Hitchhiking both ways: effect of two interfering selective sweeps on linked neutral variation

Abstract

The neutral polymorphism pattern in the vicinity of a selective sweep can be altered by both stochastic and deterministic factors. Here, we focus on the impact of another selective sweep in the region of influence of a first one. We study the signature left on neutral polymorphism by positive selection at two closely linked loci, when both beneficial mutations reach fixation. We show that, depending on the timing of selective sweeps and on their selection coefficients, the two hitchhiking effects can interfere with each other, leading to less reduction in heterozygosity than a single selective sweep of the same magnitude and more importantly to an excess of intermediate-frequency variants relative to neutrality under some parameter values. This pattern can be sustained and potentially alter the detection of positive selection, including by provoking spurious detection of balancing selection. In situations where positive selection is suspected a priori at several closely linked loci, the polymorphism pattern in the region may also be informative about their selective histories.

Figure 1.—

Polymorphism patterns along the chromosome. (A) Reduction of heterozygosity (π/π_o) in the whole population; (B) Tajima's D in a sample of size 2n = 50 chromosomes, as a function of the distance to sel₁. Solid line: selective sweeps at two close loci, with s₁ = s₂ = s = 0.1 and . Dashed line: single selective sweep with s = 0.1 and r/s = 0.05. Results are averaged over 500 simulations with population size 2N = 20,000. sel₁ is at position 0 in both cases. In the case of two selective sweeps, sel₂ is located at 0.50 cM, so the rest of the pattern (not shown) would be symmetrical over x = 0.25.

Figure 2.—

Frequency spectrum of mutations in a sample of size n = 25 diploid individuals (2n = 50 chromosomes). Solid line, expectation under standard neutrality; open bars, neu₁ (outer locus); shaded bars, neu_m (inner locus). Results are averaged over 500 simulation runs. Parameters are as in Figure 1.

Figure 3.—

Influence of the distance between selected loci. (A) Reduction of heterozygosity in the whole population; (B) Tajima's D at neu_m (solid line) or neu₁ (dashed line), in a sample of size 2n = 50, plotted against the distance between the selected loci expressed as a ratio between recombination and the selection coefficient. Mean results are over 1000 repeats, with all the parameters as in Figure 1 except for .

Figure 4.—

Power to reject neutrality after the sweeps: proportion of simulations (of 500–1000 repeats) that reject neutrality at the 5%-significance level using (A) D, (B) H, or (C) E as summary statistics, plotted against the time T (in generations) since fixation of the last beneficial mutation. Significance was assessed with standard coalescent simulations (10,000 runs), and all statistics were used in a one-sided test for negative values. Cross, neu_m; box, neu₁.

Figure 4.—

Power to reject neutrality after the sweeps: proportion of simulations (of 500–1000 repeats) that reject neutrality at the 5%-significance level using (A) D, (B) H, or (C) E as summary statistics, plotted against the time T (in generations) since fixation of the last beneficial mutation. Significance was assessed with standard coalescent simulations (10,000 runs), and all statistics were used in a one-sided test for negative values. Cross, neu_m; box, neu₁.

Figure 4.—

Power to reject neutrality after the sweeps: proportion of simulations (of 500–1000 repeats) that reject neutrality at the 5%-significance level using (A) D, (B) H, or (C) E as summary statistics, plotted against the time T (in generations) since fixation of the last beneficial mutation. Significance was assessed with standard coalescent simulations (10,000 runs), and all statistics were used in a one-sided test for negative values. Cross, neu_m; box, neu₁.

Figure 5.—

Delayed selective sweeps with varying selection coefficients: final Tajima's D at (A) neu₁, (B) neu_m, and (C) neu₂ as a function of the scaled delay τ between the introduction of the beneficial mutations at sel₁ and at sel₂ (see appendix b). Thin line, s₂ = s₁; thick line, s₂ = s₁/2; dashed line, s₂ = 2s₁. All other parameters are as in Figure 1.

Figure 5.—

Delayed selective sweeps with varying selection coefficients: final Tajima's D at (A) neu₁, (B) neu_m, and (C) neu₂ as a function of the scaled delay τ between the introduction of the beneficial mutations at sel₁ and at sel₂ (see appendix b). Thin line, s₂ = s₁; thick line, s₂ = s₁/2; dashed line, s₂ = 2s₁. All other parameters are as in Figure 1.

Figure 5.—

Delayed selective sweeps with varying selection coefficients: final Tajima's D at (A) neu₁, (B) neu_m, and (C) neu₂ as a function of the scaled delay τ between the introduction of the beneficial mutations at sel₁ and at sel₂ (see appendix b). Thin line, s₂ = s₁; thick line, s₂ = s₁/2; dashed line, s₂ = 2s₁. All other parameters are as in Figure 1.