Mammalian genetics Editorial overview Giovanna Camerino and Peter N. Goodfellow Biologica Generale e Genetica Medica, Pavia, Italy and Imperial Cancer Research Fund, London, UK Current Opinion in Genetics and Development 1992, 2:385-386 Genetic disease is a major cause of human suffering. One strategy for treatment of genetic disease has been to define the biochemical defect and to attempt rectification either by replacement of the missing protein or by modification of the individual's metabolism [1]. For m a w common genetic diseases this approach has been unsuccessful as the definition of the biochemical defect has been ditticult. In the past decade, an alternative strategy for the identification and cloning of genes responsible for genetic disease has been developed. In brief, the gene responsible for the disease is cloned based on its position in the genome. This approach was originaUy called 'reverse genetics' but fashions change and the pgeferred nomenclature is now 'positional cloning'. It was recognized by the community of 'gene mappers' that cooperative efforts to produce complete maps of the genome would greatly facilitate positional cloning of disease genes. In this issue, we have concentrated on the construction of genetic maps of man (Sefton and Goodfellow, pp 387-392; Cann, pp 393-399; Patterson, pp 400--405) and mouse (Chapman and Nadeau, pp 406-411) and have sought to illustrate how these maps have been exploited to study both human genetic disease and complex processes such as development and cancer. One of the first cooperative ventures for producing meiotic maps of the human genome was organized by CEPH (Centre d'Etude du Polymorphisme Humaine) (Cann). In addition to meiotic maps, several other types of maps are being constructed (Sefton and Goodfellow) and the integration of these maps requires increased collaboration and communication between scientists interested in the same region of the genome. A good example of progress through cooperation is provided by attempts to produce and integrate maps of chromosome 21 (Patterson). The ultimate map of the human genome will be a complete sequence, however, 3 x 109 bp is still outside the range of current technology. A possible compromise is to begin sequencing the expressed genes as defined by cDNA clones (Southem, pp 412-416). Genes recently cloned by positional strategies include those associated with Kallmann syndrome, the fragileX syndrome and myotonic dystrophy. Sufferers from Kallmann syndrome are unable to smell (anosmia) and have hypogonadism; this bizarre conjunction of symptoms is the result of a failure in neuronal migration during development. Not surprisingly, the KaUmann syn-
drome gene appears to encode a novel neuronal migration factor (Ballabio and Canlerino, pp 417-421). The fragile-X syndrome is a common cause of mental retardation and myotonic dystrophy and is an autosomal dominant disease that results in muscle wasting. These diseases both display non-Mendelian features in their inheritance patterns and this is related to the underlying mutation mechanism of amplification of trinucleotide repeats (Mandel and Heitz., pp 422---430). It is probable that this novel mechanism is the cause of other inherited and somatic genetic diseases. The improved resolution associated with better genetic maps has helped in the analysis of other examples of non-Mendelian inheritance. In Beckwith-Wiedemann syndrome the non-Mendelian component has been ascribed to 'imprinting' or differential modification of the DNA contributed by sperm and egg (Junien, pp 431-438). A possible model for imprinting is X-chromosome inactivation, which results in differential methylation of the two X chromosomes found in females; the mechanism controlling X inactivation is unknown but the finding of a sequence only expressed from the inactive X chromosome may be an important clue (Ballabio and Willard, pp 439-447). The neurodegenerative diseases associatied with 'prions' are both infectious (non-Mendelian) and inherited as autosomal dominants; the molecular basis of these perplexing diseases is still obscure but analysis of the prion genes in afflicted individuals suggests possible links between the Mendelian and non-Mendelian forms of the disease (Collinge and Palmer, pp 448-454). High resolution genetic analysis can also be used to trace developmental and biochemical pathways (Sassone-Corsi and Borrelli, pp 455-458); to distinguish diseases caused by mutations in different genes but with overlapping phenotypes (Lindsay, Ingleheam, Curtis and Bhattacharya, pp 459-466) and to analyze multigene families (Buck, pp 467-473). The application with the largest medical impact is, however, likely to be in the analysis of common diseases, such as heart disease, cancer and diabetes, which are the result of the interplay between several different genes and environmental factors. Identification of the different components contributing to these diseases is going to be a major focus of genetic research for the next few years (Todd, pp 474-478). Unfortunately, treatment is not possible for many genetic diseases even when the responsible gene has been
(~) Current Biology Ltd ISSN 0959-437X
385
386
Mammalian
genetics
cloned and the biochemical defect defined. In these cases, future hope may lie with gene therapy. One of the limiting factors in current approaches to gene therapy is our sketchy knowledge of the relationship between chromosome structure and function: insertion of genes at random into chromosomes does not guarantee correct expression. Mammalian artificial chromosomes, MACs, may allow the investigation of chromosome structure and function and, eventually, may provide suitable vectors for gene therapy (Brown, pp 479-486). Although the reviews in this issue focus on human genetics and the medical benefits that accrue from genetic mapping, other areas of research such as population and evolutionary genetics are also benefiting from the technology developed for genome analysis (Spurdle and Jenkins, pp 487-491). It is also important to stress the importance of the mouse as a genetic system. Comparison of genetic maps between mouse and man is proving to be a valuable source of models of human disease (Chapman and Nadeau) and points towards the biological importance of gene clustering and order (Trowsdale and Powis, pp 492-497). The real importance of the mouse, however, is in developmental biology. The experimental manipulations required to dissect developmental processes will only be possible in a model system and it
can be safely predicted that the next decade will reveal the rules for how a mouse is constructed (GluecksohnWaelsch, pp 498-503).
Dedication Earlier this year Dr Isobelle Oberle died. Despite her illness, Isobelle made many contributions to human genetics and was closely involved in the unravelling of the complexity of the 'fragile-X' syndrome. We would like to dedicate this issue to both her courage and her memory.
Reference FRIEDMAN T (ED): Therapy for Genetic Disease. Oxford: Oxford University Press; 1991.
G Camerino, Biologica Genemle e Genetica Medica, via Forlanini 14, 27100 Pavia, Italy. PN Goodfellow, Laboratory of Human Molecular Genetics, Imperial Cancer Research Fund, Lincoln's Inn Fields, London WC2A 3PX, UK.
drome gene appears to encode a novel neuronal migration factor (Ballabio and Canlerino, pp 417-421). The fragile-X syndrome is a common cause of mental retardation and myotonic dystrophy and is an autosomal dominant disease that results in muscle wasting. These diseases both display non-Mendelian features in their inheritance patterns and this is related to the underlying mutation mechanism of amplification of trinucleotide repeats (Mandel and Heitz., pp 422---430). It is probable that this novel mechanism is the cause of other inherited and somatic genetic diseases. The improved resolution associated with better genetic maps has helped in the analysis of other examples of non-Mendelian inheritance. In Beckwith-Wiedemann syndrome the non-Mendelian component has been ascribed to 'imprinting' or differential modification of the DNA contributed by sperm and egg (Junien, pp 431-438). A possible model for imprinting is X-chromosome inactivation, which results in differential methylation of the two X chromosomes found in females; the mechanism controlling X inactivation is unknown but the finding of a sequence only expressed from the inactive X chromosome may be an important clue (Ballabio and Willard, pp 439-447). The neurodegenerative diseases associatied with 'prions' are both infectious (non-Mendelian) and inherited as autosomal dominants; the molecular basis of these perplexing diseases is still obscure but analysis of the prion genes in afflicted individuals suggests possible links between the Mendelian and non-Mendelian forms of the disease (Collinge and Palmer, pp 448-454). High resolution genetic analysis can also be used to trace developmental and biochemical pathways (Sassone-Corsi and Borrelli, pp 455-458); to distinguish diseases caused by mutations in different genes but with overlapping phenotypes (Lindsay, Ingleheam, Curtis and Bhattacharya, pp 459-466) and to analyze multigene families (Buck, pp 467-473). The application with the largest medical impact is, however, likely to be in the analysis of common diseases, such as heart disease, cancer and diabetes, which are the result of the interplay between several different genes and environmental factors. Identification of the different components contributing to these diseases is going to be a major focus of genetic research for the next few years (Todd, pp 474-478). Unfortunately, treatment is not possible for many genetic diseases even when the responsible gene has been
(~) Current Biology Ltd ISSN 0959-437X
385
386
Mammalian
genetics
cloned and the biochemical defect defined. In these cases, future hope may lie with gene therapy. One of the limiting factors in current approaches to gene therapy is our sketchy knowledge of the relationship between chromosome structure and function: insertion of genes at random into chromosomes does not guarantee correct expression. Mammalian artificial chromosomes, MACs, may allow the investigation of chromosome structure and function and, eventually, may provide suitable vectors for gene therapy (Brown, pp 479-486). Although the reviews in this issue focus on human genetics and the medical benefits that accrue from genetic mapping, other areas of research such as population and evolutionary genetics are also benefiting from the technology developed for genome analysis (Spurdle and Jenkins, pp 487-491). It is also important to stress the importance of the mouse as a genetic system. Comparison of genetic maps between mouse and man is proving to be a valuable source of models of human disease (Chapman and Nadeau) and points towards the biological importance of gene clustering and order (Trowsdale and Powis, pp 492-497). The real importance of the mouse, however, is in developmental biology. The experimental manipulations required to dissect developmental processes will only be possible in a model system and it
can be safely predicted that the next decade will reveal the rules for how a mouse is constructed (GluecksohnWaelsch, pp 498-503).
Dedication Earlier this year Dr Isobelle Oberle died. Despite her illness, Isobelle made many contributions to human genetics and was closely involved in the unravelling of the complexity of the 'fragile-X' syndrome. We would like to dedicate this issue to both her courage and her memory.
Reference FRIEDMAN T (ED): Therapy for Genetic Disease. Oxford: Oxford University Press; 1991.
G Camerino, Biologica Genemle e Genetica Medica, via Forlanini 14, 27100 Pavia, Italy. PN Goodfellow, Laboratory of Human Molecular Genetics, Imperial Cancer Research Fund, Lincoln's Inn Fields, London WC2A 3PX, UK.
