Background selection as null hypothesis in population genomics: insights and challenges from Drosophila studies

Abstract

The consequences of selection at linked sites are multiple and widespread across the genomes of most species. Here, I first review the main concepts behind models of selection and linkage in recombining genomes, present the difficulty in parametrizing these models simply as a reduction in effective population size (N_e) and discuss the predicted impact of recombination rates on levels of diversity across genomes. Arguments are then put forward in favour of using a model of selection and linkage with neutral and deleterious mutations (i.e. the background selection model, BGS) as a sensible null hypothesis for investigating the presence of other forms of selection, such as balancing or positive. I also describe and compare two studies that have generated high-resolution landscapes of the predicted consequences of selection at linked sites in Drosophila melanogaster Both studies show that BGS can explain a very large fraction of the observed variation in diversity across the whole genome, thus supporting its use as null model. Finally, I identify and discuss a number of caveats and challenges in studies of genetic hitchhiking that have been often overlooked, with several of them sharing a potential bias towards overestimating the evidence supporting recent selective sweeps to the detriment of a BGS explanation. One potential source of bias is the analysis of non-equilibrium populations: it is precisely because models of selection and linkage predict variation in N_e across chromosomes that demographic dynamics are not expected to be equivalent chromosome- or genome-wide. Other challenges include the use of incomplete genome annotations, the assumption of temporally stable recombination landscapes, the presence of genes under balancing selection and the consequences of ignoring non-crossover (gene conversion) recombination events.This article is part of the themed issue 'Evolutionary causes and consequences of recombination rate variation in sexual organisms'.

Keywords: background selection; genetic hitchhiking; recombination; selective sweep.

Figure 1.

Models of selection with recombination. Horizontal lines represent different genetic backgrounds or haplotypes across a genomic region. Panels below the haplotypes depict qualitative levels of neutral diversity across the region, with the dashed line representing the expected level of neutral diversity in the absence of selection. Blue rectangles below the neutral diversity panels represent the location of two functionally relevant sequences where beneficial and deleterious mutations can occur. (a) CS and (b) RSS (or Draft) involve the fixation of new beneficial mutations (red circles) together with linked genetic variants. As a consequence, neutral diversity near the genomic location of the beneficial mutation is strongly reduced immediately after fixation and is expected to recover with time. The RSS/Draft model assumes that selective sweeps can occur before the complete recovery of neutral diversity from a previous sweep. (c) BGS predicts the continual appearance and elimination of deleterious mutations (black circles, shown here before being eliminated by selection) together with linked genetic variants. The deleterious mutation rate at functional sequences is assumed to be much higher than the beneficial mutation rate.

Figure 2.

Summaries of goodness of fit between high-resolution estimates of the strength of selection at linked sites across the D. melanogaster genome and levels of diversity (π) at synonymous sites. B indicates estimates of BGS following the methodology presented in [79]. B_{CL_BGS}, B_{CL_CS} and B_{CL_BGS+CS} indicate CL-based estimates of B from Elyashiv et al. [82] when including deleterious mutations, beneficial mutations or the joint effects of deleterious and beneficial mutations, respectively. Estimates of the coefficient of determination (R²) are shown for analyses of non-overlapping regions of 1, 10, 100 and 1000 kb across autosomes. R² estimates for B_{CL_BGS}, B_{CL_CS} and B_{CL_BGS+CS} are from Fig. 2 in [82] (see the text for details). In all cases, only regions with recombination rates greater than 0.1 cM per Mb were analysed.

Figure 3.

Population dynamics after a bottleneck and rapid recovery under varying intensities of BGS. (a) The relative change in diversity at neutral sites (π/π₀, where π₀ indicates neutral diversity at equilibrium), (b) estimates of Tajima's D at neutral sites after normalizing by D_min (D/D_min) [96,113] and (c) estimates of α, the fraction of adaptive amino acid substitutions [–117]. All results are based on forward simulations of a panmictic population of 10 000 diploid individuals (N) with a severe bottleneck at time 0.1N (0.22% of initial population size) and rapid recovery to the initial N after 0.01N generations. Simulations using the program SLiM [118] followed a chromosome segment of 2 Mb that contains one representative Drosophila protein-encoding gene every 10 kb (solid lines) or every 50 kb (dashed lines). Different degrees of BGS were generated through the use of different rates of total recombination observed across D. melanogaster chromosomes. Very strong BGS was accomplished with very low rates of CO (c; N × c = 1 × 10⁻⁴/bp/generation; red line), strong BGS was accomplished with low rates of CO (N × c = 1 × 10⁻³/bp/generation; green line) and moderate BGS was accomplished with a D. melanogaster genome-wide average rate of CO (N × c = 1.2 × 10⁻²/bp/generation; blue line). All simulations also included an NCO rate (g) of N × g = 4.8 × 10⁻²/bp/generation [40]. Black lines in (a) and (b) indicate results for neutral sequences not influenced by selection. Estimates of the fraction of adaptive amino acid substitutions α were obtained using the DFE-alpha programs [116,117] after jointly inferring the DFEs on amino acid mutations and demography under a two-epoch model. See electronic supplementary material for details on SLiM simulations and analyses.