Background selection theory overestimates effective population size for high mutation rates

Simple models from the neutral theory of molecular evolution are claimed to be flexible enough to incorporate the complex effects of background selection against linked deleterious mutations. Complexities are collapsed into an "effective" population size that specifies neutral genetic diversity. To achieve this, current background selection theory assumes linkage equilibrium among deleterious variants. Data do not support this assumption, nor do theoretical considerations when the genome-wide deleterious mutation is realistically high. We simulate genomes evolving under background selection, allowing the emergence of linkage disequilibria. With realistically high deleterious mutation rates, neutral diversity is much lower than predicted from previous analytical theory.

Recombination suppression and selection affect local ancestries in genomes of a migratory songbird

The patterns of genetic relatedness among individuals vary along the genome, representing fluctuation of local ancestry. The factors responsible for this variation have not been well studied in wild animals with ecological and behavioural relevance. Here, we characterise the genomic architecture of genetic relatedness in the Eurasian blackcap, an iconic songbird species in ecology and quantitative genetics of migratory behaviour. We identify 23 genomic regions with deviated local relatedness patterns, using a chromosome-level de novo assembly of the blackcap genome and whole-genome resequencing data of 179 individuals from nine populations with diverse migratory phenotypes. Five genomic regions show local relatedness patterns of polymorphic inversions, three of which are syntenic to polymorphic inversions known in the zebra finch. Phylogenetic analysis reveals these three polymorphic inversions evolved independently in the blackcap and zebra finch indicating convergence of polymorphic inversions. Population genetic analyses in these three inversions in the blackcap suggest balancing selection between two haplotypes in one locus and background selection in the other two loci. One genomic region with deviated local relatedness is under selection against gene flow by population-specific reduction in recombination rate. Other genomic islands including 11 pericentromeric regions consist of evolutionarily conserved and non-conserved recombination cold-spots under background selection. Two of these regions with non-conserved recombination suppression are known to be associated with population-specific migratory phenotypes, where local relatedness patterns support additional effects of population-specific selection. These results highlight how different forms of recombination suppression and selection jointly affect heterogeneous genomic landscape of local ancestries.

Background selection under evolving recombination rates

Background selection (BGS), the effect that purifying selection exerts on sites linked to deleterious alleles, is expected to be ubiquitous across eukaryotic genomes. The effects of BGS reflect the interplay of the rates and fitness effects of deleterious mutations with recombination. A fundamental assumption of BGS models is that recombination rates are invariant over time. However, in some lineages recombination rates evolve rapidly, violating this central assumption. Here, we investigate how recombination rate evolution affects genetic variation under BGS. We show that recombination rate evolution modifies the effects of BGS in a manner similar to a localised change in the effective population size, potentially leading to an underestimation of the genome-wide effects of selection. Furthermore, we find evidence that recombination rate evolution in the ancestors of modern house mice may have impacted inferences of the genome-wide effects of selection in that species.

The role of pseudo-overdominance in maintaining inbreeding depression

Classical models ignoring linkage predict that deleterious recessive mutations purge or fix within inbred populations, yet these often retain moderate to high segregating load. True overdominance generates balancing selection that sustains inbreeding depression even in inbred populations but is rare. In contrast, arrays of mildly deleterious recessives linked in repulsion may occur commonly enough to generate pseudo-overdominance and sustain segregating load. We used simulations to explore how long pseudo-overdominant regions (POD's) persist following their creation via hybridization between populations fixed for alternative mutations at linked loci. Balancing haplotype loads, tight linkage, and moderate to strong cumulative selective effects serve to maintain POD's, suggesting that POD's may most often arise and persist in low recombination regions (e.g., inversions). Selection and drift unbalance the load, eventually eliminating POD's, but this process is very slow when pseudo-overdominance is strong. Background selection across the genome accelerates the loss of weak POD's but reinforces strong POD's in inbred populations by disfavoring homozygotes. Further modeling and studies of POD dynamics within populations could help us understand how POD's affect persistence of the load and how inbred mating systems evolve.

Genomic background selection to reduce the mutation load after random mutagenesis

Random mutagenesis is a standard procedure to increase allelic variation in a crop species, especially in countries where the use of genetically modified crops is limited due to legal constraints. The chemical mutagen EMS is used in many species to induce random mutations throughout the genome with high mutation density. The major drawback for functional analysis is a high background mutation load in a single plant that must be eliminated by subsequent backcrossing, a time and resource-intensive activity. Here, we demonstrate that genomic background selection combined with marker-assisted selection is an efficient way to select individuals with reduced background mutations within a short period. We identified BC1 plants with a significantly higher share of the recurrent parent genome, thus saving one backcross generation. Furthermore, spring rapeseed as the recurrent parent in a backcrossing program could accelerate breeding by reducing the generation cycle. Our study depicts the potential for reducing the background mutation load while accelerating the generation cycle in EMS-induced winter oilseed rape populations by integrating genomic background selection.

Variable signatures of selection despite conserved recombination landscapes early in speciation

Recently diverged taxa often exhibit heterogeneous landscapes of genomic differentiation, characterized by regions of elevated differentiation on an otherwise homogeneous background. While divergence peaks are generally interpreted as regions responsible for reproductive isolation, they can also arise due to background selection, selective sweeps unrelated to speciation, and variation in recombination and mutation rates. To investigate the association between patterns of recombination and landscapes of genomic differentiation during the early stages of speciation, we generated fine-scale recombination maps for six southern capuchino seedeaters (Sporophila) and two subspecies of White Wagtail (Motacilla alba), two recent avian radiations in which divergent selection on pigmentation genes has likely generated peaks of differentiation. We compared these recombination maps to those of Collared (Ficedula albicollis) and Pied Flycatchers (Ficedula hypoleuca), non-sister taxa characterized by moderate genomic divergence and a heterogenous landscape of genomic differentiation shaped in part by background selection. Although recombination landscapes were conserved within all three systems, we documented a weaker negative correlation between recombination rate and genomic differentiation in the recent radiations. All divergence peaks between capuchinos, wagtails, and flycatchers were located in regions with lower-than-average recombination rates, and most divergence peaks in capuchinos and flycatchers fell in regions of exceptionally reduced recombination. Thus, co-adapted allelic combinations in these regions may have been protected early in divergence, facilitating rapid diversification. Despite largely conserved recombination landscapes, divergence peaks are specific to each focal comparison in capuchinos, suggesting that regions of elevated differentiation have not been generated by variation in recombination rate alone.

Highly pleiotropic variants of human traits are enriched in genomic regions with strong background selection

Recent studies have shown the ubiquity of pleiotropy for variants affecting human complex traits. These studies also show that rare variants tend to be less pleiotropic than common ones, suggesting that purifying natural selection acts against highly pleiotropic variants of large effect. Here, we investigate the mean frequency, effect size and recombination rate associated with pleiotropic variants, and focus particularly on whether highly pleiotropic variants are enriched in regions with putative strong background selection. We evaluate variants for 41 human traits using data from the NHGRI-EBI GWAS Catalog, as well as data from other three studies. Our results show that variants involving a higher degree of pleiotropy tend to be more common, have larger mean effect sizes, and contribute more to heritability than variants with a lower degree of pleiotropy. This is consistent with the fact that variants of large effect and frequency are more likely detected by GWAS. Using data from four different studies, we also show that more pleiotropic variants are enriched in genome regions with stronger background selection than less pleiotropic variants, suggesting that highly pleiotropic variants are subjected to strong purifying selection. From the above results, we hypothesized that a number of highly pleiotropic variants of low effect/frequency may pass undetected by GWAS.

Broad-scale variation in human genetic diversity levels is predicted by purifying selection on coding and non-coding elements

Analyses of genetic variation in many taxa have established that neutral genetic diversity is shaped by natural selection at linked sites. Whether the source of selection is primarily the fixation of strongly beneficial alleles (selective sweeps) or purifying selection on deleterious mutations (background selection) remains unknown, however. We address this question in humans by fitting a model of the joint effects of selective sweeps and background selection to autosomal polymorphism data from the 1000 Genomes Project. After controlling for variation in mutation rates along the genome, a model of background selection alone explains ~60% of the variance in diversity levels at the megabase scale. Adding the effects of selective sweeps driven by adaptive substitutions to the model does not improve the fit, and when both modes of selection are considered jointly, selective sweeps are estimated to have had little or no effect on linked neutral diversity. The regions under purifying selection are best predicted by phylogenetic conservation, with ~80% of the deleterious mutations affecting neutral diversity occurring in non-exonic regions. Thus, background selection is the dominant mode of linked selection in humans, with marked effects on diversity levels throughout autosomes.

Selective sweeps influence diversity over large regions of the mouse genome

To what extent do substitutions in protein-coding versus gene-regulatory regions contribute to fitness change over time? Answering this question requires estimates of the extent of selection acting on beneficial mutations in the two classes of sites. New mutations that have advantageous or deleterious fitness effects can induce selective sweeps and background selection, respectively, causing variation in the level of neutral genetic diversity along the genome. In this study, we analyse the profiles of genetic variability around protein-coding and regulatory elements in the genomes of wild mice to estimate the parameters of positive selection. We find patterns of diversity consistent with the effects of selection at linked sites, which are similar across mouse taxa, despite differences in effective population size and demographic history. By fitting a model that combines the effects of selective sweeps and background selection, we estimate the strength of positive selection and the frequency of advantageous mutations. We find that strong positive selection is required to explain variation in genetic diversity across the murid genome. In particular, we estimate that beneficial mutations in protein-coding regions have stronger effects on fitness than do mutations in gene-regulatory regions, but that mutations in gene-regulatory regions are more common. Overall though, our parameter estimates suggest that the cumulative fitness changes brought about by beneficial mutations in protein-coding may be greater than those in gene-regulatory elements.

Highly pleiotropic variants of human traits are enriched in genomic regions with strong background selection

Recent studies have shown the ubiquity of pleiotropy for variants affecting human complex traits. These studies also show that rare variants tend to be less pleiotropic than common ones, suggesting that purifying natural selection acts against highly pleiotropic variants of large effect. Here we investigate the mean frequency, effect size and recombination rate associated with pleiotropic variants, and focus particularly on whether highly pleiotropic variants are enriched in regions with putative strong background selection. We evaluate variants for 41 human traits using data from the NHGRI-EBI GWAS Catalog, as well as data from other three studies. Our results show that variants involving a higher degree of pleiotropy tend to be more common, have larger mean effect sizes, and contribute more to heritability than variants with a lower degree of pleiotropy. Using data from four different studies, we show that more pleiotropic variants are enriched in genome regions with stronger background selection than less pleiotropic variants. Thus, we conclude that even though highly pleiotropic variants found so far have larger average effect sizes and frequencies than less pleiotropic ones, they are likely to be subjected to stronger background selection.