Negative selection in humans and fruit flies involves synergistic epistasis

Abstract

Negative selection against deleterious alleles produced by mutation influences within-population variation as the most pervasive form of natural selection. However, it is not known whether deleterious alleles affect fitness independently, so that cumulative fitness loss depends exponentially on the number of deleterious alleles, or synergistically, so that each additional deleterious allele results in a larger decrease in relative fitness. Negative selection with synergistic epistasis should produce negative linkage disequilibrium between deleterious alleles and, therefore, an underdispersed distribution of the number of deleterious alleles in the genome. Indeed, we detected underdispersion of the number of rare loss-of-function alleles in eight independent data sets from human and fly populations. Thus, selection against rare protein-disrupting alleles is characterized by synergistic epistasis, which may explain how human and fly populations persist despite high genomic mutation rates.

Fig. 1.. Rare mutation burden under natural selection (orange, right) and population structure (yellow, left).

The mutation burden (bottom panel) is shown under the null model (gray, the absence of epistasis and population structure) and under variance-increasing (blue, antagonistic epistasis and population structure) and variance-reducing (pink, synergistic epistasis) models. μ_k is the mean of the mutation burden in subpopulation k within the population.

Fig. 2.. Simulated and empirical distributions of rare missense mutation burden.

(A) Simulations using SLiM 2.0 of unlinked sites under multiplicative selection in a finite population with heterogeneous demography (11). σ²/V_A was calculated for the rare mutation burden computed on singletons at equilibrium, with the null expectation as shown (blue dotted line). Error bars show SEM (100 replicates). (B) Missense rare mutation burden (red) computed on singletons across the genome (σ²/V_A = 2.077) and only in the crucial genome (σ²/V_A = 0.937) in the GoNL data set, overlaid with Poisson distributions (black) having identical means. The crucial genome for humans was constructed by selecting only genes with an estimated selection coefficient against heterozygous protein-truncating variants exceeding 0.2 (11).

Fig. 3.. Resampling distributions of σ²/V_A for rare LoF mutation burden in humans and D. melanogaster.

Synonymous (purple) and missense (green) alleles were resampled at the same allele frequency as LoF alleles to obtain empirical null distributions for σ²/V_A in each data set. For humans, only singletons, and for flies, only alleles up to a minor allele count of 5, are included. A one-sided P value for σ²/V_A of the rare LoF mutation burden (red) was obtained, and a joint P value for all three human data sets shown (GoNL, ADNI, MinE) was computed by meta-analysis using Stouffer’s method (11) (P = 0.0003).