Ann. Hum. Genet. (1986), 50, 1-2

Printed in Great Britain 1

Fifty years of human genetics: Plus Ca change, plus c’est la mQme chose

B Y E . B. ROBSON The Galton Laboratory, University College London

This quotation may seem a surprising introduction to an editorial note occasioned by the preparation of the fiftieth volume of a journal in a rapidly growing field like genetics. But the astonishing thing in comparing the contents list of half a century ago with that of today is the extraordinary similarity of subject matter, if not means of approach. Human genetics has long been characterized by difficult analytical problems by virtue of its dependence on existing pedigrees, but these very difficulties stimulated great developments in statistics and the 1936 Annals contained many papers by R. A. Fisher. Two of these provided approaches not fully realized until the experimental results of the ’60s and ’70s provided data for testing, “The use of multiple measurements in taxonomic problems ” and “The wave of advance of advantageous genes”. Penrose was writing on the estimation of autosomal mutation rates, and Karn was starting the series of papers on human size measurements which characterized much of the work of the ’40s.

But the most striking similarity is undoubtedly in the field of linkage studies. Ofthe twenty-two papers published in 1936 six were on linkage, whilst of thirty-two papers published in 1985 seventeen had to do with the rather broader topic of human gene mapping. Fifty years ago Haldane was writing about a possibly novel mode of inheritance in “ A search for incomplete sex-linkage in man”-a topic not unheard of today; whilst Fisher was considering tests of significance for such findings, including a point still debated in Morton’s review of Ott’s “Analysis of human genetic linkage” which appears in this issue. Fisher went to considerable lengths to stress the realities of work in human genetics on this occasion:- “an examination of actual data is of immediate importance. . .for the experience it provides of the sources of error to which this use of pedigree material is necessarily exposed. . . . It is our ignorance of the processes by which bodies of data have originated which is the sole source of ambiguity in interpretation. . . ” In maintaining this tradition the Annals has always sought for a very full description of the data used in linkage analyses, a policy even more crucial today when additive scoring methods and the sharing of material amongst different laboratories can result in a very confused literature.

Many of the difficulties arising in particular linkage analyses were foreshadowed in the 1936 papers. In writing on an analysis of the ABO blood groups in Friedreich’s ataxia Fisher first addressed the question of heterogeneity. Editors are still placed in a difficult position by well conducted linkage studies giving negative results, but the pressure on space was perhaps less in 1936, and a paper appeared from A. S. Wiener and colleagues from the Jewish Hospital at Brooklyn “On the linkage relations of the genes for allergic disease and the genes determining the blood groups, MN types and eye colour in man.” The analysis was more complete than in many recent papers concentrating on a disease locus, since tests were also made between the markers, adding P to those listed in the title. Neither was comparative work ignored as Mather produced a general analytical paper “Types of linkage data and their value” and together with Fisher reported on an experiment with mice, using animals provided by by Gruneberg and Crew.

2 E. B. ROBSON The last volume of the Annals was not dissimilar. There were, of course, a number of

chromosomal assignments of genes using experimental techniques which are new (cytochrome P450 gene family assigned to chromosome 19, Phillips et al.), but the earlier methodology has not yet been replaced. Family studies (Peptidase D and APOC2, Ball et ul.) are used together with the physical assignments to produce composite chromosome maps (A map of chromosome 19, Sherman et ul.). The use of recombinant DNA methods in providing new polymorphic markers has enlarged practical interest in the family linkage approach to the study of disease loci, and the Editors have felt it appropriate to mark this fiftieth volume of the Annals of Human Genetics by reprinting Bell and Haldane’s classical paper on the first estimate of linkage in man, The linkage between the genes for colour blindness aitd+zemophilia in man, which was written fifty years ago and first appeared in the Proceedings of The Royal Society for 1937. Julia Bell’s clinical presentation is a model of the clarity recommended by Fisher, and Haldane contrives in this first practical analysis to comment on issues such as heterogeneity, significance tests, mutation, mosaicism, localization of chiasmata and other complexities which still provoke discussion.

In concluding Haldane wrote “if an equally close linkage were found between the genes determining blood group membership and that determining Huntington’s chorea, we should be able, in many cases, to predict which children of an affected parent would develop the disease, and to advise on the desirability or otherwise of their marriage.” He might well have been disappointed that we have not quite yet reached that point. However, it is pleasing that the most promising result recently, in relation to an unmapped disease locus of major importance, is the possible linkage between the loci for cystic fibrosis and paraoxonase (Eiberg, . . . Mohr, 1985, Human Gene Mapping 8). Yes, the same Jan Mohr who described the first autosomal linkage! Editing the Annals would seem to have little in common with editing ‘Figaro’, but Alphonse Karr came to the same conclusion:- “The more things change, the more they are the same ”.

The following paper by Julia Bell and J . B. S. Haldane is reproduced in facsimile from the Proceedings of the Royal Society of London, Series B, volume 123 (1937), pages 119-150, by kind permission of the President of the Royal Society.