreased (363). An elegant analysis by Charles (364; see also 365) of the distributions of single, double, and triple exchanges with respect to physical length along the X chromo-

EXCHANGE IN RECOMBINATION-DEFECTIVE MEIOTIC MUTANTS


80


some in wild type provided insights into the nonrandom distribution of exchanges that have proved valuable in understanding the alterations in exchange caused by recombination-defective mutants. He found that single exchanges tend to be local ized in the medial portion of the chromosome arm, whereas the exchanges in double-exchange tetrads tend to be localized distally and proximally. Moreover, his analysis suggested that the distance between the exchanges in double-exchange tetrads tends to be constant. This implies that in wild type the distribution of crossovers along the chromosome arm can be thought of as reflecting the relative proportion of single and multiple exchange tetrads, since exchanges of different rank occur around different modal positions. Extending this analytical approach to meiotic mutants, Carpenter & Sandler (366) ,noted that if the process of exchange consists of two sets of events, one that determines the distribution and frequency of sites (nodes) at which exchanges may occur, and another that determines the frequency of exchange at the nodes (ex change functions), then at least three types of mutants might be distinguishable: (a) a defect in an exchange function should yield a wild-type pattern of crossovers; (b) a mutant that reduces the probability of node formation without affecting the modal position of the nodes that do form should yield a pattern of crossovers approaching that generated by single-exchange tetrads in wild type; and (c) a lesion that introduces a more random distribution of nodes would give a pattern of crossov ers more representative of physical distances between markers than found in wild type. It should be noted that this approach assumes that the probability of exchange per node is constant and therefore that interference is a property of node establish ment and not of exchange functions. A closely related, but less generally useful, procedure using the coefficient of coincidence to subdivide recombination-defective mutants into these two categories is based on an early formulation by Bridges (361 ) and has been used in several analyses of meiotic mutants (30-32, 3 1 6, 367, 368). In addition, the interaction of meiotic mutants and the interchromosomal effect has been examined for some mutants (3�, 3 1 , 3 1 6, 366-368); an interpretable separation of mutants by this criterion has not yet been achieved. Recombination-defective mutants can be divided into three groups based on their patterns of crossovers. The first group contains the two alleles of mei-9, which decrease exchange drastically yet show a pattern of crossovers identical with that found in wild type, implying that mei-9 is defective in an exchange function (32, 366). Although it has been proposed that mutants at two other loci, mu (369) and mei-S51 (370), also cause uniform decreases in crossing-over, the data are suffi ciently ambiguous to warrant withholding judgment at this time. Recombination-defective mutants of the second group (mei-41, mei-218, mei-251, mei-S282, mei-B, abo, mei-68L1 ) decrease exchange and cause alterations in the distribution of exchanges along the chromosome, implying that they are involved in the determination of the frequency and distribution of nodes. Strikingly, in all of these mutants, recombination is most severely decreased in regions where cross ing-over per unit of physical length is relatively high in wild type and decreased less severely in those regions where crossing-over per unit of physical length is relatively low in wild type (3 1, 32, 3 1 5, 3 1 6, 32 1 , 366, 367). A comparison of the distributions



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of single and double exchanges i n these mutants with the highly nonrandom distri bution found in wild type suggests that the greater congruence of the genetic and physical maps in these mutants results from a relaxation of the constraints that lead to modal positions for single and double exchanges in wild type. Because these mutants alter the probability of node formation as well as the distribution of nodes along the chromosome, it appears that both the frequency and distribution of sites at which exchange occurs in wild-type are, at least in part, determined by the same processes. The third category of recombination-defective meiotic mutant, analogous to those analyzed by Jones (37 1) in rye, contains one mutant (mei-352) that governs the distribution, but not the frequency, of nodes. This mutant does not alter the number of exchanges in the regions examined (0.94 exchanges per arm in mei-352 versus 0.95 exchanges per arm in wild type), although both the tetrad distribution and the distribution of exchanges along the chromosome are altered (32). Both of these alterations are in the direction of a more random distribution of exchanges implying a defect in the establishment of the spatial restrictions in node formation. In three meiotic mutants-c(3)Gi7, c(3)(J68, and mei- W68-the nearly complete absence of meiotic crossing-over precludes a direct examination of the distribution of exchanges or coincidence (1-3, 324, 372). In females homozygous for C(3)Gi7, the only mutant whose effect on intragenic crossing-over has been reported, intragenic, as well as intergenic, crossing-over is abolished (373). However, information on the role of these loci is available from the heterozygous effects of the mutant alleles. Those strong recombination-defective mutants that have been examined exhibit a slight dominant effect on recombination (3 1, 366, 374, 375). Carpenter & Sandler (366) noted that for the mutants they studied (mei-9·, mei-9b, and mei-218), the dominant effects on the distribution of exchange and coincidence paralleled their recessive effects. They therefore suggested that an exam ination of the heterozygous effects of mutants that abolish exchange when homozy gous might provide an alternative method of determining the recombination role of these loci. When heterozygous, both C(3)(Jl7 and c(3)(j68 produce a nonuniform increase in recombination along the chromosome and alter coincidence (372, 374), suggesting that c(3)G+ is involved in determining both the frequency and distribu tion of exchanges. Why c(3)G alleles (or mei-218), which severely reduce recombi nation when homozygous, should cause increases in recombination when heterozygous is not clear. One possibility is that when heterozygous, they cause slight perturbations in pairing that are recombinogenic, but when homozygous, the perturbations produced are sufficiently severe to preclude recombination (374). The deficiency sbdJ05, which includes the c(3)G locus, also exhibits dominant effects (as sbdJ05/c(3)G+): recombination is reduced to about 70% of wild type, and the reduction is nonuniform along the arm (3 1 , 374). The difference in the dominant effects of the mutants and the deficiency is explicable if either (a) both mutant alleles are hypomorphs (contra 376), or (b) the deficiency is deficient for at least one additional recombination-defective locus (323, 377). Although the heterozygous effects of mei- W68 have not been examined, the existence of a less severe allele, mei- W6lJLJ (3 1 5), which when homozygous reduces the frequency of recombination and alters the distribution of recombination, shows

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that this locus also controls the probability of node formation as well as node distribution.


DISJUNCTION IN RECOMBINATION-DEFECTIVE MEIOTIC MUTANTS Recom

bination-defective mutants, in addition to causing decreased levels of recombination, produce increased frequencies of nondisjunction for all chromosome pairs. There are two possible interpretations of the simultaneous disjunctional and recombina tional effects: either a normal level of recombination is a necessary condition for regular disjunction, or each of these mutants has separate effects on disjunction and exchange. Several lines of evidence strongly support the proposition that the nondisjunction produced by these mutants is a secondary consequence of a primary defect in the process of exchange. First, the mutants do not have any effect on male meiosis consistent with the observation that recombination does not occur in wild-type males. Second, in all mutants examined, nondisjunction occurs exclusively at the first meiotic division and only nonexchange chromosomes nondisjoin. Finally, and most strikingly, when the data from all of these mutants are examined, it is seen that the frequency of nondisjunction is simply, albeit nonlinearly, related to the frequency of nonexchange tetrads (35). A simple relationship between the decrease in recombination and the increase in nondisjunction over this whole array of mu tants--distinguishable from one another by a number of genetic, cytological, and biochemical criteria-suggests strongly that the observed nondisjunction is merely a consequence of the increased frequencies of nonexchange tetrads. A number of experiments have provided insights into both the conditions that result in the nondisjunction of nonexchange chromosomes in these mutants and into the nonlinear relation between the frequencies of nonexchange tetrads and nondis junction. From studies of nonmeiotic mutant situations in Drosophila, it is known that the disjunctional behavior of nonexchange chromosomes is under the control of a process called distributive disjunction that is, at least in part, distinct from that governing the disjunction of chromosomes that have undergone an exchange (354, 378). In particular, if only one pair of nonexchange chromosomes is present in a cell, the nonexchange homologues will disjoin distributively from one another and pro duce euploid gametes. If, however, two pairs of nonexchange chromosomes (AA; BB) are present, then either homologues will disjoin distributively from one another producing euploid gametes (A; B), or the nonexchange heterologues may disjoin distributively from one another to produce gametes with two copies of one chromo some and none of the other (AA;OO and OO;BB). Whether nonexchange homologues segregate from one another or from nonexchange heterologues appears to be gov erned by chromosome size; the more similar two chromosomes are in size, the more likely they are to disjoin from one another (379). In nine recombination-defective mutants representing six loci, the simultaneous disjunctional behavior of two pairs of major chromosomes has been examined and a substantial proportion of the observed nondisjunction is clearly the result of distributive disjunction (30, 32, 370, 372). In addition, the data are consistent with the notion that chromosome size governs distributive disjunction in all of these



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mutants except mei-S51 [mei-S51. a recessive. synthetic. meiotic mutant (370). is genetically complex and it is not clear that its defects in recombination and size recognition are the result of the same lesion]. With this exception. the distributive system appears to be normal in recombination-defective mutants and accounts for much of the observed nondisjunction. Indeed, it may well be that all nondisjunction in these mutants results from the nonhomologous interactions of nonexchange chromosomes because even exceptions for a single chromosome (which are not demonstrably the result of distributive disjunctions) occur almost exclusively in cells in which one or more nonhomologous chromosomes are nonexchange (35. 366, 367, 370). Particularly striking in this regard are data bearing on the origin of fourth chromosome exceptions. The tiny fourth chromosomes essentially never recombine; their disjunction is normally in sured by the distributive system (380). In all recombination-defective mutants in which the disjunctional behavior of the fourth chromosomes and recombination on one (or more) of the other chromosomes have been simultaneously monitored, it is found that fourth chromosome exceptions are recovered more frequently with non crossover heterologues than with heterologues that have recombined (366, 367, 370). Furthermore, ova simultaneously nondisjunctional for both the X and fourth chromosomes are more frequent than expected by chance, although there is no evidence of distributive disjunctions of the fourth and X chromosomes from one another. Since only nonexchange chromosomes nondisjoin, this observation also implies that fourth chromosome nondisjunction occurs preferentially in meiocytes in which the X chromosomes did not exchange, implying generally that fourth chromosome nondisjunction caused by recombination-defective meiotic mutants is conditional on the failure of exchange in one or more heterologues in the cell. Arguments suggesting that nondisjunction of the other chromosome pairs may be similarly dependent on the exchange status of heterologous chromosomes have been presented by Baker & Hall (35). For example, the nonlinear relationship between the frequency of nonexchange X chromosomes and the frequency of X chromosome nondisjunction is understandable if X chromosome nondisjunction requires nonexchange second and/or third chromosomes as well as nonexchange X chromosomes in a single meiocyte. A more severe reduction in recombination in some cells than in others could also lead to these kinds of correlations. That there are not such subpopulations of cells is strongly suggested by the independence of recombination on the X and second chromosomes in mei-S282 (367), the only one of these mutants examined in this regard. In summary, these results suggest that the primary effect of recombination defective meiotic mutants is to decrease exchange, and that the elevated frequencies of nondisjunction are simply the consequence of increased frequencies of nonex change tetrads and the manner in which nonexchange heterologous chromosomes interact to determine segregation patterns. While some nonhomologous interactions result in demonstrably distributive disjunctions, it seems clear that nonexchange heterologues can also interact in ways that lead to nondisjunctions that are not demonstrably the result of distributive disjunctions. Such interactions could, for


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example, involve distributive disjunction from a trivalent, the formation of unstable distributive associations, or the saturation of some aspect of the distributive system by the presence of large numbers of nonexchange chromosomes (32, 35, 370, 372, 381). However, some data suggest that this interpretation of the disjunctional effects of recombination-defective mutants may be somewhat simplistic. Hall (372) has noted that under this view, both mutant alleles of c(3)G should have the same disjunctional effects since they both effectively eliminate exchange, yet segregation is consistently more abnormal in c(3)(? than in C(3)(]17 in all aspects examined, suggesting that c(3)G+ acts before exchange and is requisite for both exchange and the regular segregation of nonexchange chromosomes (382, 383). Alternatively, the difference between the effects of the two c(3)G alleles might be due to either (a) different modifiers in the two stocks, or (b) the amount of nondisjunction being very sensitive to small changes in the amount of exchange when the frequency of ex change is near zero, as is true for both c(3)G alleles (35). MEIOTIC

ULTRASTRUCTURE IN RECOMBINATION-DEFECTIVE

MUTANTS

An electron microscopical examination of meiosis in several recombination-defec tive mutants has provided some information about the functions specified by the wild-type alleles of these loci. The most extensively examined mutant, C(3)(]17, lacks synaptonemal complex (376, 384, but see 385). Preliminary observations of c(3)(i68, a second allele at this locus, indicate that it too lacks synaptonemal complex and that pachytene chromosome condensation also fails to occur (386), so it is not clear whether c(3)G+ specifies a component of the synaptonemal complex or a function essential for both chromosome condensation and synaptonemal complex formation. That c(3)G+ specifies an early step in meiosis has been suggested inde pendently by Hall (372) on the basis of an extensive genetic characterization of C(3)(]17 and c(3)(? The absence of chromosome condensation and little or no synaptonemal complex is also found in mei- W68 (386). In three mutants (mei-9a, mei-218, mei-41) in which there is some residual meiotic recombination, the amount of synaptonemal complex present is comparable to wild type (386, 387) and no gross abnormalities in the structure of the complex are evident (34, 386). Although it may be coincidence that the three mutants that have no meiotic crossing-over have no synaptonemal complex whereas the three mutants with some meiotic exchange have synaptonemal complex, the observation does suggest the possibility that in Drosophila [as in E coli (388)] there is more than one pathway for recombination, and that in Drosophila the functioning of these pathways has a common requirement for the presence of synaptonemal complex. If this is the case, then only mutants that prevent the formation of (functional) synaptonemal complex would completely obliterate meiotic exchange. However, we should caution that the residual levels of crossing-over observed in mutants such as mei-9 or mei-218 are equally compatible with the notion that these mutants are hypomorphs (as mei- W68Ll clearly is).


There is only one recombination-defective mutant, mei-l (3 1 6), known in Drosophila whose effect is restricted to part of the genome. This autosomal recessive causes a decrease in recombination on the X to about 50% of the control value but has little or no effect on second or third chromosome recombination. Recombination is decreased most severely in the central region of the X chromosome, suggesting that mei-l is both chromosome and region specific. Since the pattern of recombination observed with mei-l is very similar to that of other recombination-defective mutants defective in node establishment and distribution, it may he that mei-l is defective in a process required for the normal establishment of nodes on just the X chromosome. Indeed, nondisjunction of the X chromosomes is increased only slightly in mei-l. although nonexchange X chromosomes are frequent, consistent with the notion that nondis junction of nonexchange chromosomes is dependent on the simultaneous presence of two or more pairs of nonexchange chromosomes. Why should Drosophila have both a set of functions that control recombination throughout the genome and another set of functions that control recombination specifically on the X chromosome? Two possibilities suggest themselves. First, the X. 2. and 3 differ in both their tetrad distributions and the distribution of exchanges along their lengths; it may be that these differences are the result of loci such as mei-l+, Alternatively, it may be that mei-l 's meiotic effect is a consequence of a primary lesion indirectly related to the process of exchange. For example, the X chromosome differs from other chromosomes in that all euchromatic loci on the X chromosome are dosage compensated (389), and it has been suggested that dosage compensation involves controls by autosomal loci of X chromosome gene activity (390, 391). Interestingly, mei-l maps close to a region on chromosome 3 that has the unique property that it must be present in exactly two doses for a diploid fly to survive (392) and on this basis is a candidate for the autosomal locus that controls dosage compensation (393). Thus it seems at least tenable that the primary defect in mei-} is in a component of dosage compensation and that its recombinational phenotype is a secondary consequence of this. Although the meiotic effects of abo are indistinguishable from those of other recombination-defective mutants, it has, in addition, a developmental phenotype (394, 395) that is unrelated, in any direct sense, to its meiotic effects. However, the developmental effect is related to the nature of specific segments of heterochromatin (396), and in addition, the redundancy of ribosomal DNA changes markedly in the presence of abo (397). It may well be, therefore, that the recombinational effects of abo are secondary consequences of these heterochromatic changes, suggesting that the state of the heterochromatin in an oocyte plays an important role in determining the frequency and distribution of exchanges. Finally, there are three female-specific mutants (mei-38. mei-99. and mei-l60) that may also indirectly affect meiotic chromosome behavior. These mutants all disrupt slightly a number of different aspects of meiosis: recombination is altered, nondisjunction occurs at both meiotic divisions and includes recombinant chromo somes, nondisjunction ofdifferent chromosomes pairs is positively correlated but the

THE COMPLEXITY O F GENIC EFFECTS O N RECOMBINATION


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patterns are not attributable to distributive segregations. Although these mutants may represent only slightly defective alleles of loci that directly govern chromosome behavior at a number of different times during meiosis, the plethora of minor effects suggests that they may be acting indirectly by altering some component of general cellular physiology.


RECOMBINATION-DEFECTIVE MUTANTS IN OTHER DROSOPHILA SPECIES

The recessive recombination-defective mutant c(Xj of D. subobscura (326) is the only recombination-defective mut�nt reported in a Drosophila species other than D. melanogaster. c(Xj affects only females (398), reduces recombination on all chromosomes to 3% of normal, and causes frequent nondisjunction. The cytology of c(Xj meiosis has been examined by Fahmy (399), who reports that at diakinesis only 4% of the bivalents have chiasmata; the remaining bivalents are about equally divided between cases in which the achiasmatic homologues are closely juxtaposed and cases in which the homologues are widely separated. Strik ingly, at metaphase, a substantial number of achiasmate bivalents were also present. D. subobscura probably possesses a distributive disjunction system since secondary nondisjunction occurs in XXY females of this species (400). Thus, the achiasmate bivalents observed by Fahmy may represent distributively paired nonexchange chromosomes. A low frequency of failure of proper spindle expansion at both anaphase I and I I is also observed in c(X) females; it is not clear that this has any segregational consequences. Recombination a n d DNA Metabolism That meiotic recombination and DNA repair and/or replication processes in somatic cells are in part under common genetic control in Drosophila as they are in higher plants and fungi has been demonstrated by several types of studies. MUTAGEN SENSITIVITY Strong support for the common control of meiotic and somatic DNA metabolism comes from the complementary demonstrations that some mutants isolated as recombination-defective meiotic mutants are hypersensi tive to killing by radiation and chemical mutagens, while some mutants isolated as mutagen-sensitives exhibit abnormal meiotic chromosome behavior. Smith (3 1 8) reported the isolation of an X-linked mutant (muts=mei-4JAI) hypersensitive to killing by methyl methanesulfonate (MMS). Over 50 additional MMS-sensitive mutants on the X and third chromosomes have since been isolated (3 19-320a). These mutants fall into about eight complementation groups. When homozygous in females, mutants at some of these loci cause increased frequencies of nondisjunction, suggesting that they may disrupt meiotic recombination, whereas mutants at other loci exhibit control levels of nondisjunction (3 19, 320). Among these MMS-sensitive mutants, mutS and several other mutants are allelic to mei-41. Larvae bearing mei-41 alleles have been shown to be hypersensitive to killing by X-rays, UV, ethyl methanesulfonate (EMS), nitrogen mustard, 2acetylaminofiuorene (AAF), and hydroxyurea as well as MMS (3 1 4, 3 1 8, 320, 401). The recombination-defective mutants mei-9 and mei-9b are also hypersensitive to


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killing by X rays, MMS, AAF, and nitrogen mustard, whereas mei-218. which reduces recombination as severely as mei-9, does not differ from wild type in its sensitivity to any of these agents (3 14, 402). The capability for photorepair, postreplication repair, excision repair, and the repair of single-strand breaks has been assayed in primary cell cultures and/or established cell lines derived from several of these mutants (402, 403). Excision repair was assayed using an endonuclease preparation from M. [uteus, which is specific for pyrimidine dimers, to monitor the presence of UV-induced dimers. The rate of disappearance of endonuclease-sensitive sites from DNA of mei-9 cells was 10- to 20-fold slower than that of control cells, suggesting that an early step in excision repair is defective in this mutant (402). Photorepair ofendonu clease-sensitive sites is normal in mei-9 cells. The mutant mei-218 removes endonu clease-sensitive sites (dark repair) at the control rate (402). In assays of the repair of X-ray-induced single-strand breaks, no differences could be detected among cultures of mei-9. mei-2I8, mei-4ID5, nine nonallelic mutagen sensitive (mus) mutants, and nonmutant cells (402, 403). Postreplication repair in these mutants was assayed by following the increase in molecular weight of newly synthesized DNA following UV irradiation in the pres ence or absence of caffeine. The mutants mei-41D5, mus(J) 101, mus(J) 302, and mus(l) 104 are defective in postreplication repair by this assay and have been tentatively assigned to two separate pathways of postreplication repair. It is proposed that mei-41D5, mus(l) 101, and mus(J) 302 are defective in a recombina tion-dependent, caffeine-sensitive pathway, and that mus(J) 104 is defective in a recombination-independent, caffeine-insensitive pathway (403).


REPAIR

CHROMOSOME BEHAVIOR The effects of recombination-defective meiotic mutants on somatic chromosome stability have provided a sensitive probe into the functions of the wild-type alleles of these loci in somatic cells. In particular, their effects on the frequency, size, and morphology of somatic spots arising in flies heterozygous for appropriate somatic markers provides evidence that DNA me tabolism in somatic cells and meiotic recombination are under common genetic control. The classical study of Stern (404) showed that mitotic crossing-over in Drosophila was like meiotic crossing-over in that it occurred at the four-strand stage, was limited to exchange between homologues, involved one chromatid of each homo logue, was reciprocal, and gave the same linear order of genes as the meiotic inap. Mitotic crossing-over is distinct from meiotic crossing-over in that it is much less frequent, occurs in both sexes, and does not appear to be associated with the presence of synaptonemal complex (4 1, 405). The processes also differ in that the frequency of mitotic crossing-over is roughly proportional to physical distances (406). Since some of the recombination-defective mutants produce a meiotic map approaching the mitotic map, it has been suggested that the differences between mitotic and meiotic crossing-over in wild type may result from a failure of these loci to mediate recombination in somatic cells (34). MITOTIC


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Direct tests of whether the functions specified by recombination-defective loci mediate mitotic exchange have been performed for several mutant� Le Clerc (407) reported that C(3)(]17 does not alter the frequency of spontaneous mitotic exchange. The effects of 12 additional recombination-defective mutants on spontaneous mi totic crossing-over have been examined; in no case was the frequency of somatic spots decreased (3 14). Thus, spontaneous mitotic recombination can occur indepen dently of the function specified by each of these loci. This would suggest, most easily, that mitotic and meiotic recombination are under separate genetic control. However, while none of these mutants decreases the frequency of somatic cross ing-over, many cause striking increases in the frequency of somatic spots (3 1 4). Although somatic spots can originate from mutation, chromosome breakage that results in marker loss, and mitotic recombination, the somatic spots produced by each of these mechanisms have distinct characteristics. Mitotic recombination pro duces twin spots, whereas chromosome breakage produces only single spots that may have features characteristic of aneuploidy. By such criteria, it was shown that recombination-defective mutants produce somatic spots by several different mecha nisms. That the particular pattern of effects evoked by a mutant is a character istic of its locus is shown by the similar effects of two or more alleles for many loci. Two alleles at the mei-41 locus showed an increase in somatic spots (greater than 1 S-fold) almost entirely attributable to deficiencies that delete the dominant alleles of the heterozygous somatic cell markers used. Similar effects of a third allele of this locus have been observed independently (3 19). On the other hand, for mutants at the mei- W68 locus, the increase in the frequency of somatic spots (fourfold) is almost entirely attributable to an increase in mitotic recombination. For mutant alleles of the mei-9, mei-S282, and mei-352 loci and the heterozygous deficiency sbdI05, the elevated frequency of somatic spots is due to both chromosome breakage and mitotic recombination. Finally, alleles at one recombination-defective locus, mei-218, have no effect on the frequency of somatic spots. These results demonstrate that the wild-type alleles of these loci (except mei21S+) are necessary for chromosome stability in somatic cells. The increased fre quencies of somatic spots caused by mutants at these loci are understandable if discontinuities in DNA structure can, as an alternative to being repaired, induce mitotic exchange or chromosome breakage. Thus, blockage of a repair or replica tion process by a recombination-defective mutant will increase the probability of these lesions being shunted into pathways leading to recombination or breakage. The different phenotypes exhibited by these mutants suggest that they are defec tive in the repair of several different kinds of lesions. Thus, the lesion repaired by mei-41+ can initiate chromosome breakage but not mitotic exchange, whereas mei- W6s+ functions to repair lesions that can induce mitotic exchange but not breakage. The other recombination-defective mutants that increase somatic spots would appear to be defective in the repair of a lesion(s) that can induce mitotic exchange and breakage. That mitotic recombination occurs in the presence of these mutants (defective in both meiotic recombination and also DNA metabolism in somatic cells) poses a


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problem, since it would be expected a priori that such loci would also be involved in mitotic recombination. If there exists more than one pathway of mitotic recombi nation in Drosophila, then each of these mutants may in fact be defective in mitotic recombination, but the defects are obscured by the alternative pathways. Indeed, evidence for multiple pathways for mitotic recombination has been presented by Haendle (408-4 10), who has been able to resolve two mechanisms by which X rays induce mitotic recombination in wild type. In the recombination-defective mutant C(3)(J17, the ability to respond via one of these mechanisms is lacking whereas the induction of mitotic recombination via the other mechanism is normal (4 1 1). MUTAGENICITY Further evidence that certain recombination-defective mutants are defective in some aspects of DNA metabolism comes from studies of mutant effects on spontaneous and induced mutation rates. Watson (412, 4 1 3) reports that C(3)(J17 oocytes are hypersensitive to the induction of dominant lethals by X rays and that X irradiation of either C(3)(J17 male or female germ cells induces higher frequencies of recessive lethals and translocations than in c(3)cY controls. In addition, mature sperm of C(3)(J17 males are hypersensitive to the induction of recessive lethals by EMS, but are less sensitive than controls to recessive lethal induction by the bifunctional agent, diepoxybutane (DEB). Watson suggests that the apparent decreased sensitivity to DEB results from a failure to repair cross-links in DNA causing increased dominant lethality and an apparent decrease in the frequency of recessive lethals. Consistent with this hypothesis, Watson found that DEB induces about 20% more dominant lethality in C(3)(J17 than in c(3)cY mature sperm. While these results are in agreement with those of Haendle (see above) in suggesting that C(3)(]17 is defective in a repair process, neither of the mutant alleles of c(3)G causes any increase in the frequency of spontaneous lethals (375). Males carrying the recombinatiOI1-defective mutant, mei-41A1, are hypersensitive to the induction of recessive lethals by MMS. Spontaneous recessive lethals also occur more frequently in mei-41A1 than in control males (3 1 8). In mei-S282 females, there is an increase in the frequency of spontaneous recessive lethals and these are premeiotic in origin (414). Spontaneous sex-linked recessive lethals occur at approx imately the same rate in mei-9 and control females (386). Several mutator genes have been reported in Drosophila (415). One of these, the autosomal semidominant mu (323), induces both forward and reverse mutations in females. the latter being allele specific. Mutations recovered from mu females are premeiotic in origin, and a substantial proportion are cytologically detectable defi ciencies (41 6). In mu males, on the other hand, neither the reversion of a sex-linked mutant frequently reverted in mu females (323) nor the production of sex-linked recessive lethals was elevated above control levels, suggesting that mu acts only in females (41 6). In females, but not in males, mu causes an increased frequency of nondisjunction of the sex chromosomes. and some data suggest that mu causes a decrease in recombination (369), although further analysis is necessary. These observations are consistent with the suggestion of Gold & Green (369) that mu is defective in a

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process common to meiotic recombination and DNA repair or replication in somatic cells. Another phenotype that may be indicative of de fects in DNA replication or repair is the occurrence of recombination, either goni ally or meiotically, in D. melanogaster males where crossing-over is normally absent. By this criterion also, there is evidence that DNA repair and meiotic recom. bination are under com�on genetic control. Since the initial report of a second chromosome carrying a mutant (Mr) that, when heterozygous, induces recombination in males (3 17), a number of investigators have reported similar, if not identical, mutants in a wide variety of natural popula tions of D. melanogaster (4 17-423). At least some of the male recombination in Mr lines occurs premeiotically (417, 42 1 , 424). Both second and third chromosomes recombine (417, 42 1, 424), and crossing-over occurs relative to the standard genetic map most frequently in proximal regions (417, 424, 425) but not in the centric heterochromatin itself (41 7). Mr-bearing chromosomes also induce recessive lethals, visible mutations, and rearrangements on all chromosomes (417, 420, 422, 423, 426). Although genetically complex, the major element responsible for male recombina tion in the chromosome studied by Hiraizumi and co-workers has been mapped to the proximal portion of chromosome 2 (427). These observations are consistent with Mr causing a defect in some step in DNA repair or replication (417) as well as with a number of other explanations (4 17, 4 1 9-421 , 423, 424, 427). The frequency and pattern of meiotic recombination in females heterozygous for Mr is abnormal (425, 43 1). Strikingly, the pattern of recombination in heterozygous Mr females is similar to that found in most recombination-defective meiotic mu tants; that is, Mr alters the distribution and perhaps the frequency of sites at which exchange occurs in females. Although further data are required to characterize this female effect, it seems likely that Mr is a recombination-defective meiotic mutant that also causes mitotic chromosome instability.


RECOMBINATION IN MALES

Disjunction-Defective Meiotic Mutants In Drosophila females there are two pathways of normal disjunction at meiosis I: (a) exchange-mediated disjunction and (b) distributive disjunction of nonexchange chromosomes. The disjunctional effects of recombination-defective meiotic mutants (see above) are consistent with the implications from nonmeiotic mutant situations (354) that the presence or absence of an exchange determines which of these path ways mediates a given chromosome's segregational behavior (but see 43 1a). That an exchange in the case of exchange-mediated disjunction, or the lack of an ex change in the case of distributive disjunction, is not sufficient to guarantee regular segregation via either of these pathways is shown by meiotic mutants that disrupt one, or both, of these. Such mutants; termed disjunction-defective meiotic mutants, serve as probes into the functions, beyond exchange, that control meiotic chromosome disjunction. Since flies homozygous for all but one of the known disjunction-defective mutants have good viability, it seems unlikely that many of these loci play a major role in mitotic chromosome segregation. This suggests that these mutants identify a set of functions



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whose existence i s not explicitly recognized in most traditional considerations of meiosis: to wit processes, in addition to exchange, that are uniquely important for regular chromosome segregation at meiosis. There are three female-specific disjunction-defective mutants, cand (3 13, 432), I(J)TW-6cs (325, 433, 434), and a mutant ca in D. simulans homologous to cand (327) in D. melanogaster, that greatly increase nondisjunction of both exchange and nonexchange chromosomes at the first meiotic division. The disjunction of nonex change chromosomes is more severely disrupted than is the disjunction of exchange bivalents, suggesting that an exchange can, to a limited degree, compensate for the functions lacking in these mutants. There is substantial meiotic chromosome loss, particularly of chromosome 4, in these mutants, and, at least for ca and cand, there is mitotic loss in the progeny of mutant females of maternally derived chromosomes as well. Although gametes simultaneously exceptional for the X and 4 are as frequent as would be expected by chance from the overall frequencies of X and 4 exceptions, there is a striking departure from random expectation in the types of double excep tional gametes produced: gametes that are disomic for any chromosome tend to be disomic for heterologous chromosomes as well, while gametes that fail to receive a particular chromosome are nonrandomly nullosomic for heterologous chromo somes. Moreover, at least in the case of ca"d females, whether or not a chromosome will be lost during the mitotic divisions of its progeny seems to be independent of that chromosome's previous disjunctional behavior, but dependent on the disjunc tional history of nonhomologous chromosomes! Thus, the frequency of X chromo some mitotic loss varies as a function of whether it is recovered in a mono-4, nullo4, or diplo-4 ova, but within each of these three classes is independent of whether the X itself had nondisjoined at the preceding meiosis. Although these correlations are not well understood, two general hypotheses about the defect in cand have been proposed (35, 432). Wald (435) cytologically examined the meiotic divisions in ca of D. simulons females. She found that the spindle of the first meiotic division was distorted and that meiosis frequently resulted in the production of supernumerary nuclei. Similar abnormalities have been reported for ca"d in D. melonogoster (P. Roberts, quoted in 432). Clark (436) noted the similarities between the divergent spindle mutant in maize and co in Drosophila. Davis (432) suggested that the meiotic and first embryonic spindles are defective in cond females and that this leads to nondisjunc tion during the reductional meiotic division and to loss during the equational meiotic and early embryonic divisions. Baker & Hall (35), on the other hand, h.ave noted that the observations are equally compatible with the hypothesis that chromo some segregation is abnormal because of a defect in some part of the chromosome (perhaps the centromere) necessary for regular orientation or segregation at the first meiotic division followed by misbehavior of defective chromatids. Under this view, the spindle abnormalities are secondary consequences of a primary defect in chromosome structure. The similarities between the meiotic effects of cand and /(1)TW-6CS suggest that the latter is also defective in some function necessary for proper orientation or segregation in females. However, /(1)TW-6cs is also a cold-sensitive embryonic


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lethal and its meiotic effects, which are semidominant, are also potentiated by the cold. This would seem to suggest that this function is also involved in mitotic cell division; however, because both meiotic divisions are normal in males and nondis junction does not occur at the second meiotic division in females, the defect likely does not involve a general feature (for example, spindle formation) of the mitotic apparatus. That at least some meiotic functions are specific for distributive disjunction is shown by the disjunction-defective mutant, nod (38 1). Nondisjunction in nod females occurs at the first meiotic division and involves only those chromosomes whose disjunction is, in noar females, insured by the distributive system (e.g. chromosome 4, other nonexchange chromosomes, and compound chromosomes). Nondisjunction is associated with meiotic chromosome loss, particularly of chromo some 4. Analysis ofthe patterns of segregation in situations involving distributive segrega tions of trivalents led to the sug!5estion that the recognition aspect of the distributive system is normal in nod; the defect appears to involve random segregation at anaphase I of distributively paired chromosomes. For example, if in wild type three chromosomes A, B, and C normally form a trivalent and segregate AB from C, in the presence of nod A and B go independently of C, but not of each other; that is, AB, C, ABC, and O-bearing gametes are formed equally frequently. Since most exchange bivalents disjoin properly in nod females, nod+ function is necessary at meiosis only for distributive disjunctions. That nod does not influence the frequency of somatic recombination or chromosome breakage (3 14) is consistent with the notion that noar specifies a function unique to female meiosis. All four disjunction-defective mutants are similar in that they produce high frequencies of chromosome loss at meiosis and in some cases in the early mitotic divisions of the embryo. The chromosomes lost mitotically are invariably those derived from the disjunction-defective female. Similar patterns of meiotic and post meiotic loss occur in a wide variety of plant species when univalents are produced at meiosis I as the consequence of a chromosome's failure to have undergone exchange (437). However, only relatively low frequencies of chromosome loss are produced by the recombination-defective mutants in Drosophila, which, a priori, would be expected to generate situations similar to those causing substantial loss in plants. This difference is most probably a consequence of the distributive system in Drosophila. Here, the lack of an exchange between homologues does not result in the homologues behaving as univalents, but instead places the nonexchange chromosomes under the control of an alternative pathway leading to regular ana phase I disjunction. This is supported by the observation that the loss of nonex change chromosomes 4 is frequent in nod females. That loss is frequent in other disjunction-defective mutants is also consistent with this view, since in these cases chromosomes under the control of either exchange-mediated disjunction or the distributive process fail to segregate normally and thus are at least functionally univalents by anaphase I. Thus in Drosophila, as in plants, pairing may be required during some stages of prophase-metaphase to insure regular segregation at subse quent divisions.


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Mutants Affecting Meiosis II

In contrast to the large number of loci revealed by mutants essential for a normal meiosis I in Drosophila, only four loci are known at which mutants disrupt chromo some behavior in meiosis II. It has been suggested that this relative paucity of mutants means either that meiosis II is less complex or that the second division is essentially mitotic in character-that is, mutants affecting the second division also affect mitosis and hence are not viable (32, 35). All mutants that increase nondisjunction at the second meiotic division affect chromosome behavior in both sexes, suggesting that the second meiotic division is under common control in the two sexes (30, 3 1 1 , 3 1 2, 438). However, since the meiotic loci identified to date represent the subset of such loci that is dispensable for viability and functional gamete formation, the apparent completely separate genetic control of meiosis I in the two sexes may be a consequence of the types of mutant screens that have been employed. The first of these mutants affecting meiosis I I that we will consider, mei-S332 (438), increases nondisjunction of all chromosomes to the same extent in both sexes. Cytological examination of meiosis in mei-S332 males has revealed that sister centromere separation is frequently precocious, occasionally occurring as early as anaphase I. Thus, mei-S33]+ specifies a gene product concerned with insuring that sister centromeres remain together between the first and second divisions, a process unique to meiosis. Sandler et al (439) have presented evidence that ring chromosomes are frequently converted into dominant lethals in mei-S332 females and that this dominant lethal ity results from an impaired ability to resolve interlocked sister ring chromosomes at anaphase II, suggesting that normal centromere function is necessary for the resolution of such interlocked complexes. Peculiarly, ring chromosomes are also transmitted less efficiently in females carrying the recombination-defective mutant c(3)G (440). Another mutant, ord (3 12), is unique in that it is both recombination-defective and disjunction-defective. That or� must specify an early step in meiosis, at least in females, is evident from the drastic reduction in recombination and the alteration in the distribution of exchanges along the chromosome. That or� is also required for normal disjunction is evident from the high frequencies of nondisjunction that occur at both meiotic divisions in both ord males and females. While the overall frequencies of nondisjunction are the same in the two sexes, the ratio of reductional to e.quational exceptions differs slightly. In females, nondisjunction occurs approxi mately independently of whether or not a chromosome has undergone an exchange. Cytological examination of meiosis in ord males revealed a normal number of bivalents at prophase of the first division. At anaphase I, some single chromosomes (or chromatids) lag on the metaphase plate. However, these laggards apparently reach a pole since loss is not detected genetically. Abnormalities are more frequent at the second division, with sister centromeres often separated at metaphase II and nondisjoining at anaphase II. These observations suggest that ord causes the preco cious relaxation of forces that hold tetrads together (3 1 2).


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Preliminary observations utilizing complete reconstructions of serial sections of oocytes indicate that ord exhibits gross abnormalities at pachytene (386). Synap tonemal complex is present in approximately normal amounts but is not continuous along the bivalent arms. Moreover; the reconstructions include loops and branches, suggesting that pairing may be abnormal. Thus, orar specifies a product that is requisite for normal disjunction of all chromosomes at both meiotic divisions in both sexes, recombination in females, and normal synapsis of homologues at pachytene. This unique array of effects suggests that during meiosis orar either controls the activity of a number of meiotic genes, specifies a product that is needed for a hitherto unrecognized process that occurs early in meiosis or even premeiotically and is necessary for recombination as well as disjunction at both divisions, or specifies a product that is used several times during meiosis (3 12). Although the data do not distinguish among these possibilities, it is worth noting with respect to the last possibility that meiosis differs from mitosis in that three events of the cell cycle are delayed in meiosis. Thus, some DNA synthesis is delayed until zygotene and pachytene (37), sister centromere separation is delayed until anaphase II, and the separation of sister chromatid tips may be delayed until anaphase I to provide a mechanism for preventing chiasmata from being terminalized off the chromosome (437). If orar specified a function that was shared by the processes involved in these three events, then ord might well generate the array of observed effects. Finally, two mutants that increase nondisjunction at the second meiotic division in both sexes, the X-linked eq (322) and the second chromosome mei-G87 (3 1 1), appear to affect only the chromosome they are on. The reported dominance of eq suggests it might be defective in a site necessary for the X chromosome to respond to the product of one of the genes controlling meiotic disjunction. Because mei-G87 is recessive, it is probably not defective in such a responding site. Male-Specific Meiotic Mutants

The majority of mutants isolated to date that affect chromosome behavior in males act during the first meiotic division and do not affect all chromosomes in the complement. These include 20 X-linked mutants (32) that affect X- Y disjunction but have no effect on chromosome 4, two alleles of the second chromosome recessive mei-S8 (30) that affect chromosome 4 only, and the second chromosome recessive mei-G1 7 (3 1 1) that affects the sex and second chromosomes but not chromosome 4. There are two male-specific mutants that affect all chromosome pairs; these are the third chromosome recessive mei-081 that increases nondisjunction of at least chromosomes 1, 2, and 4 at the first division (30, 3 1 1) and the second chromosome recessive pal (44 1) that causes loss of all chromosomes. That most male-specific meiotic mutants affect only a subset of the chromosomes is in striking contrast to the situation in females. A possible explanation for the chromosome-specific effects of these loci is suggested by the observation that proper disjunction during male meiosis is mediated (at least for the sex chromosomes) by processes that hold homologues together at special pairing sites located in the basal



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heterochromatin (442). Thus, if these pairing processes are specific to limited por tions of the genome, the chromosome-specific meiotic mutants may be defects in loci controlling these processes (32, 3 1 1). A second general observation from studies of male meiotic mutants is that the occurrence of meiotic drive (38) is frequently associated with the disruptions caused by these mutants. Baker & Carpenter (32), from the observation that the 20 X- Y specific mutants they studied all appeared to cause drive, suggested that meiotic drive may be a normal property of male meiosis when pairing, and therefore disjunc tion, of homologues fails to occur properly. If this is true, then other mutants that are chromosome-specific should also cause meiotic drive. In fact, the other two chromosome-specific male meiotic mutants (mei-S8 and mei-G1 7) do produce an excess of nullosomic, as compared to disomic, exceptional gametes, although it is not known if this is the result of meiotic drive or chromosome loss (35, 3 1 1). Additional evidence that meiotic drive is a consequence of defective pairing has come from the study of structurally abnormal chromosomes (443). That mei-G1 7 is defective in pairing is supported by the observation that most of the gametes simultaneously exceptional for the sex and second chromosomes are of the types expected if the two sex chromosqmes were segregating from the two second chromosomes as if the normal specificity of homologue recognition were disrupted by this mutant, with the consequence that nonhomologous pairing some times occurred (3 1 1). pal (44 1) is unique among meiotic mutants in that it causes loss, but not nondis junction, of all chromosome pairs, although chromosomes differ in their susceptibil ity to pal-induced loss. A site responsible for the insensitivity versus sensitivity of the X chromosome to pal maps to the basal region of the X chromosome at, or near, the centromere. Baker (441) has suggested that pat+ acts during male meiosis to specify a product that is a component of, or interacts with, the centromeric region of chromosomes and is necessary for the normal segregation of paternal chromo somes. The patterns of chromosome loss caused by pal in males and by the disjunc tion-defective mutant cand in females are strikingly similar. It may be, therefore, that the wild-type alleles of these loci perform analogous functions necessary for regular meiotic segregation in the two sexes. Moreover, there are dramatic increases in the frequencies of somatic loss of paternally derived chromosomes during the first several nuclear divisions of the zygote among the progeny of homozygous pal males; here also the patterns of loss are similar to those observed for maternally derived chromosomes in the progeny of Cand females, suggesting even more strongly that the wild-type alleles of .these loci perform analogous functions in insuring regular segregation of chromosomes (44 1). Finally, it should be noted that although males of most Drosophila species lack meiotic crossing-over, three species are known in which male crossing-over does occur, at least in particular strains. D. ananassae males exhibit meiotic exchange, although the frequency is generally much lower than in females and the distributions of exchange events along the chromosomes differ between the two sexes (328, 329,


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444--45 3). Male crossing-over requires the simultaneous presence of particular al leles at each of three loci (328, 329). There are conflicting reports regarding the presence of synaptonemal complex at pachytene in males of male-recombination strains. Grell, Bank & Gassner (454) report that there is no synaptonemal complex, whereas Moriwaki & Tsuijita (455) observed "imperfectly developed" synaptonemal complex. Recombinants between nonoverlapping heterozygous inversions have been detected among the progeny of D. willistani males (456); in this species, also, the frequency of recombination in males is much lower than in females. The final instance of male recombination is that of Mr-bearing lines of D. melanagaster already discussed. HIGHER PLANTS There are many reports on disturbances of meiosis in higher plants. These distur bances-one category of which is meiotic mutants-are usually detected as individ uals exhibiting reduced pollen production, seed set, or fruit yield, sometimes in association with alterations in overall growth habit. The use of these phenotypes as a diagnostic selects not only for meiotic mutants (which decrease fertility by generat ing aneuploid meiotic products thus causing gametic and zygotic lethality) but also for mutants in all other processes required for functional gamete formation as well as nong�nic developmental anomalies. The identification of meiotic mutants among this array usually involves (a) cytological evidence that the earliest detectable abnormalities are in meiotic cells and that the surrounding nutritive cells, as well as flower development, are normal and (b) genetic evidence that the cause of the anomalous meioses segregates as a single (recessive) mutant. In many studies, a meiotic mutant has been identified by these criteria; in many others, the genetic basis, if any, of the reported abnormal meiotic phenotype is unknown. We here restrict our consideration to those cases in which a meiotic mutant has been identi fied by both of the above criteria. We further, because of space limitations, restrict our attention mainly to mutants that affect both megasporogenesis and microsporogenesis. Although sex-specific (most frequently male-sterile) mutants have been studied in many aspects (29, 457-459), most of these mutants appear to be defective in processes involving either premeiotic developmental events or the cellular milieu of the meiocytes, both of which differ between male and female meiosis in plants. In fact, in those cases in which male-sterile mutations affect meiosis, the phenotype appears to be fundamen tally different from that of mutants affecting both megasporogenesis and micros porogenesis. In particular, the abnormalities in the former usually result in meiotic arrest and cell death, whereas the latter typically do not cause meiotic arrest; the nonfunctional gametes are caused by aneuploidy. It should be noted, however, that since details of meiosis in the two sexes may differ (frequency and distribution of exchange, for example), there may be sex-specific meiotic functions; some cases, therefore, may be wrongly omitted from this review. Mutants are considered below in the order in which they produce cytologically detectable disruptions of meiosis. Although this method of presentation reveals


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striking similarities among the types of mutants found in different plant species, it has the disadvantage of separating mutants within a species. Since comprehensive mapping and/or allelism tests have, to our knowledge, been performed only in maize, tomatoes, and soybeans, a summation of mutants within other species may overestimate the number of mutationally defined meiotic functions.


Premeiotic Mitosis and Commitment to Meiosis

That the premeiotic mitotic divisions are in some respect different from other mitoses is suggested by the existence of several mutants in which cytokinesis is eliminated specifically in these divisions (460-463). Nuclear meiotic events are typi cally quite reguiar in these cases, although the meiotic cytokineses may also fail. That the decision to undergo a meiotic, as opposed to a mitotic, division is under genic control is shown by the mutant ameiotic in maize (464-466) in which meiotic divisions are absent in both male and female tissues. Palmer (466) observed normal premeiotic mitotic divisions in mutant plants. However, at the stage when normal microspore mother cells within an anther are undergoing a synchronous first meiotic division, ameiotic "microspore mother cells" undergo a synchronous mitotic divi sion, the "ameiotic mitosis," and then degenerate. Palmer also observes that the ameiotic mitosis differs from a typical somatic mitosis in two respects: (a) the prophase chromosomes are extended, approaching the length of pachytene bivalents, although they do not show the typical pachytene chromomere structure (and, of course, no synapsis); and (b) the spindle is acuminate (spindle-shaped) as is the meiotic spindle (mitotic spindles are typically barrel shaped). Although these observations may indicate that some meiotic functions are being expressed in the ameiotic mitosis, they could also result from conditions (such as cell size) that are correlated with, but probably not integral to, meiosis (466). Stern & Hotta (37) have noted the similarity between the phenotype of ameiotic and the consequences of explanting lily anthers at or near the end of the premeiotic S period, suggesting that the defect in ameiotic might be this late in the sequence of premeiotic events. A mutant possibly defective in the initiation of meiosis is as) in Brassica campes tris (467). There is no pachytene synapsis; univalents congress at metaphase and divide equationally at anaphase I. Meiosis II does not occur, and diploid pollen are produced. Finally, in Triticum, the mutant ds (diploid spores) results in a failure of the reductional division with the consequence that two diploid microspores are formed (467a). Prophase

I

Most of the reported plant meiotic mutants appear to be defective in prophase I processes. In many species, pachytene and prepachytene stages are not amenable to light microscope analysis; thus, the first stages in which abnormalities can be ob served in all forms are diakinesis and prometaphase. Based on the behavior and appearance of chromosomes at these stages the extant meiotic mutants fall into two broad categories. By far the most numerous class of mutants are asyndetics mutants that produce elevated frequencies of univalents at metaphase I. The second

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SANDLER

class of mutants consists of those mutants that produce frequent disruptions of chromosomal integrity characterized by either a high frequency of bridges and fragments, extensive chromosome fragmentation, or a "sticky" phenotype (a gener alized chromosomal clumping). With respect to these mutants, we are concerned with two primary questions: What can be said from the characteristics of a mutant about the function specified by its wild-type allele? What role does this function play in insuring the normality of subsequent meiotic stages? Information on the asyndetic mutants is examined first. It is generally accepted, following Darlington (44), that chiasmata are necessary for the maintenance of bivalents in diplotene-diakinesis to insure proper disjunction at anaphase I. Thus, the presence of univalents at meta phase I in asyndetic mutants is taken as indicative of a defect in a process required either for the normal frequency and/or distribution of exchange, or for the preven tion of complete chiasma terminalization until anaphase of the first meiotic division. That univalents result from decreased frequencies of exchange is strongly supported by the demonstration that, among chromosomes present as bivalents, the frequency of chiasmata is reduced in most asyndetic mutants (468-478). With respect to specifying the recombinational roles of the wild-type alleles of asyndetic mutants, the major categorization made is between defects in functions requisite for synapsis (asynaptic mutants) and defects in processes other than synap sis that mediate exchange (desynaptic mutants). Although this distinction is clearly important, in many species pachytene is not amenable to analysis at the level of light microscopy, and even in those species in which it is, it is difficult to ascertain whether synapsis, if it occurs, is normal in extent in all cells. Despite these problems, asyndetic mutants are usually classified as asynaptic or desynaptic. Unfortunately, the situation is further complicated because the terms asynaptic and desynaptic have not been used consistently. Soost (47S), recognizing the difficulties of making a cytological distinction between asynapsis and desynapsis, suggested that asynapsis be used in all cases except those in which synapsis could be shown to be normal; only some authors have followed his suggestion. Thus, the name of a mutant does not necessarily indicate whether its defect involves synapsis. With these reservations, we may note that asynaptic mutants have been reported in many plant species (29, 467, 467a, 469, 470, 472, 473, 47S, 477-499). The best-documented case of asynapsis is that of two allelic mutants in durum wheat ( Triticum durum), in which no bivalents are formed (478, 496). One of these mutants has been studied by both light and electron microscopy (497). With the light microscope, no recognizable zygotene or pachytene stages are observed. Elec tron microscopy revealed that univalents possess prominent axial cores, but that no central element, and hence no synaptonemal complex, is formed. Desynaptic mutants have also been reported in a wide range of plant species (29, 47 1 , 474, 476, 478, 498, SOO-S21b). Evidence for desynapsis, when available, comes from light microscopy of pachytene, or, in those species in which pachytene analysis is not possible, from the parallel juxtaposition of univalent homologues when they are first resolvable. The observation of such a juxtaposition does not, however, prove


ASYNDETIC MUTANTS



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that the homologues were either completely or normally synapsed. This is the extent of the characterization of the primary lesion in the majority of asyndetic mutants. However, in the case of some asyndetic mutants, studies of the mutants' effects on the distribution of chiasmata (or recombination) have provided further insights into the roles of their wild-type alleles in mediating exchange. In nonmutant forms of most plants, there is at least one chiasma per pair of homologues, most often, in fact, at least one per arm (unless one arm is very short). Although the strategies used by different species to distribute chiasmata, both intra- and interchromosomally, differ widely (at one extreme are forms with a large number of apparently randomly distributed chiasmata; at the other extreme are forms with a low number of localized chiasmata), in all forms both the frequency and the distribution of chiasmata are under genic control. Following the analysis of recombination-defective meiotic mutants developed in Drosophila (30, 32, 366) and rye (37 1), two broad categories of recombination-defective mutants can be defined: (a) mutants in which the fre quency of chiasmata (exchange) is reduced but the chiasmata formed are distributed as in wild-type--these are defined as exchange functions; and (b) mutants in which the distribution of chiasmata is altered relative to wild type, whether or not the frequency of chiasmata .is reduced-these are defined as functions that specify preconditions for exchange. The prototype for such an analysis in plants is the study by Jones (37 1 , 522, 522a) of a rye genotype (an F2 segregant from an interspecific cross between Secale dighoricum and S. turkestanicum) in which the constraints on chiasma localization are relaxed. In wild-type rye (Secale spp. 2n = 1 4), chiasmata tend to be localized distally and there is usually one chiasma per bivalent arm. In Jones' genotype (which has a complex genetic basis), on the other hand, statistical considerations suggest that chiasmata are randomly distributed among cells, among chromosomes, and along bivalents (37 1 , 522). Moreover, from comparisons of chiasma distributions in this extreme distributional genotype, in less extreme segregants, and in wild-type, Jones was able to show that the distributions of chiasmata among cells, among chromosomes, and along chromosomes were all highly correlated and thus under common genic control. Based on this analysis, Jones (37 1) has suggested that recombination in rye may be a two-step process. In wild type there are relatively few potential sites for exchange and these are localized in the distal regions of the bivalents. The probability that an exchange will occur at such a site is uniformly high, resulting in the localized and regular distribution of chiasmata both among and within bivalents. In the distributional genotype, on the other hand, constraints that limit the locations of sites at which exchange is possible are lacking. Thus, although the probability that an exchange will occur is not altered, exchanges now exhibit a Poisson distribution throughout the genome, producing the random pat terns of chiasmata observed. Although mutants can, by this procedure, be divided into those defective in functions that determine where exchanges can occur and those that mediate ex change at these sites, it has been noted that the occurrence of chiasma terminaliza tion in many species complicates comparisons of the distributions of chiasmata along a chromosome. Moreover, in the case of aSYndetic mutants, such comparisons ,


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are subject to special difficulties because the mutants could conceivably alter the progression of chiasma terminalization relative to other cellular events. Compari sons of the effect of mutants on the distribution of chiasmata among chromosomes and among cells are not subject to this problem. Unfortunately, few mutants have been analyzed in this manner. One mutant in which chiasma distributions have been analyzed is a recessive asyndetic mutant in rye characterized by Prakken (473) in which the total number of chiasmata was reduced, and, in addition, those chiasmata that were formed (a maximum of one per arm) were even more frequently distally located than were those in wild type. Synapsis at pachytene was nearly normal, although intercalary asynapsis appeared to be somewhat more frequent than in wild type. Although Prakken's mutant shows considerable variation between plants in mean number of chiasmata per cell (2.6-6.4, as compared to a control mean of 1 2.6), probably caused by variations in environmental conditions and/or genetic background, Prakken notes that within plants, total chiasmata were randomly (i.e. binomially) distrib uted over total potential bivalents and that the proportion of bivalents with chi asmata in both arms (ring bivalents) was constant for the various cell classes (i.e. 0, 1, . . . , 7 bivalents). These data also show that cell classes are binominally distributed and the proportion of ring bivalents is that expected from independent and equal probabilities of chiasma formation on the two arms of each bivalent. Thus, if each of the 14 arms is chiasmate with probability p ( mean number chiasmata per cell -:- 14) and arms are independent, then the distribution of bivalents across cells is given by the terms of [g + (1 - g)]1, where g is the probability of bivalent formation per homologue pair (mean number of bivalents per cell ..:.. 7; g 2p p 2), and the proportion of bivalents with two chiasmata should equal p/(2 - p). A comparison of these expectations with the observed distributions for each of the nine plants studied by Prakken shows good agreement (but see 523). Moreover, the proportion of ring bivalents equals p /(2 - p) over the 2.4-fold range of variation in p among plants. One of the most striking features of these data is that they are consistent with the probability of chiasma formation being the same for all 14 arms. Yet, as Prakken notes, three of the chromosomes in rye are acrocentric; in wild-type rye, monochiasmate bivalents nonrandomly result from the failure of chiasma for mation in the short arms of these chromosomes, suggesting that these arms are genetically, as well as physically, short. Since in Prakken's mutant the probability of chiasma formation for the different arms appears equal and indeed Prakken notes "the few chiasmata present are rather often found in the short arms instead of the long ones," it must be that the wild-type allele of this locus specifies a function that allows exchanges to occur more frequently in long chromosome arms than in short ones. In addition, the function specified by this locus is necessary not only for the normal frequency of exchange but also for the normal distribution of exchanges along the chromosome, since, in the mutant, exchange is more localized than in wild type. Mutants similar to Prakken's have been reported in species where chromosomes are even more disparate in length. In Vicia /aba (2n = 1 2) there are one long and five short pairs of chromosomes. In wild type, the long chromosome has 2.2 times =

=



WI

as many chiasmata as the average short chromosome, yet in seven asyndetic mutants examined by Sjodin (477), the frequency of chiasmata and the frequency of univa lents are constant for all six chromosome pairs. Here, however, chiasmata are apparently not preferentially terminally located. One type of defect that could result in this phenotype is a disruption in the temporal relations of prophase events (524, 525). Other mutants that alter the probability of chiasma formation differentially throughout the genome and are thus defective in processes that are preconditions for exchange, include as in maize (469, 480, 48 1), a mutant in peas (470), as in Oenothera (472), ds in common wheat (474), aS4 and aSh in tomatoes (514), 229A in peas (526), and the asyndetic Scots Pine (534). In contrast to mutants that alter the distribution of chiasmata, several mutants -"X" strain of Crepis capillaris (47 1), mutants A 35 and A 11 of Vicia/aha (47 1) -reduce the total number of chiasmata per cell, but the distribution of chiasmata among and along chromosomes (or the probability of bivalent formation) are pro portional to chromosome length. This is also true for the distributions of chiasmata in the wild type of these species. The mutants al and a4 in Lycopersicon esculentum (475) discussed below may also fall into this category. Mutants such as these identify loci that specify products directly involved in exchange itself. In only a very few asyndetic mutants has genetic recombination, as well as chiasma formation, been examined. One of these, the asynaptic mutant (as) in Zea mays (479), is perhaps the most thoroughly analyzed of all plant meiotic mutants. The amount of asyndesis in as varies dramatically among plants, ranging from complete asyndesis (no bivalents at metaphase J) to nearly complete syndesis at metaphase (469, 48 1). The distribution ofbivalents across cells is not binomial (527). Two doses of As are required for normal recombination (528) and syndesis (529). Zygotene-pachytene synapsis is often incomplete in as; unsynapsed regions are predominantly intercalary and short arms are more often completely synapsed than long arms (48 1). Among plants, the amount of asynapsis at pachytene correlates well with the amount of asyndesis at diakinesis and metaphase J (469, 48 1). More over, the pattern of arms synapsed at pachytene correlates well with the pattern of arms chiasmate at diakinesis-metaphase J and equational separation of heterozygous knobs at diakinesis does not occur, suggesting that premature resolution of chias mata does not occur. Thus, the defect in as appears primarily to involve synapsis, with the result that chiasma formation is limited to those chromosomal regions that are synapsed at pachytene (480, 48 1). However, recombination in several genetic intervals (469; 530; Dempsey, and Rhoades & Dempsey cited in 481), assayed in seeds from haploid female gametes, is as high or higher than in wild type. Although haploid gametes represent only a minority of meiotic products (presumably those derived from meioses with high bivalent frequencies), a failure to recover nonexchange bivalents is not sufficient to account for the genetic results (Dempsey, cited in 48 1). This is because (a) although reduced, crossing-over in diploid gametes (presumably derived from meioses with low bivalent frequencies) is not zero, and (b) the absolute number of crossovers is increased in as relative to As. Miller (48 1) notes that intervals assayed for crossing-


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over are located primarily in short arms or centromeric regions, regions that are preferentially synapsed at pachytene. He suggests that crossing-over is more fre quent in synapsed regions in as than in the same regions in wild type, a response perhaps comparable to the compensatory recombination observed in other genetic systems in maize (48 1) and the interchromosomal effect on recombination in Dro sophila (355). Similar effects, as discussed, are characteristic of many recombina tion-defective mutants in Drosophila. In only four other mutants have both chiasmata and crossing-over been examined. In ds in Hordeum vulgare (504, 50S), pachytene synapsis occurs but lapses prema turely; the numbers of chiasmata and bivalents are reduced, and a corresponding reduction in the frequency of crossing-over is observed. Riley & Miller (53 1) report X-ray treatment increases the number of rearrangements in ds relative to a nonmu tant control; Swietlinska & Evans (532), however, report no difference in the type or frequency of aberrations induced by X rays, nitrogen mustard, or diepoxybutane. Soost (475) examined the nonallelic mutants aSJ and aS4 in tomato (Lycopersicon esculentum ): synapsis at pachytene is frequently incomplete in both mutants and chiasmata per bivalent, as well as bivalents per cell, are reduced; as/I which has a higher level of pachytene synapsis than aS4> also has more chiasmata per cell and per bivalent. Although aSJ exhibits only 61 %, and aS4 only 36%, as many chiasmata on the nucleolar chromosome as wild type, the frequency of crossing-over in a distal region of this chromosome assayed in diploid seeds is not reduced by either mutant. Moens (5 14) examined crossing-over in aSJ and aS4 in several regions on the nucleo lar chromosome including approximately the same interval examined by Soost. In the distal intervals, aSJ gave normal levels of crossing-over; aS4, however, exhibited elevated levels of recombination (2.5-fold) as did aSb (2.0-fold), an asyndetic mutant for which allelism with aSJ or aS4 was not tested. For the two distal regions examined, recombination was increased to the same extent in both regions in aS4, whereas in aSb the two regions were affected to differing extents. Neither aS4 nor aSb appeared to decrease crossing-over in a more proximal interval. All three mu tants increased the coefficient of coincidence-as} slightly, aS4 and aSb to 1 .0. Synaptonemal complex of normal morphology is present in all three mutants. Moens reports abnormal chromosome condensation at diakinesis and fragmentation at anaphase I in aS4. The disparity between the genetic and cytological observations in asJ may be resolved if nonexchange bivalents are selectively rendered nonrecover able by nondisjunction and aneuploid gamete formation (475, 5 1 4). The increases in crossing-over reported by Moens in aS4 and aSb. however, cannot be due solely to selection; Moens suggests that these "genes cause interference with the process of genetic exchange at meiosis, either directly or indirectly through changes prior to exchange." That both aS4 and aSb alter the coefficient of coincidence, and that aSb alters the distribution of crossovers, suggest that both mutants are defective in functions that specify preconditions for exchange. The differences in behavior of aS4 as reported by Soost and by Moens do not appear to be reconcilable. Soos1's analysis of aS4 indicates that the defect involved is of the same type as that of as}; Moens' analysis implies instead that aS4 is of the "sticky" type discussed below.



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Finally, there is one case in Hypochaeris radicata (533) in which the mutant appears to control chiasma formation on a chromosomal basis. The mutant is recessive; pachytene synapsis is normal, but chiasma formation generally fails for one specific homologue pair. When this pair is achiasmate, the number of chiasmata per bivalent for the remaining three bivalents is increased slightly. When it is chiasmate, the number and locations of chiasmata per bivalent, including the specific pair, are normal. The net result is that the total number of chiasmata per cell in the mutant equals that of wild type. Parker (533) suggests that the defect involves some function(s) required for exchange on a chromosomal basis; if the function is per formed, chiasma formation is normal, but if it is not performed, chiasma formation fails. Since the cytology of postprophase stages in pollen mother cells is adequate in nearly all plant species, there is information on the events from metaphase I on for essentially all asyndetic mutants. In addition to the univalents by which mutants are characterized, most asyndetic mutants also exhibit elongated or mUltiple spindles, failure of congression, lagging univalents, misdividing univalents, and the formation of micronuclei and/or restitution nuclei. That these abnormalities are indirect effects of the mutants (resulting from the increased frequency of univalents) is indicated by (a) similar aberrant behavior in nonmutant cases in which asyndesis results from numerical or structural aberra tions; (b) a correlation between the frequency of univalents and the types of later meiotic abnormalities in mutants with variable expression; and (c) equivalent mei otic abnormalities in mutants of the same relative strength in different species (29, 520). In general, as pointed out by Prakken (473), the frequency of univalents is a good predictor of subsequent meiotic behavior in most forms. If there are few or no bivalents, univalents do not congress, divide equationally, or misdivide; the first division spindle(s) is frequently abnormal, but the second division is relatively normal. If, on the other hand, bivalents are present, the spindle is normal, univalents tend to congress (although frequently late), divide equationally and/or misdivide at the first division, and the second division is frequently irregular. Together, these observations suggest that normal organization and functioning of the spindle at both meiotic divisions is dependent on the presence of normally organized chromosomes --either as bivalents at meiosis I or as undivided univalents at meiosis II. There is, however, much variability among species. Thus, in Vicia (477) no univalents divide equationally, while in Oenothera (472) all univa1ents divide equationally. In addi tion, there is variability owing to genetic differences (496), and possibly to different mutants within a species (508). Most asyndetic mutants exhibit abnormal chromosome condensation at meta phase I with the univalents typically more condensed. and bivalents less condensed. than normal. There are, however, several mutants in which abnormal condensation is emphasized. The first such mutant reported was long in Matthiola incana (535539), in which bivalents at metaphase are longer than normal. Somatic chromosome condensation is normal, but there is evidence of fragmentation during the premeiotic THE CONSEQUENCES OF ASYNDESIS


104


mitosis of pollen mother cells. The frequency of rod (monochiasmatic) bivalents is elevated in the mutant at both diakinesis and metaphase, indicating an initial failure of short arms to participate in chiasma formation. However, the number of chias mata per bivalent at diakinesis and metaphase is not reduced. Similar condensation defects have been noted in an asyndetic rye line in which one plant had chromo somes less contracted than normal (540) and a plant with long metaphase chromo somes in barley (541). In the elongate mutant (el) in Zea mays (542, 543). the chromonemata are relatively uncoiled at both meiotic divisions of microsporogenesis. Segregation dur ing microsporogenesis is normal, although there is occasional centromere mis division and neocentromere activity at anaphase II. The haploid spores may undergo a supernumerary mitosis without chromosomal replication immediately after the quartet stage. Although duets of presumptive unreduced cells were ob" served in interphase, diploid pollen was not detected either cytologically or ge netically. On the other hand, el acts in megasporogenesis to produce some diploid, or near diploid, eggs. Segregation of centromere-linked markers indicates that most of the diploidy results from failure of equational separation of centromeres (542, 543); however. approximately 20% results from failure of reductional separation (543). It has been suggested (542, 543) that the diploid eggs result from meioses in which there is but a single division; however, whether the decision "reductional versus equational" is determined at the cellular or at the chromosomal level has not been determined (543). Nel (543) observed that both sexes exhibit increases in recombination in regions near the centromeres although the magnitudes of the increases differ for the different chromosomes examined. The pattern of response is similar to that observed from the effects of the Knob- l 0 chromosome, of B chromosomes, of sex, and of the asynaptic mutant (543). In the case of Knob- 1O (544, 545) and asynaptic (48 1), alterations in recombination parallel alterations in the extent of synapsis, suggesting the possibility of a synaptic effect of el as well. In contrast to the undercondensation produced by the mutants just considered, bivalents in the mutant short chromosome in Hordeum vulgare (546) are more condensed than normal at late diakinesis; they are, however, normal or even ex tended in length at pachytene. Univalents are present at metaphase I in this mutant, suggesting either premature complete terminalization of chiasmata or, possibly, a defect in chiasma formation. Somatic chromosomes are normal. That abnormalities in condensation are not exclusively the result of exchange defects is shown by plants in Alopecurus (49 1) that had either long or short chromosomes, but normal chiasma frequencies and no segregational difficulties. MUTANTS AFFECTING CHROMOSOME INTEGRITY Although anaphase bridges and chromosome fragments are reported as minor features of the phenotypes of many of the asyndetic mutants we have discussed, in these cases the effects are likely the result of misdivision or equational division of univalents (4) and not of alterations in either the quality of the chiasmata (reciprocity, homology) or in the



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maintenance of chromosomal integrity. In contrast, we now examine prophase defective mutants that do result in frequent chromosome breakage. The first category of such mutants is characterized by the presence of frequent bridges and fragments at anaphase I and II that appear to arise from defective exchange events. Typical of such mutants are four (229A, 231, 2805, and 3807) in Pisum sativum that, in addition to frequent bridges and fragments at both anaphase I and II, also reduce the frequency of chiasmata (526, 547). It is suggested, following a proposal by Lewis & John (548), that the bridges and fragments reflect faulty or incomplete performance of the processes of exchange (526, 547). That such bridges arise from abnormalities in chiasma formation is strongly supported by Klein's (526) observations that the frequency of such bridges is directly correlated with the frequency of chiasmata and that the size distribution of the fragments produced closely parallels the distribution of distances between the tips of chromosomes and the sites of regular (reciprocal) chiasmata. This suggests that, in the mutant, the chiasmata may be reversed (U type). Similar evidence has been presented by Jones (549, 550), who observed that in both normal rye (see also 55 1 , 552) and in a genotype that grossly altered the distribution of chiasmata, the distribution of V-type chiasmata parallels that of regular chiasmata. Although, to our knowledge, clearly documented mutants of this type have not been reported in other species, plants exhibiting high frequencies of anaphase bridges and fragments and decreased numbers of chiasmata have been reported in several species (524, 553-560). The remaining mutants that disrupt meiotic chromosome integrity do not appear to be limited to causing disruptions at the sites of exchange; these mutants fall into two categories-"stickies" and "fragmenters." Sticky mutants are characterized by generalized chromosomal clumping during early prophase. In the archetypical sticky mutant, sf in Zea mays (56 1 , 562), chromosomes do not individualize from the synizetic knot ( zygotene); the dense mass of chromatin appears to be torn apart mechanically during anaphase I and numerous bridges and acentric fragments are present. Individualized chromatin bodies are more common at the second meiotic division than at the first, but, again, chromatin bridges and acentric fragments occur. The frequency of transmissible fragments, reciprocal translocations, and new mutations is greatly increased among the few progeny of homozygous Sf plants. Mitotic chromosome stability is also affected in homozygous st tissue; the frequencies of sectoring in vegetative tissue and scarring and sectoring in endosperm are very high, indicating elimination of chromosomes or chromosome fragments. Deficiencies and fragments are observed at mitotic metaphase in root tips, although the chromosomes are not visibly sticky. The histone/DNA ratio is normal (563). Beadle (562) enumerates the striking similarities between the effects of st and the consequences of X irradiation in plants. Schwartz (562a) reports a less drastic allele, st', in which stickiness and sectoring are primarily limited to the endosperm; st' is temperature-sensitive. Johnsson (49 1) describes a sticky mutant in Alopecurus myosuroides in which an occasional highly abnormal "bivalent" may be distinguishable; the configurations are asymmetric and frequently appear to involve more than two chromosomes. The =


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mutants A 11 in Viciafaba (477) and the aS4 in Lycopersicon esculentum examined by Moens (5 14) appear to be representative, though less drastic, examples of the sticky group. Martini & Bozzini (564) have analyzed a sticky mutant in durum wheat in which somatic chromosome integrity is apparently normal. The mutant, 211, in Pisum (499) that exhibits multiple meiotic abnormalities including prolonga tion of meiosis, chromosome breakage, stickiness, and degeneration may also be of this type. Single plants exhibiting a sticky phenotype have been reported in several species (565-568). In Collinsia tinctoria there is another mutant, cst, that exhibits a sticky phenotype (52 1 , 569). In cst, chromosomes are clumped and overly condensed at pachytene. In occasional cells extreme fragmentation occurs. Even though chromosomes may have individualized by metaphase I, orientation and movement frequently fail to occur. The authors note that the sticky phenotype exhibited by cst is similar to that observed when zygotene-pachytene DNA synthesis is blocked during lily micros porogenesis (37). cst is unique among meiotic mutants in that it has an allele, Cds, that exhibits a different phenotype; plants homozygous for C ds exhibit marked asyndesis. cst/cds has the sticky phenotype of cst, suggesting that cst is the less defective allele. A final phenotype indicative of a defect in a function necessary for maintaining meiotic chromosome integrity-an extreme, nonlocalized, fragmentation of all chromosomes-is characteristic of the mutant as-1 in Brassica campetris (467). In as-J, pachytene synapsis is absent, separation is equational at anaphase I, and meiosis II is absent. Fragmentation is also occasionally seen in cst in Collinsia (569) and in short chromosome in Hordeum (546). In Triticum, the gene fr (fragmenta tion) (485) exhibits a normal phenotype through metaphase I; by anaphase I, however, up to 70 fragments are seen. Chromatin bridges are common, particularly at anaphase II. No division occurs in the microspores and the pollen are sterile. Meiosis I Spindle

The mutant dv (divergent spindle) in Zea mays (436) exhibits a highly aberrant meiotic spindle in microsporogenesis. Rather than converging to the two poles, spindle fibers are parallel or divergent, and the spindle may be greatly elongated. Congression and disjunction of bivalents are normal, but owing to the divergence of the spindle, the chromosomes fail to converge at the poles. Each chromosome or group of chromosomes forms a nucleus; each nucleus, regardless of the number of chromosomes, goes through the prophase II stages and produces its own spindle at metaphase II. The various spindles in a given dyad cell may fuse if parallel, although the various spindles are frequently not parallel. The second division spindles may also be divergent. Consequently, there may be more than four spores per "tetrad," and most (42-95%) microspores are multinucleate. However, it appears that pollen development and function are normal even in multinucleate microspores, provided that the haploid complement is present. The first pollen mitosis typically has a single, biacuminate spindle, although divergence at the tube-nucleus pole was occasionally observed. Clark (436) suggests that the normality of this spindle results from a definite spindle orientation at this division.



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dv is the only sex-specific mutant considered in this section; it is female-fertile and semisterile as a male. Female meiosis has not been examined cytologically. It is included for two reasons: (a) its existence suggests a possible difference in the genetic control of meiotic and mitotic spindle morphologies [mitotic spindles in dv are of the normal barrel shape (436)]; and (b) male and female meiosis in com differ in the orientation of the second-division spindles; in males, the second-division spindles are perpendicular to the plane of the first division, whereas in females the two divisions are colinear. The pollen sterility in dv is apparently due entirely to aneu ploidy (436) which appears to result solely from failure of proper orientation of second-division spindles; all other divisions distribute chromosomes regularly to two ends of the cells. Thus, the female fertility of dv might be due simply to the normal difference between the orientations of the second division spindles in the two sexes. Two single plants in Agropyron (570) exhibited divergent metaphase I spindles similar to those of dv. That the meiotic and mitotic spindles may be at least partly under separate control is further suggested by the mutant m in Clarkia (57 1), in which approxi mately half of the cells have two complete spindles at metaphase I. Meiosis II is evidently normal. Entry into Meiosis II

The phenotype of the mutant dy (dyad) in Datura stramonium demonstrates that the entry into the second meiotic division is under genic control (572). In dy, the first meiotic division is normal in both megasporogenesis and microsporogenesis, but no second division occurs: telophase I is followed by a prolonged interphase during which postmeiotic mitotic replication is accomplished. At the time of the first gametophyte mitosis, the chromosomes, each with two chromatids, are present as closely juxtaposed pairs. Thus, meiotic chromatid separation, which normally oc curs at anaphase II, is here delayed until the first postmeiotic mitosis. Subsequent mitoses are normal in both sexes and diploid spores are formed. The mutant is leaky; in 1-5% of meioses, a normal second division occurs, and, when it does, it generally occurs in both dyad nuclei suggesting that this locus acts before cytokinesis of the first division. Second Division

Normally, sister centromeres do not show autoorientation until metaphase II and do not separate until the onset of anaphase II. As already discussed, univalents may show precocious autoorientation and chromatid separation at metaphase-anaphase I. That the normal delay of these processes until anaphase II involves genetically specified events is clear from the existence of mutants in which these processes occur precociously. These include pc [precocious centromere (chromosome) division] in tomato (573), Lamm's mutant in tomato (574), and Johnsson's mutant in Alopecu rus mysuroides (49 1). The phenotypes of these three mutants are similar (the two tomato mutants could not be tested for allelism). In all three mutants, sister chroma tids are separate at prophase II, tend to remain adjacent until anaphase II, but then move to the poles randomly. They differ primarily in the time of separation (John-

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sson's during late anaphase I, Lamm's during telophase I, pc usually during inter kinesis) and also in that a metaphase II plate is not formed in 10hnsson's mutant, but is formed in Lamm's mutant and in pc.


Postmeiotic Mutants

Most mutants whose first phenotypic effect is manifested after the completion of the second meiotic division appear to be defective in gametogenesis and hence are outside the scope of this review. Mutants of one class, however-the polymitotic mutants-may be defective in a meiotic function, namely the termination of the meiotic cycle of divisions and the reentry into the mitotic cycle. In wild-type microsporogenesis in maize, the telophase II nuclei enter a prolonged interkinesis before initiating the gametophyte mitoses. In po (polymitotic) maize (575-577), however, prophase chromosome condensation for the first pollen mitosis occurs very soon after telophase II. That there has been no intervening DNA synthesis is evidenced by the singleness of the chromosomes. The univalent chromo somes are distributed all along the spindle and appear to move to the poles indepen dently of one another. The first supernumerary division may be followed by up to five additional supernumerary divisions, all without chromosome replication; appar ently, as long as there is at least one chromosome present, the cell can divide. Examples of similar polymitotic behavior have been observed in several other plant species (468, 49 1 , 578). Beadle (576, 577), noting the similarity between the supernumerary divisions in po and meiosis I in haploids, suggested that the defect in po involves a function that controls the timing of cell division. However, because the second meiotic division is unique in that it is the only division in the life cycle that is not preceded by chromosome replication, and because entry into this special division is under genic control (as evidenced by the mutant, dy), it is ponderable that the function of the wild-type allele of po is that of ensuring reentry into the normal (chromosome replication before division) division cycle. Under this view, the supernumerary divisions are effectively extra meiosis lIs. MAN Owing almost certainly to limited pedigree data, no proven examples of meiotic mutants have been exhibited in humans. There are, nevertheless, four kinds of suggestive evidence worth noting. The first, and weakest because susceptible to several interpretations, is the nonrandom clustering of chromosomal abnormalities within kindreds; the second consists of a number of cases of heritable changes in morphology of specific regions of mitotic chromosomes; the third is the existence of gene-controlled disorders associated with mitotic chromosome instability and/or defective DNA repair processes similar to those of recombination-defective meiotic mutants in other species; the fourth consists of instances of meiotic anomalies in several sterile males with some evidence that these represent meiotic mutants segre gating in families.



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The nonrandomness of chromosomal abnormalities and its possible interpreta tions have been discussed by Hecht et al (579), who note that there are three relevant kinds of observations-persons with double chromosomal abnormalities, single fam ilies with unlikely combinations of chromosomal abnormalities, and population studies in which families detected because one member contains a chromosome abnormality are found to have another member with a different abnormality. Of these, the last represents the strongest evidence for a familial tendency towards meiotic irregularities which in turn might imply the presence of a meiotic mutant. Such studies include kindreds with two cases of Klinefelter's syndrome among the sibs of ten XXY men (580, 581), one sib and one cousin with Down's syndrome in the families of three XXX women (582), one XO individual among the sibs of 37 people with Down's syndrome (583), three sibs and one uncle with Down's syn drome in the families of 60 trisomic-D\ or trisomic-I 8 individuals (579, 584, 585), and one XYY brother among the sibs of 30 XXY men (586). There are many reports of single families which contain surprising combinations of chromosomal anomalies; the authors frequently suggest a meiotic mutant as the cause. These include autosome-sex chromosome combinations (58 1, 587-595), autosome-autosome combinations (579, 596-599), and sex chromosome-sex chromosome combinations (586, 593). Similarly, multiple instances of Down's syn drome among progeny of young mothers (600) and the same sex chromosome anomaly among sibs (586) are more frequent than expected by chance. Finally, Hamerton et al (601) report that of 1 3 3 males with Down's syndrome, two were also XXY. In summary, it seems likely that chromosome anomalies are nonrandomly clus tered. It is, however, by no means clear to what extent, if any, this nonrandomness is caused by segregating meiotic mutants. Other possibilities for which some evi dence exists are physiological, viral, or other environmental factors predisposing to anomalous chromosome behavior (602-606); the possibility that nonhomologous chromosomes can segregate from one another in man as they do in Drosophila (607, 608); and the obvious technical problems of undetected translocations, parental gonadal mosaicism, and ascertainment bias. There are a few known cases of heritable cis-dominant effects on the mitotic morphology of specific chromosome regions-perhaps regions containing repeated DNA sequences (609). These include a region of uncoiling (6 1 0-6 12), an abnormal secondary constriction with possible chromatid breakage (61 2-61 5), and regional abnormal DNA synthesis (616-618). Whether such cases have meiotic effects, per haps similar to those of cog mutants in Neurospora, is not yet known. A locus involved in the control of recombination on chromosome 2 1 is suggested by the observation that patients with Down's syndrome (owing either to trisomy 2 1 or to an unbalanced translocation) have a somewhat increased number of chiasmata per cell (6 19). That this is not a general consequence of hyperploidy is indicated by normal chiasma counts in XYY males (620, 62 1) and in individuals with "extra, unidentified small centric chromosomes" (6 19). A possible autosomal dominant mutation with mitotic effects on chromosome stability has been reported by Zellweger & Abbo (594). In this case, the proband


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was a female with Down's syndrome who showed mosaicism for a DID transloca tion, a DIG translocation, and for XX/XO tissue. In addition, her brother was an XYIXO mosaic and both her father and paternal grandfather were mosaic for a DID translocation. Meiotic studies have not been done in this case. Six additional genetic conditions in man with effects on chromosome stability in mitosis are Bloom's syndrome (622, 623), Fanconi's anemia (624), Louis-Bar syn. drome (625), xeroderma pigmentosum (626, 627), incontinenetia pigmenti (628), and porokeratosis of Mibelli (629). While these conditions are similar in that they result in chromosomal instability, they differ from one another in many ways, and, moreover, any or all of them may be genetically heterogeneous. In the case of Bloom's syndrome, fibroblasts and blood lymphocytes exhibit recombination between homologues and nonhomologues, high frequencies of sister strand exchange, centric and acentric chromosome fragments, anaphase bridges, abnormal DNA synthesis, and pseudodiploid clones (630-635). Moreover, German (636) reports that although sexual development in Bloom's syndrome appears nor mal, of three affected men who have married, none has children and one evaluated for fertility had no active sperm. He suggests, therefore, that meiosis may well be abnormal. In the case of Fanconi's anemia, chromosome breakage has been observed both in fibroblasts (630) and in blood lymphocytes (624, 637) but not in all patients

(638, 639). It has been suggested that the condition results in a defect in a process essential for the repair of DNA cross-links (640, 641). A comparison of Fanconi's anemia with Bloom's syndrome (642) showed that while both conditions produced chromosomal aberrations, the frequencies and types of aberration differed markedly in the two cases. In the case of Fanconi's anemia there is no meiotic information. In the case of Louis-Bar syndrome, chromosome breakage and pseudodiploid clones in blood lymphocytes have been reported (625, 632, 643-646), but again whether as regular features of the condition is not yet clear (632, 644). Moreover, although X rays induce a high incidence of chromatid aberrations in mutant cells (647), this is not a consequence of a reduced ability to repair single-strand breaks (648). Meiosis in this case has not been examined. In the case of xeroderma pigmentosum, there is almost no chromosome breakage and perhaps only an occasional pseudodiploid clone (626). In addition, Hulten, et al (649) examined a mutant male and found that he had a normal chiasma frequency, and Wolff et al (650) found that mutant cells have normal frequencies of sister chromatid exchanges. Despite these observations, the defect in xeroderma pigmentosum is likely in a DNA repair system since mutant cells are UV-sensitive (627); for this reason, the condition is noted here. A kindred containing two sisters and a maternal aunt with incontinentia pigmenti has been studied cytologically in lymphocyte cultures (628). The abnormalities consisted of frequent chromatid and chromosome gaps and breaks. The authors attribute the chromosomal instability to the gene causing the disease although the cytological effects were observed in the propositus and her phenotypically normal mother, but not in her mutant sister. Finally, fibroblast cultures from four patients with porokeratosis of Mibelli were examined cytologically (629); a high proportion exhib ited chromosome aberrations of a variety of types with no specific aberration being



III

invariably present. No meiotic studies have been done for either of these last two conditions. The cytological basis of infertility in humans has been studied almost exclusively in males owing to the opportunity for biopsy. We have been able to find reports of abnormal meiotic chromosome behavior in 1 7 infertile males with apparently nor mal karyotypes who may, therefore, carry meiotic mutants. de Grouchy & Lum broso (65 1) report an azoospermic male in whom half of the primary spermatocytes examined had 46, rather than 23, tetrads; no multivalents were observed. Dutrillaux & Gueguen (652) report a case showing a low chiasma count in addition to polyploid cells. Among 50 karyotypically normal but azoospermic males (619, 653-655), eight exhibited spermatogenic arrest, one at pachytene and seven at diakinesis-metaphase I. Among these seven, two had normal chiasma counts but did show some univalents and fragments, two had only a few degenerating cells at diakinesis and thus chias mata could not be counted, and two showed pairing abnormalities, a reduced chiasma count, multivalents, univalents, and fragments. Furthermore, one of these men produced rare sperm that had a DNA content consistent with random orienta tion and movement of all the chromosomes in the complement. In the last of these seven men, in addition to a low chiasma count and asynaptic regions, there was an increased proportion of cells in late leptotene - early zygotene, an absence of the XY body at pachytene, and an incomplete and morphologically abnormal synaptonemal complex. Genetic causation in these cases is suggested by the facts that two of these azoospermic men were from consanguinous marriages and another had a childless sister. Another putative meiotic mutant in an azoospermic but otherwise healthy and normally developed man has been reported by Chaganti & German (656). The meiotic anomalies include an absence of chiasmata, unpaired segments at pachyt�ne, and no stages beyond diakinesis. That this is a genetic condition (possibly X-linked) is suggested by the fact that the patient's mother's brother and his mother's sister's son are also sterile. Skakkebaek et al (657) report on the meiotic cytology of 1 8 control and 74 infertile men with normal karyotypes. Among the sterile males, three showed spermatogenic arrest before the second meiotic division and one of these also exhibited meiotic anomalies in meiosis I. One other sterile male showed meiotic arrest at metaphase II. Simiarly, Koulischer & Schoysman (658) examined 202 sterile males. Among these, one had a low chiasma count and another showed "altered pachytene pairing" of one to several bivalents per cell, polyploid metaphase I cells, degenerating meta phase I cells, and no metaphase II cells. A not uncommon feature in these cases is the observation of polyploid sper matocytes. Pogosianz & Brujako (659), however, note that polyploid meiocytes of various kinds have been reported not only in fertile men (657, 660-662) but also in males of other mammals (663-665); they suggest, therefore, the possibility that this might be a common developmental abnormality during mammalian spermiogenesis. Another common observation is that pairing defects are often accompanied by an


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absence of cells in the second meiotic division. Beechey (666) has reported on a sterile male mouse that exhibited an abnormal dissociation of only the XY bivalent that had been paired at pachytene but was not by metaphase I . There were no stages beyond metaphase I. Beechey suggests, therefore, the possibility that XY associa tions are necessary in order that meiosis progress into the second division. Both these points are also discussed by Skakkebaek et al (657). Finally, suggestive evidence for the occurrence of meiotic drive associated with aberrations for chromosome 9 in man have been reported by a number of workers (667-67 1). The observations to date are rather similar to those of preferential segregation of t-Ioci in mice (672) and segregation-distortion in Drosophila (38), which could mean that although abnormal chromosomes 9 have been the indicators of the segregation patterns, the basic phenomenon may be genic. ACKNOWLEDGMENTS

The authors are very grateful to Drs. T. Ashley, R. S. K. Chaganti, S. Fogel, J. Haemer, L. H. Hartwell, H. Hoehn, G. Jones, C. Lawrence, D. D. Perkins, L. & S. Prakash, R. K. Mortimer, M. M. Rhoades, D. Schwartz, and H. Stem for having read and criticized sections of this review. In addition, for allowing us access to unpublished work, we would like to thank our colleagues: W. Boram, 1. Boyd, S. Fogel, M. Green, J. Haber, J. Haendle, Y. Hiraizumi, R. Holliday, D. Lindsley, J. Mason, P. Moens, R. Mortimer, D. Perkins, L. & S. Prakash, H. Roman, B. Slatko, P. Smith, and T. Wright. Literature Cited 1 . Gowen, M. S., Gowen, J. W. 1922. Complete linkage in Drosophila melano gaster. Am. Nat. 56:286-88 2. Gowen, J. W. 1928. Mutation, chromo some nondisjunction and the gene. Science 68:2 1 1-12 3. Gowen, J. W. 1933. Meiosis as a genetic character in Drosophila melanogaster. J. Exp. Zool 65:83-106 4. John, B., Lewis, K. R. 1965. The mei otic system. Protoplasmologia, Band VI/F/1 . Vienna & New York: Springer 5. Nicoletti, B. 1968. II controllo genetico della meiosi. Aui Assoc. Genet. Ital 1 3 : 1-7 1 6. Emerson, S. 1967. Fungal genetics. Ann. Rev. Genet. 1 :201-20 7. Catcheside, D. G. 1968. The control of genetic recombination in Neurospora crassa. In Replication and Recombina tion o/Genetic Material, ed. W. J. Pea cock, R. D. Brock, 2 1 6-26. Canberra: Aust. Acad. Sci. 8. Holliday, R. 1968. Genetic recombina tion in fungi. See Ref. 7, pp. 1 57-74 9. Fincham, J. R. S. 1 970. Fungal genetics. Ann. Rev. Genet. 4:347-72

10. Fogel, S., Mortimer, R. K. 1 97 1 . Recombination i n yeast. Ann. Rev. Genet. 5:2 1 9-36 1 1 . Putrament, A. 1 9 7 1 . Recombination and chromosome structure in euca ryotes. Genet. Res. 1 8:85-95 12. Haber, J. E., Halvorson, H. O. 1972. Regulation of sporulation in yeast. Curro Topics Dev. Bioi. 7:61-82 13. Stadler, D. R. 1973. The mechanism of intragenic recombination. Ann. Rev. Genet. 7: 1 1 3-27 14. Tingle, M., Singh Klar, A. J., Henry, S. A., Halvorson, H. O. 1973. Ascos pore formation in yeast. Symp. Soc. Gen. Microbiol 23:209-43 1 5 . Zickler, D. 1973. Fine structure of chromosome pairing in ten Asco mycetes: meiotic and premeiotic (mi totic) synaptonemal complexes. Chro mosoma 40:401-16 1 6. Holliday, R. 1974. Molecular aspects of genetic exchange and gene conversion. Genetics 78:273-87 17. Whitehouse, H. L. K. 1 974. Advances in recombination research. Genetics 78:237-45


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Genetic evidence suggests that Spata22 is required for the maintenance of Rad51 foci in mammalian meiosis.

Hormonal control of meiosis: specificity of the 1-methyladenine receptors in starfish oocytes.

Hormonal control of reinitiation of meiosis in starfish. The requirement of 1-methyladenine during nuclear maturation.

Genetic Interactions Between the Meiosis-Specific Cohesin Components, STAG3, REC8, and RAD21L.

Genetic analysis in the dinoflagellate (Crypthecodinium (Gyrodinium) cohnii: evidence for unusual meiosis.

Genetic control of the immune response.

Towards the genetic control of invasive species.

The effect of immigration on genetic control.

The genetic control of immune responses.

Genetic Control Of Malaria Mosquitoes.

Genetic control of diabetes mellitus.

Plant genetic control of nodulation.

The meiosis-specific modification of mammalian telomeres.

Morphogenesis of the synapton during yeast meiosis.

Genetic regulation: the Lac control region.

IME4, a gene that mediates MAT and nutritional control of meiosis in Saccharomyces cerevisiae.

Genetic control of fatty acid metabolism, especially study of genetic control of cholesterol.

Genetic conflicts: stronger centromeres win tug-of-war in female meiosis.

The molecular biology of meiosis in plants.

The transcriptome landscape of early maize meiosis.

Another piece of the meiosis puzzle.

The "Cost of Meiosis": is there any?

Evidence that masking of synapsis imperfections counterbalances quality control to promote efficient meiosis.

Genetic control of invasive plants species using selfish genetic elements.