Pervasive hitchhiking at coding and regulatory sites in humans.
Pervasive hitchhiking at coding and regulatory sites in humans.
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DOI：
10.1371/journal.pgen.1000336
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发表时间：
2009-01
期刊：
影响因子：
4.5
通讯作者：
Petrov, Dmitri A.
中科院分区：
文献类型：
--
作者：
Cai, James J.;Macpherson, J. Michael;Sella, Guy;Petrov, Dmitri A.
许多努力和兴趣都集中在评估自然选择，特别是积极的自然选择在塑造人类基因组方面的重要性。尽管正选择扫描已经识别出可能与人类正选择相关的候选基因座，但此类扫描并不能表明适应在人类中是否普遍存在。基于麦克唐纳-克赖特曼测试推理的研究原则上可用于评估正选择的程度，该研究表明在人类基因组中可以检测到适应，但与果蝇或大肠杆菌相比不太常见。功能位点的积极自然选择和纯化自然选择都会影响相连的非功能位点的多态性水平和模式。在这里，我们通过分析人类中性多态性模式与黑猩猩重组率、功能密度和功能分歧的关系来寻找这些效应。我们发现，重组较低的区域和功能密度或分歧较高的区域中中性多态性水平较低。在控制了 GC 含量、简单重复密度、选择性约束、突变率和测序覆盖深度的变化后，这些相关性仍然存在。我们认为，这些结果最合理的解释是功能位点的自然选择（无论是循环选择性扫描还是背景选择）对连锁中性多态性水平的影响。编码位点和调控位点的自然选择似乎都会影响连锁中性多态性，使全基因组中性多态性减少 6%，在人类基因组基因丰富的一半中减少 11%。这些发现表明，在中性人类多态性的研究中，不能忽视连锁位点自然选择的影响。有许多报道证据表明人类基因组中特定基因座的正选择。基于人类和黑猩猩基因组比较的其他论文也表明适应性进化可能相当普遍。与此同时，令人惊讶的是，很难找到明确的证据来证明正选择或负选择（背景）正在影响中性位点的全基因组变异模式。在这里，我们通过使用人类多态性的两个全基因组数据集来评估阳性或背景选择的普遍性。我们记录了以下区域的中性多态性水平显着较低：(i) 基因和/或调控区域密度较高，(ii) 蛋白质或调控分歧较高，以及 (iii) 重组较低。这些模式对于许多可能的混杂因素来说是稳健的，并且表明在人类基因组研究中不能忽视连锁位点选择的影响。
Much effort and interest have focused on assessing the importance of natural selection, particularly positive natural selection, in shaping the human genome. Although scans for positive selection have identified candidate loci that may be associated with positive selection in humans, such scans do not indicate whether adaptation is frequent in general in humans. Studies based on the reasoning of the MacDonald–Kreitman test, which, in principle, can be used to evaluate the extent of positive selection, suggested that adaptation is detectable in the human genome but that it is less common than in Drosophila or Escherichia coli. Both positive and purifying natural selection at functional sites should affect levels and patterns of polymorphism at linked nonfunctional sites. Here, we search for these effects by analyzing patterns of neutral polymorphism in humans in relation to the rates of recombination, functional density, and functional divergence with chimpanzees. We find that the levels of neutral polymorphism are lower in the regions of lower recombination and in the regions of higher functional density or divergence. These correlations persist after controlling for the variation in GC content, density of simple repeats, selective constraint, mutation rate, and depth of sequencing coverage. We argue that these results are most plausibly explained by the effects of natural selection at functional sites—either recurrent selective sweeps or background selection—on the levels of linked neutral polymorphism. Natural selection at both coding and regulatory sites appears to affect linked neutral polymorphism, reducing neutral polymorphism by 6% genome-wide and by 11% in the gene-rich half of the human genome. These findings suggest that the effects of natural selection at linked sites cannot be ignored in the study of neutral human polymorphism. There is much reported evidence for positive selection at specific loci in the human genome. Additional papers based on comparisons between the genomes of humans and chimpanzees have also suggested that adaptive evolution may be quite common. At the same time, it has been surprisingly hard to find unambiguous evidence that either positive or negative (background) selection is affecting genome-wide patterns of variation at neutral sites. Here, we evaluate the prevalence of positive or background selection by using two genome-wide datasets of human polymorphism. We document that levels of neutral polymorphism are substantially lower in the regions of (i) higher density of genes and/or regulatory regions, (ii) higher protein or regulatory divergence, and (iii) lower recombination. These patterns are robust to a number of possible confounding factors and suggest that effects of selection at linked sites cannot be ignored in the study of the human genome.
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影响因子：
64.8
作者：
Bustamante, CD;Nielsen, R;Hartl, DL
通讯作者：
Hartl, DL
影响因子：
3.1
作者：
Cai, James J.
通讯作者：
Cai, James J.
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影响因子：
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Begun, David J.;Holloway, Alisha K.;Stevens, Kristian;Hillier, LaDeana W.;Poh, Yu-Ping;Hahn, Matthew W.;Nista, Phillip M.;Jones, Corbin D.;Kern, Andrew D.;Dewey, Colin N.;Pachter, Lior;Myers, Eugene;Langley, Charles H.
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Langley, Charles H.
影响因子：
64.8
作者：
Bustamante, CD;Fledel-Alon, A;Clark, AG
通讯作者：
Clark, AG
影响因子：
10.7
作者：
Bierne, N;Eyre-Walker, A
通讯作者：
Eyre-Walker, A