Constraining models of dominance for nonsynonymous mutations in the human genome

Dominance is a fundamental parameter in genetics, determining the dynamics of natural selection on deleterious and beneficial mutations, the patterns of genetic variation in natural populations, and the severity of inbreeding depression in a population. Despite this importance, dominance parameters remain poorly known, particularly in humans or other non-model organisms. A key reason for this lack of information about dominance is that it is extremely challenging to disentangle the selection coefficient (s) of a mutation from its dominance coefficient (h). Here, we explore dominance and selection parameters in humans by fitting models to the site frequency spectrum (SFS) for nonsynonymous mutations. When assuming a single dominance coefficient for all nonsynonymous mutations, we find that numerous h values can fit the data, so long as h is greater than ~0.15. Moreover, we also observe that theoretically-predicted models with a negative relationship between h and s can also fit the data well, including models with h = 0.05 for strongly deleterious mutations. Finally, we use our estimated dominance and selection parameters to inform simulations revisiting the question of whether the out-of-Africa bottleneck has led to differences in genetic load between African and non-African human populations. These simulations suggest that the relative burden of genetic load in non-African populations depends on the dominance model assumed, with slight increases for more weakly recessive models and slight decreases shown for more strongly recessive models. Moreover, these results also demonstrate that models of partially recessive nonsynonymous mutations can explain the observed severity of inbreeding depression in humans, bridging the gap between molecular population genetics and direct measures of fitness in humans. Our work represents a comprehensive assessment of dominance and deleterious variation in humans, with implications for parameterizing models of deleterious variation in humans and other mammalian species.