An Estimate of the Mutational Damage in Man from Data on Consanguineous Marriages.

In a diploid, outbreeding organism like man the deleterious mutants carried by the population are only partly expressed in each generation, being largely concealed by heterozygosis with more favorable alleles. However, the total hidden-mutational damage carried by the population can be estimated indirectly from the detrimental effects of consanguineous marriage. This method, applied to mortality data of Arner,1 provided the basis for the statement that "a calculation from ... results of inbreeding in man ... leads to the conclusion that every person on the average contains heterozygously at least one lethal gene or group of genes which [homozygously would ] ... kill an individual... between birth and maturity."2 The calculation itself was not given, however, and the stated figure of one lethal equivalent per person represents a conservative estimate, being a good deal lower than the most probable value (nearly two) actually indicated by the data. Recently Slatis3 has used a similar procedure for estimating the number of heterozygous genes that, if homozygous, would cause detectable rare abnormalities and has arrived at a tentative estimate of eight such genes per person. His conclusions are qualified by the fact that the subjects were selected for having abnormalities, some of which may not have been simple recessives. In this paper we shall present calculations whereby, using death rates both from Arner's and from two other published studies of consanguineous marriages, we have attempted to measure the total mutational damage. We shall also show how, by making some assumptions about the manner in which the mutations are expressed (and hence with less assurance), we have estimated the amount of mutational damage actually expressed each generation. Finally, we shall use the data to estimate the total mutation rate in man. Human Consanguinity Data.-The selection of families on the basis of the consanguinity of the parents has both advantages and disadvantages. The disadvantages of this approach are that a large sample is required and that the sociological concomitants of consanguineous marriage (rural-urban differences, etc.) may be confounded with the genetic effects. The advantages are that it is not biased by selection of particular genetic entities and that homozygosity for two or more deleterious genes with possibly synergistic effects is unlikely at the low levels of inbreeding found in man. Three published studies on consanguineous marriage fulfil the condition of a large sample. It is questionable whether they also meet the requirement for separation of genetic effects from the sociological correlates of inbreeding. The most recent and useful data (summarized in Table 1) were obtained by Sutter and Tabah4 from