On the Trail of Linked Selection

Distinguishing the relative roles of positive and negative selection along with demographic history in shaping genetic diversity has been a decades-long endeavor. Understanding the forces structuring genetic variation informs us not only about the factors maintaining diversity but also about the fundamental evolutionary parameters that influence natural populations, including the rate and strength of positive selection, the deleterious genetic load experienced by populations, and the factors driving genome evolution. Most attempts at modeling demography, positive selection, or negative selection typically do so by ignoring the contribution of the other forces. Because multiple forces are acting simultaneously, these inferences likely overestimate the role of single evolutionary forces and can lead to biased interpretations. In this issue, Elyashiv et al. [1] make important advances towards addressing this problem by presenting a novel approach to simultaneously estimate the parameters of positive and negative selection based on the spatial patterns of neutral genetic variation and apply this method to Drosophila. Elyashiv et al.’s [1] approach takes advantage of a long-held prediction that patterns of neutral variation can reveal the action of selection at linked sites. Maynard Smith and Haigh first recognized the potential impacts of linked selection in 1974 when they modeled the reduction in neutral genetic diversity that would occur near a site under positive selection, often termed a selective sweep, and argued that this process would reduce diversity genome-wide given sufficiently high rates of positive selection [2]. Support for their theory was first obtained when molecular population genetic data from Drosophila showed a correlation between diversity and recombination rate, which was consistent with the idea that selective sweeps are common and have a stronger impact on neutral diversity in regions of low recombination [3,4]. However, Charlesworth and colleagues proposed an alternate explanation: negative selection against the continuous influx of new deleterious mutations (background selection) will also reduce nearby neutral diversity, causing a similar correlation between recombination and genetic diversity [5]. This model has been used to show that many of the major patterns of variation in diversity across the Drosophila genome are explainable by this process [6]. Since this alternative mechanism was first proposed, understanding the relative importance of positive and negative selection on linked neutral diversity has been an ongoing challenge in population genetics [7]. Although evidence has continued to mount for the negative relationship between recombination and diversity due to linked selection [8], the expectation that both sweeps and background selection are strongest in regions of low recombination made it difficult to identify what selective forces are responsible for lower diversity in low recombination regions. A number of proposed signals in the data have been thought to be unique predictions that could help distinguish the models, including the allele frequency spectrum in regions of low recombination [3,9] and the exact shape of the relationship between recombination and diversity [10]. However, by broadening background selection predictions to include a class of slightly