Main model fits and substitution rate predictions for: 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 can be thought
of as a “linked selection signal" that reflects the impact of
selection varying according to the placement of functional regions and
recombination rates along the genome. Previous work has shown that
negative selection against the steady influx of new deleterious mutations
into conserved regions is the predominant mode of selection in humans.
However, the theoretic model that underpins these results, classic
Background Selection theory, 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 the linked
selection, which models the effects of weak draft created according to how
polygenic additive fitness variance is distributed along the genome. We
use a recent model that jointly predicts the equilibrium fitness variance
and substitution rates due to both strong and weakly deleterious
mutations, we estimate the distribution of fitness effects (DFE) and
mutation rate across three human populations. While our model can
accommodate weaker selection, we initially find evidence across three
human populations of very strong selection against deleterious mutations
consistent with previous work. However, the corollary predicted
substitution rates for conserved regions are unreasonably low, and in
disagreement with observed rates. We hypothesize this could be due to
selected sites experiencing a further diminished population size due to
selective interference. When we account for this in our method, we find
evidence of weakly deleterious mutations in conserved regions which brings
the predicted substitution rate into agreement with observations. However,
these models lead to implausibly large mutation rate estimates. Overall,
while our model of the genomic linked selection signal brings us a step
towards uniting population and quantitative genetic selection models with
the substitution process, our work suggests considerable uncertainty
remains about the processes generating fitness variance in humans.