C. Genetics of Man Enzyme polymorphisms in man

Abstract

There are a large number of different enzymes synthesized in the human organism, and many of these probably contain more than one structurally distinct polypeptide chain. If current theories about genes and proteins are correct we must suppose that the primary structure of each of these different polypeptides is determined by a separate gene locus, and that there are probably also other loci which are specifically concerned with regulating the rate of synthesis of particular polypeptides or groups of polypeptides. Furthermore, we may expect that genetical diversity in a human population will to a considerable extent be reflected in enzymic diversity. That is to say, in differences between individuals either in the qualitative characteristics of the enzymes they synthesize, or in differences in rates of synthesis. The work I am going to discuss was largely aimed at trying to get some idea of the extent and character of such genetically determined enzyme diversity among what may be regarded as normal individuals. When my colleagues and I started on this line of work about three years ago the information available about this aspect of the subject was very limited. It had of course been recognized for quite a long time that there are many rare metabolic disorders, the so-called ‘inborn errors of metabolism’, which are due to genetically determined deficiencies of specific enzymes (Harris 1963). These conditions can in general be attributed to mutant genes which result either in the synthesis of an abnormal enzyme protein with defective catalytic properties, or in a gross reduction in rate of synthesis of a specific enzyme protein. By and large such genes appear to be relatively uncommon and have frequencies of between 0·01 and 0·001 in the general population. Heterozygotes often show a partial enzyme deficiency though they are usually in other respects quite healthy. A few cases are also known where a specific enzyme deficiency occurs quite commonly in certain populations. The most extensively studied example of this is glucose 6-phosphate dehydrogenase deficiency, and it seems likely that in this particular case the relatively high incidence in certain populations is attributable to a specific selective advantage which the deficiency may confer in situations where endemic malaria is an important selective agent (Motulsky 1964).