Negative linkage disequilibrium between amino acid changing variants reveals interference among deleterious mutations in the human genome

Abstract

Evolutionary forces like Hill-Robertson interference and negative epistasis can lead to deleterious mutations being found on distinct haplotypes. However, the extent to which these forces depend on the selection and dominance coefficients of deleterious mutations and shape genome-wide patterns of linkage disequilibrium (LD) in natural populations with complex demographic histories has not been tested. In this study, we first used forward-in-time simulations to predict how negative selection impacts LD. Under models where deleterious mutations have additive effects on fitness, deleterious variants less than 10 kb apart tend to be carried on different haplotypes relative to pairs of synonymous SNPs. In contrast, for recessive mutations, there is no consistent ordering of how selection coefficients affect LD decay, due to the complex interplay of different evolutionary effects. We then examined empirical data of modern humans from the 1000 Genomes Project. LD between derived alleles at nonsynonymous SNPs is lower compared to pairs of derived synonymous variants, suggesting that nonsynonymous derived alleles tend to occur on different haplotypes more than synonymous variants. This result holds when controlling for potential confounding factors by matching SNPs for frequency in the sample (allele count), physical distance, magnitude of background selection, and genetic distance between pairs of variants. Lastly, we introduce a new statistic HR(j) which allows us to detect interference using unphased genotypes. Application of this approach to high-coverage human genome sequences confirms our finding that nonsynonymous derived alleles tend to be located on different haplotypes more often than are synonymous derived alleles. Our findings suggest that interference may play a pervasive role in shaping patterns of LD between deleterious variants in the human genome, and consequently influences genome-wide patterns of LD.

Local fitness and epistatic effects lead to distinct patterns of linkage disequilibrium in protein-coding genes

“…The combined effect of the strength of selection and dominance on interference is indeed nontrivial (Figure 4A), as observed by G arcia and L ohmüeller (2021). Some parameter regimes can cause strong negative LD between pairs of negatively selected variants, with moderately selected recessive variants having stronger signals of interference than additive selection (Figure 4B).…”

“…The effect of non-additive selection on correlations between mutations has received increased attention recently. For example, G arcia and L ohmueller (2021) used large-scale forward simulations to explore how dominance impacts patterns of LD, showing that LD depends on the magnitudes of both the selection and dominance coefficients in a nonlinear way. R oze (2021) found an analytic expression for LD between pairs of strongly deleterious mutations under steady-state demography, showing that LD can be either positive or negative depending on the strength of dominance.…”

“…Positive average LD between both missense and synonymous mutations has been reported in humans, Drosophila , and other species (S ohail et al ., 2017; S andler et al ., 2021), while others have found that nonsynonymous mutations show lower LD than synonymous mutations (G arcia and L ohmüeller , 2021). The similarity of their gene-wide LD observed in this study (Figure 8) might suggest that interference or interactions between missense mutations are minimal, or at least no stronger than those between synonymous mutations.…”

“…Previous theoretical and simulation studies have shown that interference and interactions between selected mutations reduce the efficacy of selection at linked loci, impacting substitution rates, the deleterious mutation load, and dynamics of segregating mutations (H ill and R obertson , 1968; B irky and W alsh , 1988; B arton , 1995; M cVean and C harlesworth , 2000). Interference and synergistic epistasis between moderately deleterious mutations are both expected to cause negative LD between selected mutations, which can be readily tested using population genetic data (S ohail et al, 2017; S andler et al, 2021; G arcia and L ohmueller , 2021). Here, I used a closed numerical approach to generate expectations for LD under a wide range of selective scenarios, and then compared patterns of LD in human populations between classes of coding mutations using unbiased estimators for LD from unphased genotypes.…”

“…Both S andler et al . (2021) and G arcia and L ohmüeller (2021) have recently reevaluated patterns of LD between coding variants in humans, fruit flies, and Capsella grandiflora , and suggested interference and dominance may instead be driving patterns of LD (G arcia and L ohmüeller , 2021) or questioned whether LD between loss-of-function variants is significantly different from zero (S andler et al ., 2021).…”