Selection might also be responsible for keeping genetic effect sizes low, as variants of larger effect may be selected against and eventually disappear19. Long-term stabilizing selection minimizes the production of individuals at the extremes of a trait29, in part by reducing the additive genetic effects of alleles already present or those arising de novo by mutation30 to levels potentially beneath the ability of studies of feasible size to detect them. Selection may also contribute to differences in the ability to detect loci in different complex diseases, if genetic susceptibility to some diseases is more strongly affected by selection than other diseases, or if environmental perturbations vary in intensity across diseases. Immune and infectious agents have been recognized as among the strongest selection pressures in human evolution31, and immune-related genes have been strongly implicated in Crohn’s disease and other immune-mediated diseases3, suggesting either that pleiotropic effects of these variants reduce the efficiency of negative selection, or that strong environmental perturbation in modern societies might expose the disease risk associated with these variants. Selection may thus explain why disease allele frequencies are low and allelic effects are small, but this should manifest as low, rather than missing, heritability.
