IN MEMORIAM

Of Mice and Cats (both calico): Mary F Lyon, FRS (1925–2014) John M. Opitz* Pediatrics (Medical Genetics), Pathology, Human Genetics, Obstetrics and Gynecology, University of Utah School of Medicine, Salt Lake City, Utah Manuscript Received: 8 April 2015; Manuscript Accepted: 19 April 2015

What is it about us mere humans to be so deluded about our evanescence as to allot a tot of extra life to those most meritorious in the service of humanity, hanging others “at Tyburn” and betting the rest of us will attain a “normal” span of life? And then again, suddenly, reality kicks us hard in the gut, unbelieving, hurting until pain is relieved by grief. What, Mary Lyon no more? As inconceivable as that seems involving Mary as a person, it comes as an enormous relief to realize that the conceptual revolution wrought by Dr. Mary Frances Lyon, the scientist (Fig. 1), is not only imperishable but will continue to flourish exuberantly like one of those centuries-old floribunda hedge roses glorious in June-time color and fragrance, home to nesting thrushes and to a thoughtful mother hedgehog with her six children. In her half-century of work at Harwell Mary Lyon

How to Cite this Article: Opitz JM. 2015. Of mice and cats (both calico): Mary F Lyon, FRS (1925–2014). Am J Med Genet Part A 167A:1957–1961.

engendered more than a dozen directions of research from the behavior of X-chromosomes in gonosomal aneuploidy, in X–X, X– Y, and in X-autosomal translocations, to dosage compensation, to carrier detection in heterozygotes of X-linked mutations and the clonal nature of mammalian females and its implications. As such the effect Mary Lyon and the Lyon hypothesis (L.H.) has had on Western Biology can be compared to that of Aristotle (epigenesis), Harvey (circulation), Darwin and Wallace (natural selection), Mendel (segregation), Boveri and Sutton (the chromosomal theory of heredity), then Mary Lyon and the theory of dosage compensation of X-linked genes in mammals. That surely is enough accomplishment for a single person of normal stature, sharp intellect, and kindly nature.

1962 I well remember the day in 1962 having just begun my fellowship in Madison when Klaus Patau burst out of the men’s room on the fourth floor of the SMI building where we were then housed before moving into the new Genetics Building on Henry Mall, ran (literally) into me, expostulating in great excitement: “Have you heard…seen the last issue of the American Journal of Human Genetics?” I had not, and over the next hour or so was transfixed with awe and intellectual pleasure as Patau laid out for me what became known instantaneously as the Lyon hypothesis. It took a

FIG. 1. Mary F. Lyon at age 48; photo taken in 1973 upon election to the Royal Society. Copyright: Godfrey Argent studio; courtesy of the Royal Society.

Ó 2015 Wiley Periodicals, Inc.

This article was published online on 5 May 2015. An addendum was subsequently added. This notice is included in the online and print versions to indicate that both have been corrected on 23 May 2015.  Correspondence to: John M. Opitz, Department of Pediatrics, 295 Chipeta Way, Salt Lake City, UT 84108. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 5 May 2015 DOI 10.1002/ajmg.a.37141

1957

AMERICAN JOURNAL OF MEDICAL GENETICS PART A

1958 while for the well-neigh miraculous explanatory power of that postulate to sink in and to envision its possible predictions. So that when a gifted graduate student, Mary Jo Ylitalo Sullivan [Sullivan, 1972] began to work on the Lyon hypothesis under my direction in 1972, the resulting thesis required 187 pages to summarize progress till then on mammalian dosage compensation in general, on genes translocated to the X, the postulated or observed increased phenotypic variability in heterozygotes for X-linked mutations (as compared to the hemizygotes), evidence of variegation in humans and other mammals, cytological and biochemical evidence for the hypothesis. Rarely, or perhaps never until that time, had a mouse geneticist had such a massive influence on human genetics. The human geneticist though quickest to appreciate the merits of the Lyon hypothesis and its potential application to humans was Victor McKusick [1962a], who in 1962 published a beautiful review on the human X-chromosome for the Quarterly Review of Biology, fashioned into a book [1964] and condensed into an editorial for the Annals of Internal Medicine. As I recall, it was the tabulation of Xlinked disorders from 1962 (pp 81–113) that was the initial impetus for McKusick’s MIM, later OMIM. Also his close affiliation with the Jackson labs, co-sponsor of the annual summer Bar Harbor course, made the rest of us appreciate the pertinence of mouse biology to humans over and above their abominable stink and virtual absence of detectable intelligence (give me rather a decent rat!).

Lyon, 1961 In 1962 Patau was doubly chagrined having not himself thought of this consequence of the Barr body in (most) cells of female mammals and having missed Mary Lyon’s succinct initial one page summary of the hypothesis in Nature in 1961. To quote her in extenso [Lyon, April 22 1961]: “The present communication suggests that the evidence of mouse genetics indicates: (1) that the heteropyknotic Xchromosome can be either paternal or maternal in origin, in different cells of the same animal; (2) that it is genetically inactivated. The evidence has two main parts. First, the normal phenotype of XO females in the mouse shows that only one active X-chromosome is necessary for normal development, including sexual development. The second piece of evidence concerns the mosaic phenotype of female mice heterozygous for some sex-linked mutants. All sex-linked mutants so far known affecting coat colour cause a “mottled” or “dappled” phenotype, with patches of normal and mutant colour, in females heterozygous for them. At least six mutations to genes of this type have been reported, under the names mottled, brindled, tortoiseshell, dappled, and 26K. They have been thought to be allelic with one another, but since no fertile males can be obtained from any except, in rare cases, brindled, direct tests of allelism have usually not been possible. In addition, a similar phenotype, described as “variegated,” is seen in

females heterozygous for coat colour mutants translocated on to the X-chromosome. It is here suggested that this mosaic phenotype is due to the inactivation of one or other X-chromosome early in embryonic development. If this is true, pigment cells descend from cells in which that chromosome carrying the mutant gene was inactivated will give rise to a normal- coloured patch and those in which the chromosome carrying the normal gene was inactivated will give rise to a mutant-coloured patch. There may be patches of intermediate colour due to cellmingling in development. The stripes of the coat of female mice heterozygous for the gene tabby, Ta, which affects hair structure, would have a similar type of origin. Falconer reported that the black regions of the coat of heterozygotes had a hair structure resembling that of the Ta hemizygotes and homozygotes, while the agouti regions had a normal structure. Thus this hypothesis predicts that for all sex- linked genes of the mouse in which the phenotype is due to localized gene action the heterozygote will have a mosaic appearance, and that there will be a similar effect when autosomal genes are translocated to the X-chromosome.” Four months later Lyon had synthesized an astonishing body of material (82 references) in mice, cats, dogs, and humans for her 1962 paper in the American Journal of Human Genetics, the length of time between receipt of MS and its publication a probable reflection of the consternation it must have occasioned in the human genetics community, unused to serious reflection on the Tabby, Scurfy, Mottled, Brindled, Tortoiseshell mouse (or cat). My copy of Mary Lyon’s 1963 paper on “Attempts to test the inactive-X theory of dosage compensation” was a gift from F. Clarke Fraser, mouse and human geneticist, with his annotations, and the beautiful color plate of heterozygous dappled mice and those carrying Cattanach’s translocation. Generations of geneticists have been raised on Figure 1 from that publication (Fig. 2): See also Lyon [1974], Figure 4.4 in Migeon’s “Females are Mosaics” Migeon [2007] with Scott F. Gilbert, the distinguished developmental biologist, acknowledged as her student, thus, also Fig. 2.23 and Fig. 2.24 in Gilbert’s edition 10 Gilbert [2014] of calico mother Rainbow and her cloned calico kitten “CC.”

Boris As quoted above [Lyon, 1961], since only one active X chromosome is required for normal morphological development in the XO mouse and a normal male with XX/XY sex determining mechanism, then Lyonization in XXY males should result in a calico coat and a Barr body as in a normal female or, to put it another way, all calico male cats are expected to be XXY or variant thereof. Boris was initially loved as a biological curiosity and lurid subject of uncomprehending cocktail party chatter but then rapidly lost favor with his owners in Wisconsin as he began to spray.

OPITZ

1959

FIG. 2. “Diagrammatic representation of the inactive-X theory. The inactive X is represented as circular, and the active one as rod-shaped.” Fig. 1 of Lyon, 1963. Reprinted with permission from Genetic Research, Cambridge.

Whereupon, when offered, I bought him for $300–housed him in the animal facilities of the University of Wisconsin Anatomy Department where he received excellent care, could spray contentedly in all four heavenly directions, slept or ate most of the day, became grossly overweight, contracted a nasty case of diabetes and an unscheduled but peaceful death in his sleep, was embalmed and ultimately dissected, yielding nothing of interest except for a few variants which could have been no more than minor deviations from normal. Thus, Mary Lyon was correct—the extra X in this confirmed male calico cat was so effectively turned off (inactivated) as to enable normal morphological development (except for testes). But then I have never ceased to wonder why so many, if not all, human Klinefelter males have so many minor anomalies as to suggest an aneuploidy syndrome [q.v. Opitz, 2014]. A related point pertains to the XO mouse which, Lyon [1961] pointed out, allows normal development and makes the genetic coat color analysis clear. And yet, how many times have medical geneticists dealing with the human “XO” (45,X) condition in clinic or at autopsy wondered why such (Ullrich)-Turner syndrome girls are so abnormal when the mouse homolog appears so normal. If XO-ness is the genetic equivalent of complete inactivation of the second X, then why does the human Turner syndrome present as a sublethal aneuploidy syndrome? For an important discussion see Ashworth et al. [1991]. In any event, I doubt any of Mary Lyon’s cats, including “Cindy,” always calico, were males.

Disappointment …not pertaining to Mary Lyon who seems to have been serenely successful in all she tackled professionally, but to this writer, once a member of a committee charged with a faculty recruitment but then too young and lacking the stature required to convince fellow committee members to appoint Mary Lyon a professor in the Department of Medical Genetics at the University of Wisconsin. My papers concerning this matter are already in storage at the American Philosophical Society or may have been purged after a half century of committee service. My memory of those events (to be verified or clarified from collateral evidence) remains that Dr. Lyon was open to consider negotiations, but that the vigorous objections of a single distinguished faculty member influenced the majority of the committee to a No vote. As a former zoologist I had wanted so much to work more closely with Dr. Lyon, knowing from personal experience that corn and mammalian geneticists were much more likely to work with clinical, medical geneticists who were otherwise considered a second class lot but necessary evil in a department dominated by population and evolutionary geneticists.

Gr€uneberg It is a most pleasant reminder of Mary Lyon’s magnanimity and generosity to reread the footnote of her 1974 Review Lecture on the mechanisms and evolutionary origins of variable X-chromosome

1960 activity in mammals: “This paper is dedicated to Professor H. Gr€ uneberg, F. R. S., on his retirement from the Chair of Animal Genetics at University College London.” Gr€ uneberg is remembered as one of a group of brilliant geneticists and developmental biologists to leave Germany in the 1930s including Charlotte Auerbach (Edinburgh), Ursula Mittwoch (London), Gr€ uneberg, Salome Glu¨cksohn-Waelsch (New York), Victor Hamburger (St. Louis), Richard B. Goldschmidt, and Curt Stern (Berkeley), Walter Landauer (Connecticut). In the UK, Gr€ uneberg continued his work on genetic skeletal disorders “on animals,” mostly mice, rats, rabbits, but also Ancon sheep, cattle, dogs, chickens, etc. This work culminated in his beautifully illustrated text “The Pathology of Development” [1963], a morphologist’s delight and indispensable resource for everyone working in developmental pathology of the skeleton with its marvelous figures, definition of “quasi-continuous variations” (p. 243), and odd mistranslations of Plate’s [1910] concept “Pleiotropie” by one who should have known better (“pleiotropism,” taken over by McKusick). Lord Acton may be paraphrased to the effect that all men tend to blunder but that great men blunder greatly. The same might be said of Gr€ uneberg and his quixotic pursuit of the Lyon hypothesis. Basing himself initially (1966a) on the dental phenotype of the tabby (TA/þ, an X-linked trait) mouse he extended his analysis to human X-linked traits [Gr€ uneberg 1966a, b, 1967]. Thus, in 1967 he concluded: “Contrary to all claims made for them (for a summary see Lyon, 1966), none of these genes (taken one at a time and carried in a normal Xchromosome) provided any critical evidence in favor of the L.H. Indeed, those genes for which detailed information is available (mainly those in the mouse) behave in a way quite contrary to the L. H.” In their biographical memoir of Gr€ uneberg, Lewis and Hunt [1984] alluded severally to the man’s “single minded” nature, a virtue in performing meticulous scientific work but a potential vice if obsessive. Such obsessiveness may put blinders on an investigator, engender “convenient” forgetfulness, selective citation and verbose overkill, and a curious obtuseness in the face of intuitively obvious, convincing logic immediately and overwhelmingly accepted as incontrovertible by the community of biologists. In her interview with Gitschier [2010] Mary agreed that “Gr€ uneberg did…make things difficult in the early days of Xinactivation,” impressed as he was that Mary lacked the stature or required eminence to “put forward such a major idea.” And that he seems to have misunderstood the implications of “the sizes and shapes of stripes and patches” of different coat color in the heterozygotes as NOT requiring a single precursor cell in which case the stripes and patches would have been either purely mutant or non-mutant, not mixed. In their biographical note on Gr€ uneberg, Lewis and Hunt [1984] concluded “…that there is now little doubt that, with a few notable exceptions, the hypothesis of random X-inactivation as a mechanism of dosage compensation is essentially correct. This was recognized by Gr€ uneberg in a recent memorandum” (Published?). Rastan [2013] states that Mary Lyon’s election in 1973 to the Royal Society might have occurred sooner if Gr€ uneberg “had not initially disbelieved the Lyon hypothesis.” I myself am unsure of the outcome of the matter but remember vividly that while he was at it, Gr€ uneberg caused quite an uproar in the genetics community

AMERICAN JOURNAL OF MEDICAL GENETICS PART A taking aim at any and all supporters of Lyon, especially at those claiming to have found evidence for the Lyon hypothesis in heterozygote manifestations of X-linked conditions. That identified me as prime offender not just in my enthusiasm for the theory but claiming to have found, to me, convincing carrier manifestations in female transmitters of angiokeratoma corporis diffusum (Fabry disease) [Opitz et al., 1965] [Gr€ uneberg, 1967; p.245]. Again, my correspondence with Gr€ uneberg is in Philadelphia, but my recollection is that he finally gave up and stopped hounding me. In retrospect I wonder who else besides Mary Lyon and I were in his firing line at the time. Mary emerged quietly triumphant.

Mary Frances Lyon The information page of the UK Genetics Society (GS), dealing with prizes, gives the following biographical information on Dr. Lyon in connection with the Mary Lyon medal. Born in 1925 in Norwich, Mary developed an early interest in biology and went on to read Zoology, Physiology, and Biochemistry at Girton College, Cambridge in 1943 influenced also by writings of Waddington on genetics and developmental biology. Mary began PhD work with R. A. Fisher at Cambridge but moved to better mouse and lab facilities in Edinburgh under Falconer. After attaining her PhD Mary began work with T. C. Carter in Edinburgh to study the genetic hazards of radiation in mice with mutagenesis experiments. Carter’s group eventually moved to the MRC Radiobiology Unit at Harwell in Oxfordshire where Mary spent the rest of her professional life. There she not only pioneered work on the Lyon hypothesis but also brought the T-complex of mice under intense scrutiny. In collaboration with the David Whittingham lab at Cambridge Mary brought about FESA (Frozen Embryo and Sperm Archive), the only facility in the UK for the archiving and distribution of mouse strains. After her official retirement in 1986 Mary must have been pleased at the establishment in 2004 of the national MRC Mary Lyon Center at Harwell for functional mouse genomics. She may have even lived to see the establishment by the GS of the Mary Lyon medal, too small an honor for one, whom many I have known deemed ready for the Nobel Prize. Few in our field have been so fortunate to live to 89, enjoy lunch with a glass of sherry on Christmas day and to stop living during a peaceful nap (Rastan, 2015), I hope with a beloved girl calico cat like “Cindy” on her lap.

REFERENCES Ashworth A, Rastan S, Lovell-Badge R, Kay G. 1991. X-chromosome inactivation may explain the difference in viability of XO humans and mice. Nature 351:409–408. Gilbert SF. 2014. Developmental biology, edition 10. Sunderland MA: Sinauer. Gitschier J. 2010. The gift of observation: An interview with Mary Lyon. PLoS Genetics 6:e1000813. Gr€ uneberg H. 1963. The pathology of development. Oxford, Blackwell. Gr€ uneberg H. 1966a. The molars of the tabby mouse, and a test of the ‘single active X-chromosome’ hypothesis. J Embryol Exp Morphol 15:233- 244.

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Gr€ uneberg H. 1966b. More about the tabby mouse and about the Lyon hypothesis. J Embryol Exp Morphol 16:569–590.

McKusick VA. 1962b. On the X chromosome of man. Q Rev Biol 37: 1962 (entire issue)

Gr€ uneberg H. 1967. Sex-linked genes in Man and the Lyon hypothesis. Ann Hum Genet, London 30:239–257.

McKusick VA. 1964. On the X chromosome of man. AIBS. vii -141. Washington 6, D .C. Appendix: A catalog of X-borne mutations in man (pp 81–113).

Lewis D, Hunt DM. 1984. Hans Gr€ uneberg. Biograph Memoirs Roy Soc Publishing DOI: 10.1098/rsbm.1984.0008. Lyon MF. 1974. Mechanisms and evolutionary origins of variable Xchromosome activity in mammals. Proc R Soc London B 187:243–268. Lyon MF. 1963. Attempts to test the inactive-X theory of dosage compensation in mammals. Genet Res, Cambridge 4:93–103. Lyon MF. 1961a. Gene action in the X- chromosome of the mouse (Mus musculus, L). Nature 190:372–373. Lyon MF. 1961b. Sex chromatin and gene action in the mammalian Xchromosome. Am J Hum Genet 14:135–148. McKusick VA. 1962a. On the X chromosome of man. Editorial. Ann Int Med 56(6):991–996.

Migeon BR. 2007. Females are mosaics. Oxford, Oxford University Press. Opitz JM. 2014. Serendipity or prepared mind? Recollections of the KOP translocation (1967) and of one form of Perrault syndrome. Am J Med Genet Part C 166C:387–396. Opitz JM, Stiles F, Wise D, Gemmingen G, von Kierland RR, Race RR, Sanger R, Cross EC, DeGroot WP. 1965. The genetics of angiokeratoma corporis diffusum and its linkage to the Xg locus. Am J Med Genet 17:325–342. Rastan S. 2015. Mary F Lyon, Nature 518:36. Sullivan MJY. 1972. The Lyon hypothesis. MS Thesis (Medical Genetics), University of Wisconsin.

ADDENDUM At a recent EMBO Workshop at the University of G€ ottingen, Germany, Sir Richard Gardner, FRS, Universities of York and Oxford, kindly informed me that for the last ten years of her life Mary Lyon had experienced progressively disabling Parkinson disease. Death occurred without cat on lap. Professor Gardner confirmed that in the UK also there had been voices considering Dr. Lyon worthy of a Nobel Prize. John M. Opitz

Of mice and cats (both calico): Mary F Lyon, FRS (1925-2014).

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