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

Abstract

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 r 2 decay. We then examined empirical data of modern humans from the 1000 Genomes Project. LD between derived nonsynonymous SNPs is more negative compared to pairs of derived synonymous variants. This result holds when matching SNPs for frequency in the sample (allele count), physical distance, magnitude of background selection, and genetic distance between pairs of variants, suggesting that this result is not due to these potential confounding factors. 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 deleterious alleles tend to be located on different haplotypes more often than are neutral alleles. Our findings suggest that either interference or negative epistasis plays a pervasive role in shaping 2 patterns of LD between deleterious variants in the human genome, and consequently influencing genome-wide patterns of LD.3

Linkage disequilibrium between rare mutations

“…In these cases, we saw that ancient nested mutations will create an excess of coupling linkage (f AB > f A f B ) that qualitatively resembles the effects of antagonistic epistasis. This excess coupling linkage has previously been observed in computer simulations and in genomic data from diverse organisms (Garcia and Lohmueller, 2020;Sandler et al, 2020;Sohail et al, 2017), where it has fueled an ongoing debate about the inference of epistasis from patterns of nonsynonymous and synonymous LD in a variety of species. Our analytical calculations suggest a potential mechanism for this counterintuitive behavior, and they demonstrate that this effect will generically arise even in the absence of admixture or other complex demographic scenarios.…”

“…While there has been some progress in predicting patterns of linkage disequilibrium under particular selection scenarios [e.g., hitchhiking near a recent selective sweep (Kim and Nielsen, 2004;McVean, 2007;Pfaffelhuber et al, 2008;Pokalyuk, 2012;Stephan et al, 2006)] we currently lack analogous theoretical predictions for the empirically relevant case where a subset of the observed mutations are deleterious. This is a crucial limitation, since numerous studies have documented differences in the genome-wide patterns of LD between synonymous and nonsynonymous mutations (Arnold et al, 2020;Garcia and Lohmueller, 2020;Rosen et al, 2018;Sohail et al, 2017) or for genic vs intergenic regions of the genome (Eberle et al, 2006), where purifying selection is thought to play an important role. Several recent studies have begun to explore these effects in computer simulations (Arnold et al, 2020;Garcia and Lohmueller, 2020;Ragsdale and Gravel, 2019).…”

“…This is a crucial limitation, since numerous studies have documented differences in the genome-wide patterns of LD between synonymous and nonsynonymous mutations (Arnold et al, 2020;Garcia and Lohmueller, 2020;Rosen et al, 2018;Sohail et al, 2017) or for genic vs intergenic regions of the genome (Eberle et al, 2006), where purifying selection is thought to play an important role. Several recent studies have begun to explore these effects in computer simulations (Arnold et al, 2020;Garcia and Lohmueller, 2020;Ragsdale and Gravel, 2019). Yet without a corresponding analytical theory, it can be difficult to understand how these patterns depend on the underlying parameters of the model, or to determine when more exotic forces like positive selection, epistasis, or ecological structure are necessary to fully explain the observed data.…”

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

“…However, the combined effect of non-additive selection within a locus and interference has received less attention. G arcia and L ohmueller (2020) used large-scale forward simulations to explore the effect of dominance on patterns of LD, showing that LD depends on both the magnitude of the selection and dominance coefficients in a nonlinear way, but note that expensive large-scale simulations are needed to explore these effects as no closed form approach to computing those expectations exist. The method presented here provides such a closed form approach, so that expectations of signed LD and other two-locus statistics can be computed more efficiently and accurately.…”

“…They interpreted this as evidence for widespread synergistic epistasis between these mutations, in which the fitness reduction of multiple mutations is greater than the product of that of each individual mutations independently. Within the past year or two, both S andler et al (2020) and G arcia and L ohmueller (2020) have 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 ohmueller , 2020) or questioned whether LD between loss-of-function variants is significantly different from zero (S andler et al , 2020).…”