A quantitative genetic model of background selection in humans.

Across the human genome, there are large-scale fluctuations in genetic diversity caused by the indirect effects of selection. This "linked selection signal" reflects the impact of selection according to the physical placement of functional regions and recombination rates along chromosomes. Previous work has shown that purifying selection acting against the steady influx of new deleterious mutations at functional portions of the genome shapes patterns of genomic variation. To date, statistical efforts to estimate purifying selection parameters from linked selection models have relied on classic Background Selection theory, which is only applicable when new mutations are so deleterious that they cannot fix in the population. Here, we develop a statistical method based on a quantitative genetics view of linked selection, that models how polygenic additive fitness variance distributed along the genome increases the rate of stochastic allele frequency change. By jointly predicting the equilibrium fitness variance and substitution rate due to both strong and weakly deleterious mutations, we estimate the distribution of fitness effects (DFE) and mutation rate across three geographically distinct human samples. While our model can accommodate weaker selection, we find evidence of strong selection operating similarly across all human samples. Although our quantitative genetic model of linked selection fits better than previous models, substitution rates of the most constrained sites disagree with observed divergence levels. We find that a model incorporating selective interference better predicts observed divergence in conserved regions, but overall our results suggest uncertainty remains about the processes generating fitness variation in humans.