ON SOME TRENDS IN UNDERSTANDING THE GENETICS OF MAN JAMES V. NEEL and WILLIAMJ. SCHULL* Introduction The objectives and directions of scientific investigation in the United States are currently coming under a scrutiny such as they have perhaps not enjoyed since the nineteenth century [i]. Efforts to meet some ofthe very proper questions being raised can proceed from either oftwo viewpoints, the very general—which runs the risk oflacking the substance on which to base a solid philosophy—and the more specific—which quickly can assume the form ofspecial pleading. In this presentation, despite the risks, we will attempt to be rather specific about a particular area, on the thesis that from such communications, ifproperly executed, comes the stuffon which to base the discussions which ultimately lead to a reasonable consensus . But the hope ofa consensus with these present thoughts and emphases was not a primary consideration in the preparation of this communication . The emergence in the past twenty years ofthe study ofhuman genetics as a strong and rapidly moving discipline is surely one of the significant currents in modern biology and medicine. This article will attempt to appraise some trends which suggest that the future ofthe study ofhuman genetics holds some directions and emphases which have thus far been insufficiently appreciated. The implications of these developments for * Department ofHuman Genetics, University ofMichigan Medical School, Ann Arbor. Publication ofthis paper in Perspectives has been supported in part by contributions from the United Health Foundations, Inc., and The National Foundation. In a wide-ranging review of this nature, detailed referencing is impossible; we have mentioned only key articles or reviews. To those whose important contributions are not specifically named, we apologize. We do wish to acknowledge the extent to which the preparation ofthis article has profited from discussions with Drs. Walter Bodmer, George Brewer, James Crow, Th. Dobzhansky, Henry Gershowitz, Robert Krooth, T. E. Reed, Donald Rucknagel, C. R. Shaw, Margery Shaw, Donald ShrefBer, Charles Sing, C. Stern,John Sved, and Richard Tashian. 565 human welfare cannot be honestly appraised at the moment but may be considerable. Many ofthe points to be mentioned are "in the air" to an extent that the authors claim no great originality but hope to have combined the fragments in a worthwhile fashion. The presentation is aimed at the scientific community rather than the professional geneticist and, space limitations being what they are, will ofcourse, out ofthe mass ofmaterial available, emphasize those facts which best illustrate our general thesis. For the purposes of this discussion, we shall recognize the following fields within the study of human genetics: biochemical, chromosomal, somatic cell, clinical, population, and formal (mathematical). These areas are not clearly demarcated, as illustrated, for example, by the union ofbiochemical and clinical genetics in the study of such a disorder as cystic fibrosis ofthe pancreas. We shall not touch upon the field of somatic cell genetics at all, but in developing our theme willfirst refer briefly to selected developments in four ofthe remaining five fields, reserving comments on some developments in mathematical genetics until later. The most impressive recent developments have been in the biochemical and cytological aspects of human genetics. The wide-scale employment ofnewly developed, inexpensive, and easily operated apparatus to screen for abnormalities in protein molecules has revealed an unsuspected wealth of inherited biochemical variations, some of which have now been characterized down to the ultimate unit ofchange in a protein, the amino acid. Many ofthese variants occur with a frequency such that the genetic systems of which they are a component must be termed "polymorphic," that is, upward of2 per cent ofthe population is heterozygous at this locus, a frequency which, as pointed out by Ford [2], is not likely to be maintained by mutation. Because ofthe importance which polymorphisms will assume in what follows, it seems necessary to digress long enough to establish certain facts concerning their genetic properties. Consider a locus at which a gene A may undergo mutation to a variety ofalleles, ofwhich we will consider only one, A'. ???' when homozygous results in a phenotype which is superior in some respect to that associated with A, then it will in time replace A in the population (except in the...