Obstruction of adaptation in diploids by recessive, strongly deleterious alleles
Obstruction of adaptation in diploids by recessive, strongly deleterious alleles
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DOI：
10.1073/pnas.1424949112
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发表时间：
2015-05-19
影响因子：
11.1
通讯作者：
Blundell, Jamie R.
中科院分区：
文献类型：
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作者：
Assaf, Zoe June;Petrov, Dmitri A.;Blundell, Jamie R.
隐性有害突变是常见的，在人类中引起许多遗传疾病，并在大多数有性繁殖的二倍体中产生近交抑郁症。自然种群中大量的隐性有害突变表明，当新的适应性突变发生时，它们很可能出现在染色体上，然而隐性有害突变的动态及其对适应性的影响仍然知之甚少。在这里，我们建立了一个隐性有害突变如何影响遗传相关的显性有益突变的命运的模型。在这种情况下，适应性突变的频率轨迹发生了巨大的变化，导致了我们所说的“交错扫描”。它因其三个阶段的轨迹而命名：(i)最初，两个连锁突变在罕见的情况下具有选择优势，并且会一起增加频率，然后（ii）在较高的频率下，隐性搭便车者暴露于选择并可以通过杂合子优势（交错阶段）导致平衡状态，（iii）最后，如果重组解除两个突变的连接，那么有益的突变可以完成对固定的扫描。通过分析和模拟，我们发现强烈有害的隐性突变可以大大降低附近有益突变的固定概率，从而在基因组中产生抑制适应的区域。这些突变还可以显著延长一个有益突变扫描到固定所需的代数，并导致选择的基因组特征与软扫描或部分扫描相似。我们表明，隐性有害变异可能影响人类和果蝇的适应。
Recessive deleterious mutations are common, causing many genetic disorders in humans and producing inbreeding depression in the majority of sexually reproducing diploids. The abundance of recessive deleterious mutations in natural populations suggests they are likely to be present on a chromosome when a new adaptive mutation occurs, yet the dynamics of recessive deleterious hitchhikers and their impact on adaptation remains poorly understood. Here we model how a recessive deleterious mutation impacts the fate of a genetically linked dominant beneficial mutation. The frequency trajectory of the adaptive mutation in this case is dramatically altered and results in what we have termed a "staggered sweep." It is named for its three-phased trajectory: (i) Initially, the two linked mutations have a selective advantage while rare and will increase in frequency together, then (ii), at higher frequencies, the recessive hitchhiker is exposed to selection and can cause a balanced state via heterozygote advantage (the staggered phase), and (iii) finally, if recombination unlinks the two mutations, then the beneficial mutation can complete the sweep to fixation. Using both analytics and simulations, we show that strongly deleterious recessive mutations can substantially decrease the probability of fixation for nearby beneficial mutations, thus creating zones in the genome where adaptation is suppressed. These mutations can also significantly prolong the number of generations a beneficial mutation takes to sweep to fixation, and cause the genomic signature of selection to resemble that of soft or partial sweeps. We show that recessive deleterious variation could impact adaptation in humans and Drosophila.