Fifty Years of Genetic Epidemiology, with Special Reference to Japan

J Hum Genet (2006) 51:269–277 DOI 10.1007/s10038-006-0366-9 MINIREVIEW Newton E. Morton Fifty years of genetic epidemiology, with special reference to Japan Received: 13 December 2005 / Accepted: 18 December 2005 / Published online: 15 February 2006 Ó The Japan Society of Human Genetics and Springer-Verlag 2006 Abstract Genetic epidemiology deals with etiology, dis- Introduction tribution, and control of disease in groups of relatives and with inherited causes of disease in populations. It The Japan Society of Human Genetics (JSHG) was took its first steps before its recognition as a discipline, established at a time when the science it represented was and did not reach its present scope until the Human growing so explosively that Carlson (2004) signalised the Genome Project succeeded. The intimate relationship death of classical genetics. Compared to their predeces- between genetics and epidemiology was discussed by sors, geneticists in 1956 were more distrustful of eugenics Neel and Schull (1954), just a year after Watson and and more committed to cytogenetics, biochemistry, and Crick reported the DNA double helix, and 2 years be- medical genetics, but not yet prepared for the genomic fore human cytogenetics and the Japan Society of Hu- revolution that the double helix would ultimately bring man Genetics were founded. It is convenient to divide (Yanase 1997). Population genetics was beginning to the next half-century into three phases. The first of these split into two major branches, one concerned with events (1956–1979) was before DNA polymorphisms were that took place in the past under poorly known forces of typed, and so the focus was on segregation and linkage systematic pressure and chance (evolutionary genetics), of major genes, cytogenetics, population studies, and the other dealing with etiology, distribution, and control biochemical genetics. The next phase (1980–2001) pro- of disease in groups of relatives and with inherited gressively identified DNA polymorphisms and their causes of disease in populations (genetic epidemiology). application to complex inheritance. The last phase began Here, I shall deal with the latter, divided into four with a reliable sequence of the human genome (2002), periods: before the JSHG, before DNA polymorphisms, followed by exploration of genomic diversity. Linkage before the human genome, and after genome diversity. continues to be useful to study recombination and to map major genes, but association mapping gives much greater resolution and enables studies of complex inheritance. The generation now entering human Before the JSHG (1950–1955) genetics will have collaborative opportunities un- dreamed of a few years ago, without the independence Historians of science may well identify the paper by that led to great advances during the past half-century. Watson and Crick (1953) demonstrating DNA struc- ture as the most significant advance in the years Keywords Genetic epidemiology Æ Segregation Æ immediately preceding formation of the JSHG, but its Linkage Æ Association mapping Æ Human genome Æ full effect was not felt for half a century. In its place Genetic diversity Æ Linkage disequilibrium Æ one benchmark was identification of the first autoso- Genetic loads mal linkage in man (Mohr 1951), later revised by recognition that ‘‘recessive’’ Le is a marker for the Se locus (Mohr 1954). In the interval, Goodall et al. (1953) discovered linkage between elliptocytosis and N.E. Morton the Rh blood group, and, simultaneously, Fujii and Human Genetics Division, Southampton General Hospital, Tsuchitori reported five Japanese families with ellipt- School of Medicine, University of Southampton, ocytosis. I was in the Atomic Bomb Casualty Com- Duthie Building (MP 808), SO16 6YD Southampton, UK mission (ABCC) at the time of their discovery and had E-mail: [email protected] Tel.: +44-2380-796536 the pleasure of analysing the blood group data by the Fax: +44-2380-794264 standard method at that time (Fujii et al. 1955). James 270 Renwick, who was serving in the British Medical Corps stationed in Hiroshima, developed an intense Before DNA polymorphisms (1956–1979) interest in linkage analysis, which he applied in many distinguished papers on his return to England. Even at The founding year of the JSHG saw the beginning of that early stage after a devastating war, Japan was human cytogenetics (Tjio and Levan 1956) with new influencing genetic developments in other countries. In techniques that for the first time revealed the normal this respect it contrasts sharply with Germany and human karyotype of 46 chromosomes. From this came a Communist countries, where genetics was virtually shower of discoveries, including aberrations in chro- destroyed by antisemitism and Lysenkoism, respec- mosome number and rearrangements that provided tively. critical evidence for gene localization. Simultaneously, The strength of Japanese genetics was illustrated the elegant but rather unreliable methods for linkage dramatically by the link that developed with a young, detection were replaced by lods based on exact proba- frail, and brilliant geneticist named Motoo Kimura, then bility ratios that were more powerful and easier to apply not widely known even in his own country. His brief to large pedigrees (Morton 1955). The first success was reports in the National Institute of Genetics, Mishima, with elliptocytosis, which was shown to map to more showed a remarkable command of the higher mathe- than one locus (Morton 1956). The need for a conser- matics used in evolutionary genetics by Wright and vative lod (Z>3) was demonstrated by a probability Fisher. In turn, he was anxious to understand recent argument that now gives the false discovery rate (FDR) work by Gustave Malecot (1948), whose classical paper for other applications including genome scans and I took to Japan. I enjoyed translating the French to microarrays (Storey and Tibshirani 2003). It is indis- Kimura but hesitated over certain equations. He always pensable for determining the likelihood that an appar- found them obvious, and so we went successfully ently significant result in a preliminary sample is a type I through the whole work. I wrote to James Crow in error. Madison, Wisconsin about this extraordinary experi- Several other factors contributed to the success of ence. After a purgatorial year in Iowa, Kimura came to linkage analysis. First, the growth of medical genetics Wisconsin and we shared an office until we finished our provided a number of rare diseases inherited as reces- doctorates with Crow. We enjoyed stimulating discus- sives or dominants with high penetrance that could be sions with him, Sewall Wright, and each other in both demonstrated by segregation analysis with appropriate branches of population genetics. Kimura’s unique ability allowance for ascertainment bias (Morton 1959). Good was quickly recognised internationally, and for many estimates of these parameters made for simple linkage years he and Crow took every opportunity to work to- analysis (Table 1). Secondly, the relatively small number gether in Madison and Mishima. of blood groups was exponentially augmented by en- Of course, these academic pleasures were secondary zymes and other proteins whose chromosomal locations to the main task of the Genetics Program of the ABCC, could be estimated by family studies, somatic-cell based on fear that animal experiments might underesti- hybridisation, DNA/RNA annealing, or gene-dosage mate genetic risks in humans. At the same time, it was effects. The growing linkage map led to annual confer- recognised that most mutations could not be detected in ences, beginning in 1973. LIPED (Ott 1976) imple- the first generation by methods, phenotypes, and mented an algorithm of Elston and Stewart (1971)to dosimetry then available. The Genetics Program pro- give the first widely used computer program for pedi- duced no unpleasant surprises, but one puzzle remains: grees. Inevitably, linkage analysis was extended from the initial analysis (Neel et al. 1953) showed a barely major genes to complex inheritance in which oligogenes significant deficiency of sons from irradiated mothers combine independently with polygenes and environ- (consistent with X-linked mutation), but this diminished mental factors (Fig. 1). Identity by descent for single as time went on, and in the last analysis was reversed as markers was the initial method (Suarez et al. 1978). It an effort was made to improve anamnestic dosimetry subsequently had some successes, but many failures. (Schull et al. 1966). Most experimental studies did not Unaffected relatives provided little information, and include sex ratio, and the few that did gave inconsistent ascertainment of affected relatives was arbitrary. estimates suggestive of germinal selection (Morton Affectedness in two relatives could be caused by different 1997). It was a great tribute to Neel and Schull that they genetic mechanisms. The advances in molecular genetics steered the program through these complexities and still that would provide autozygosity mapping of recessive had boundless energy for other research with their many disease (Smith 1953) and unravel complex inheritance Japanese colleagues. had not yet been made. Table 1 Classes of causal alleles Allelic class Usual frequency Penetrance Segregation analysis Linkage analysis Major gene Rare High + þþ Oligogene Common Low À + Polygene Common Very low ÀÀ 271 Polygenes Deleterious mutations were known from research on Drosophila and the mouse to have a large recessive component, but clinical

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