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

Author summary Many mutations in genomes are deleterious, decreasing fitness in carriers. Popular methods to quantify deleterious mutations model mutations independently while ignoring the correlations between nearby variants. Theory predicts that a deleterious mutation can influence the frequency change of variants located nearby along the genome. Here we use simulations under population genetic models with parameters relevant to humans to show that pairs of deleterious mutations located near each other in the genome tend to have different correlations between them as compared to pairs of neutrally evolving SNPs. Specifically, if an individual carries the deleterious allele at one variant, that individual is less likely to carry the deleterious allele at a nearby variant. We then searched for these patterns in both low and high-coverage human genetic variation datasets from multiple populations. We found that pairs of deleterious alleles tend to be found in different individuals more frequently than are pairs of neutrally evolving variants at the same frequency, even after controlling for confounding factors. Our results suggest that the interference between deleterious alleles is common across the human genome, which has implications for inferring demographic history, natural selection, and associating variants with complex traits. 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 H-R((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.