The accumulation of mildly deleterious missense mutations in individual human genomes has been proposed to be a genetic basis for complex diseases. The plausibility of this hypothesis depends on quantitative estimates of the prevalence of mildly deleterious de novo mutations and polymorphic variants in humans and on the intensity of selective pressure against them. We combined analysis of mutations causing human Mendelian diseases, human-chimpanzee divergence and systematic data on human SNPs and found that about 20 percent of new missense mutations in humans result in a loss of function, while about 27 percent are effectively neutral. Thus, more than half of new missense mutations have mildly deleterious effects. These mutations give rise to many low frequency deleterious allelic variants in the human population as evident from a new dataset of 37 genes sequenced in over 1,500 individual human chromosomes. Surprisingly, up to 70 percent of low frequency missense alleles are mildly deleterious and associated with a heterozygous fitness loss in the range 0.001-0.003. Thus, the low allele frequency of an amino acid variant can by itself serve as a predictor of its functional significance. Several recent studies have reported a significant excess of rare missense variants in disease populations compared to controls in candidate genes or pathways. These studies would be unlikely to work if most rare variants were neutral or if rare variants were not a significant contributor to the genetic component of phenotypic inheritance. Our results provide a justification for these types of candidate gene (pathway) association studies and imply that mutation-selection balance may be a feasible mechanism for evolution of some common diseases.

Body weight is a quantitative trait with significant heritability in humans. To identify potential genetic contributors to this phenotype, we resequenced the coding exons and splice junctions of 58 genes in 379 obese and 378 lean individuals. Our 96Mb survey included 21 genes associated with monogenic forms of obesity in humans or mice, as well as 37 genes that function in body weight-related pathways. We found that the monogenic obesity-associated gene group was enriched for rare nonsynonymous variants unique to the obese (n=46) versus lean (n=26) populations. Computational analysis further predicted a significantly greater fraction of deleterious variants within the obese cohort. Consistent with the complex inheritance of body weight, we did not observe obvious familial segregation in the majority of the 28 available kindreds. Taken together, these data suggest that multiple rare alleles with variable penetrance contribute to obesity in the population and provide a deep medical sequencing based approach to detect them.