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 I963). 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). Virtually all these enzyme deficiencies have been identified in the first instance because of some more or less striking clinical or metabolic disturbance of which they were the cause. They therefore represent a highly selected group of mutants,

Enzyme polymorphisms in man

SUMMARY We have begun a measured genotype approach to the genetic analysis of lipid and lipoprotein variability This approach enables one to simultaneously estimate the frequencies and effects of alleles at specific loci along with the residual polygenetic variance component In this study we consider the contribution of three common alleles at the locus coding for apolipoprotein E to interindividual variation of total cholesterol, betalipoprotein, and triglyceride levels A sample of 102 nuclear families consisting of 434 individuals was studied The frequencies of the €2, €3, and €4 alleles in this sample are 0*137,0740, and 0123, respectively In separate analyses of cholesterol and betalipoprotein levels, a complete model that includes the effects of the six apo E genotypes, unmeasured polygenes, and individual specific environmental effects fits these data significantly better than a reduced model that does not include the effects of the apo E polymorphism or a reduced model that does not include the effects of polygenes On the average the €2 allele lowers total cholesterol and betalipoprotein levels by 0425 mmol/l and 081 1 units, respectively The €4 allele is associated with an average increase of these phenotypes by 0255 mmol/l and 0628 units, respectively Simultaneous estimates of the interindividual variability of total cholesterol levels attributable to the apo E polymorphism and to residual polygenic effects are 8 % and 56 % , respectively For betalipoprotein levels, we simultaneously estimate these values to be 7 yo and 42 Yo, respectively A reduced model including the effects of polygenes but not the effects of the apo E polymorphism fitted the triglyceride data as well as the complete model The estimate of the fraction of interindividual variability associated with polygenetic effects was 265 % We review our present understanding of the genetic architecture underlying variability of cholesterol levels in the population at large and infer that the majority of the genetic variability may be accounted for by polymorphic gene loci with moderate effects on cholesterol levels

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The use of measured genotype information in the analysis of quantitative phenotypes in man

Improved laboratory methods allow one to investigate the contribution of measured allelic variability at a locus physiologically involved in determining the expression of a quantitative trait. We present statistical methods that incorporate measured genotype information into the analysis of a quantitative phenotype that allows one simultaneously to detect and estimate the effects of a measured single locus and residual polygenic effects. Likelihoods are presented for the joint distribution of the quantitative phenotype and a measured genotype that are appropriate when the data are collected as a sample of unrelated individuals or as a sample of nuclear families. Application of this method to the analysis of serum cholesterol levels and the concentration of the group specific component (Gc) are presented. The analysis of the contribution of the common Gc polymorphism to the determination of quantitative variability in Gc using samples of related and unrelated individuals presents, for the first time, the simultaneous estimation of the frequencies and the effects of the genotypes at a measured locus, and the contribution of residual unmeasured polygenes to phenotypic variability.

https://deepblue.lib.umich.edu/bitstream/handle/2027.42/65935/j.1469-1809.1986.tb01037.x.pdf?sequence=1

The use of measured genotype information in the analysis of quantitative phenotypes in man. I. Models and analytical methods.

Clinical significance of the human acid phosphatases: A review☆

https://science.sciencemag.org/content/sci/149/3687/936.full.pdf

Electrophoretic Variation in Enzymes

Genetical studies on human red cell acid phosphatase.

SUMMARY

Red cell glucose-6-phosphate dehydrogenase (G-6-PD) activity was measured in fourteen XXX, eleven XX Y, three XO individuals, four individuals who were 17 but had testicular feminization, and in appropriate male and female controls. No evidence for any quantitative relationship between the number of X-chromosomes present and the level of red-cell G-6-PD activity was observed. Since G-6-PD is known to be determined by at least one gene locus in the X-chromosome, these results in agreement with others imply complete dosage compensation.



In thirteen patients with thyrotoxicosis a significant elevation of the mean level of red cell G-6-PD was demonstrated, indicating that such increases could be detected under the general conditions of the investigation.



The results are discussed in terms of various hypotheses accounting for dosage compensation.

D. A. Hopkinson

Papers

Genetical studies on human red cell acid phosphatase.

Red cell glucose-6-phosphate dehydrogenase activity in individuals with abnormal numbers of X-chromosomes