Aspects of genetics in paediatrics : scientific proceedings of the 3d Unigate Workshop held at the Royal College of Physicians, St. Andrew's Place, London, May 1975 / edited by Donald Barltrop.

  • Unigate Paediatric Workshop 1975 : London, England)
Date:
1976
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Licence: Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)

Credit: Aspects of genetics in paediatrics : scientific proceedings of the 3d Unigate Workshop held at the Royal College of Physicians, St. Andrew's Place, London, May 1975 / edited by Donald Barltrop. Source: Wellcome Collection.

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    Enzyme polymorphisms D. A. HOPKTNSON M.R.C. Human Biochemical Genetics Unit, Galton Laboratory, University College London Genetically determined polymorphism may be defined as that situation in which individual mem¬ bers of the population can be divided into two or more categories, each relatively common, according to the distinctive manner in which they synthesize a particular enzyme or protein (Harris, 1969). The existence of such biochemical polymorphisms has been recognized for many years in man and in many other species. In humans the classical examples, since the early part of this century, were the ABO and other blood group polymorphisms. Later, in the fifties and early sixties, polymorphic situations were recognized in the haemoglobins, haptoglobins, transferrins and other plasma proteins. In those days genetic polymorphism was generally regarded as a rather special phenomenon, occurring at a relatively small, restricted, number of the structural genes in the total genome. In the last decade genetic poly¬ morphisms of many different enzymes have been discovered, the polymorphic histocompatibility systems have been revealed and numerous other protein polymorphisms have also been recognized (such as the tti-antitrypsin polymorphism which will be discussed later by Dr Fagerhol). In all, about 50 different biochemical polymorphisms have been identified in human populations (Harris, 1975). About 30 of these are enzyme polymorphisms and the rest involve non-enzyme proteins in serum and saliva. With this explosive growth of information has come the realization that polymorphisms are a relatively common and widespread feature of the human organism. Parallel studies on other species have led to the same conclusion. This presentation will be concerned exclusively with studies on man and will concentrate on the data assembled during the last decade on the enzyme polymorphisms. Molecular mechanisms The molecular mechanisms underlying the bio¬ chemical polymorphisms appear to be generally straightforward in the sense that the multiple alleles which give rise to the genetic variation must have arisen by spontaneous mutation in individuals in previous generations and have been transmitted since then from generation to generation in either a random fashion or under the influence of natural selection until they reached the frequencies with which they are observed today. The evidence, derived almost entirely from studies on human haemoglobin, indicates that many and indeed probably the majority of the spontaneous mutations involve simply a single base change in the DNA of a particular gene in which one base is substituted by another. Due to the nature of the genetic code a very large number of different alleles can in principle be generated at a single gene locus by this simple mechanism of point mutation. However, the code is degenerate and a substantial proportion (about 23%) of such mutations would be expected to be synonymous and would not lead to a change in the structure of the protein since the new codon will lead to the incorporation of the same amino acid in the polypeptide chain as the original codon. These synonymous mutations may however influence the rate of synthesis of the particular protein even though the structure is unchanged. A smaller number (about 4%) of mutations might be expected to involve a base change which alters a triplet from one which specifies a particular amino acid to one which specifies chain termination, and in such cases the protein which is synthesized would lack a relatively large or relatively small portion of its chain. The effect on function may be devastating or minimal or somewhere between these two ex¬ tremes but usually one would expect a considerable disruption of protein structure and loss of functional activity from such mutations. In most cases (about 73%) mutations will lead to a 59