Synergistic interaction of heterozygous deletions impairs performance and confers susceptibility to disease at all ages

Summary 

Rare recessive conditions are more common in the offspring of cousin unions than in the general population even in communities in which less than 0.5% of all marriages are between first cousins. It is shown that if the human genome has 30,000 genes in the haploid set then (Y+X)⁶/(Y)⁵<19, where X is the mean number of new mutations entering the human genome per generation and Y is the mean number of heterozygous deletions in the germ line of adults. This places an upper limit on X of 1.3. Functions specifying the frequency of homozygous deletions in the offspring of cousin and sibling unions are also derived in terms of X and Y. The best estimates with these three measures are that Y is between 6 and 10, and X between 0.5 and 1.3. Data on mutation rates in bacteria, worms, yeast, flies and mice are consistent with these estimates. It is argued that selection against heterozygous deletions must occur in order to prevent progressive build up in the genome; furthermore, it is postulated that the selection must be based on synergistic interaction. If heterozygous deletions interact synergistically to degrade biological performance then this has implications for human fertility, for polygenic disease, for the genetic basis of polygenic traits such as intelligence and the association between birth weight and adult disease (Barker’s phenomenon) and the links between status and health inequality. The concept proposed is that a large set of genes specify each aspect of biological capability; the genes specify a redundant system so that one or two deletions will have minimal effect; but several deletions will interact synergistically to degrade performance and cause disease.