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

While there has been extensive work on patterns of linkage disequilibrium (LD) for neutral loci, the extent to which negative selection impacts LD is less clear. Forces like Hill-Robertson interference and negative epistasis are expected to 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 LD in natural populations with complex demographic histories has not been tested. In this study, we first used forward-in-time simulations to generate predictions as to how 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, generating an excess of negative LD relative to pairs of synonymous SNPs. In contrast, for recessive mutations, there is no consistent ordering of how selection coefficients affect r2 d...