The Effect of Strong Purifying Selection on Genetic Diversity
The Effect of Strong Purifying Selection on Genetic Diversity
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DOI：
10.1534/genetics.118.301058
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发表时间：
2018-08-01
期刊：
影响因子：
3.3
通讯作者：
Desai, Michael M.
中科院分区：
文献类型：
--
作者：
Cvijovic, Ivana;Good, Benjamin H.;Desai, Michael M.
纯化选择降低了直接选择位点和相连中性位点的遗传多样性。这一过程被称为背景选择，被认为在塑造自然群体基因组多样性方面发挥着重要作用。然而，尽管背景选择很重要，但它的影响尚未得到充分理解。先前对该过程的理论分析采用了基于结构化聚结的向后时间方法。虽然它们提供了一些见解，但这些方法要么仅限于非常小的样本，要么在计算上令人望而却步。在这里，我们对非重组位点的中性突变和有害突变的轨迹进行了新的前向时间分析。我们发现，强大的净化选择会带来非常丰富的动态：中性突变可以表现出类似扫荡的行为，而有害突变可以达到相当高的频率，即使它们最终肯定会灭绝。我们对这些动态的分析使我们能够计算全站点频谱的解析表达式。我们发现，只要背景选择足够强，导致遗传多样性减少，它也会导致位点频谱的严重扭曲，这可以模仿种群扩张或正选择的影响。由于这些失真在频谱的低频端和高频端最为明显，因此它们在较大样本中变得尤为重要，但在较小样本中可能影响较小。我们还应用我们的前向时间框架来计算其他量，例如多态性的最终命运或其祖先背景的适应性。
Purifying selection reduces genetic diversity, both at sites under direct selection and at linked neutral sites. This process, known as background selection, is thought to play an important role in shaping genomic diversity in natural populations. Yet despite its importance, the effects of background selection are not fully understood. Previous theoretical analyses of this process have taken a backward-time approach based on the structured coalescent. While they provide some insight, these methods are either limited to very small samples or are computationally prohibitive. Here, we present a new forward-time analysis of the trajectories of both neutral and deleterious mutations at a nonrecombining locus. We find that strong purifying selection leads to remarkably rich dynamics: neutral mutations can exhibit sweep-like behavior, and deleterious mutations can reach substantial frequencies even when they are guaranteed to eventually go extinct. Our analysis of these dynamics allows us to calculate analytical expressions for the full site frequency spectrum. We find that whenever background selection is strong enough to lead to a reduction in genetic diversity, it also results in substantial distortions to the site frequency spectrum, which can mimic the effects of population expansions or positive selection. Because these distortions are most pronounced in the low and high frequency ends of the spectrum, they become particularly important in larger samples, but may have small effects in smaller samples. We also apply our forward-time framework to calculate other quantities, such as the ultimate fates of polymorphisms or the fitnesses of their ancestral backgrounds.