Mutation and disease in man.

Efforts to evaluate the burden of genetic disease maintained by mutation pressure are reviewed. Various individuals and committees have suggested that approximately 1800 per 100,000 liveborn infants will ultimately exhibit clearly defined disease due to chromosomal or point mutation. Direct estimates of human chromosomal and point mutation now permit the identification of about 370 per 100,000 liveborn infants with defect due to mutation in the preceding generation. Recent technical advances permit the study of mutation to shift to the protein level. In Amerindians, mutations resulting in electrophoretic variants of a series of proteins of the blood serum and erythrocyte occur at at rate of 1.6 x 10(-5)/locus/generation. While it is debatable what proportion of electrophoretic variants result in impaired health as heterozgotes or homozgotes in man, we are increasingly aware of disease due to an absence of enzyme or receptor protein due to homozygosity for "null" alleles. A conservative calculation of the possible impact of these "null" mutations on health proceeds as follows: if the rate of mutation to electrophoretic variants in man is only 1.0 x 10(-5)/locus/generation, and if in man the ratio of nulls to electrophoretic variants is only 2:1 rather than 5:1 of Drosophila, then null mutants with respect to protein should be 2.0 x 10(-5)/locus/generation. There are perhaps 5,000 proteins in man whose absence can lead to disease. It is clear we are just beginning to recognize a class of mutations whose impact on health in toto may exceed the commonly visualized gross phenotypic abnormalities. However, many of the conceptuses homozygous for these null mutations may be eliminated in utero and not come to clinical attention.