Natural selection affects multiple aspects of genetic variation at putatively neutral sites across the human genome.
Natural selection affects multiple aspects of genetic variation at putatively neutral sites across the human genome.
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DOI：
10.1371/journal.pgen.1002326
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发表时间：
2011-10
期刊：
影响因子：
4.5
通讯作者：
Nielsen R
中科院分区：
文献类型：
--
作者：
Lohmueller KE;Albrechtsen A;Li Y;Kim SY;Korneliussen T;Vinckenbosch N;Tian G;Huerta-Sanchez E;Feder AF;Grarup N;Jørgensen T;Jiang T;Witte DR;Sandbæk A;Hellmann I;Lauritzen T;Hansen T;Pedersen O;Wang J;Nielsen R
进化生物学的一个主要问题是自然选择如何塑造人类基因组的遗传变异模式。先前的工作已经记录了重组率较低的基因组区域的遗传多样性减少。然而，尚不清楚遗传变异的其他总结（例如等位基因频率）是否也与重组率相关，以及这些相关性是否可以仅通过针对有害突变的负选择来解释，或者是否也需要作用于有利等位基因的正选择。在这里，我们试图通过分析来自欧洲个体的三个不同的全基因组重测序数据集来解决这些问题。我们记录了不同基因组特征之间的几个显着相关性。特别是，我们发现在低重组区域中平均次要等位基因频率和多样性降低，并且人类多样性、人黑猩猩差异和平均次要等位基因频率在基因附近降低。群体遗传模拟表明，作用于有利突变的正向自然选择或作用于有害突变的负向自然选择可以解释这些相关性。然而，对非同义突变具有强正选择和很少负选择的模型预测中性多样性和非同义分歧之间的负相关性比实际数据中观察到的更强，这支持了整个基因组中负选择而不是正选择的重要性。此外，我们表明，弱有害等位基因的广泛存在，而不是少数强阳性选择的突变，是中性遗传多样性和重组率之间相关性的原因。这项工作表明，自然选择影响了整个人类基因组中相关中性变异的多个方面，并且不需要正选择来解释这些观察结果。虽然研究人员已经确定了在正达尔文自然选择下进化的候选基因，但人们对人类基因组有多少受到自然选择的影响以及正选择是否在塑造整个人类基因组变异模式方面比针对有害突变的负选择发挥了更大的作用知之甚少。为了解决这些问题，我们将三个全基因组重测序数据集中的遗传变异模式与自然选择的群体遗传模型结合起来。我们发现重组率较低的基因组区域的遗传多样性和平均次要等位基因频率降低。此外，基因附近的遗传多样性、人类与黑猩猩的差异和平均次要等位基因频率都降低了。总体而言，虽然我们不能排除一小部分突变的正选择，但包含整个人类基因组中许多弱有害突变的模型可以更好地解释全基因组重测序数据的多个方面。这项工作指出负选择是塑造变异模式的重要力量，并表明整个人类基因组的编码和非编码位点都存在许多弱有害突变。了解此类突变对于了解人类进化和常见疾病的遗传基础非常重要。
A major question in evolutionary biology is how natural selection has shaped patterns of genetic variation across the human genome. Previous work has documented a reduction in genetic diversity in regions of the genome with low recombination rates. However, it is unclear whether other summaries of genetic variation, like allele frequencies, are also correlated with recombination rate and whether these correlations can be explained solely by negative selection against deleterious mutations or whether positive selection acting on favorable alleles is also required. Here we attempt to address these questions by analyzing three different genome-wide resequencing datasets from European individuals. We document several significant correlations between different genomic features. In particular, we find that average minor allele frequency and diversity are reduced in regions of low recombination and that human diversity, human-chimp divergence, and average minor allele frequency are reduced near genes. Population genetic simulations show that either positive natural selection acting on favorable mutations or negative natural selection acting against deleterious mutations can explain these correlations. However, models with strong positive selection on nonsynonymous mutations and little negative selection predict a stronger negative correlation between neutral diversity and nonsynonymous divergence than observed in the actual data, supporting the importance of negative, rather than positive, selection throughout the genome. Further, we show that the widespread presence of weakly deleterious alleles, rather than a small number of strongly positively selected mutations, is responsible for the correlation between neutral genetic diversity and recombination rate. This work suggests that natural selection has affected multiple aspects of linked neutral variation throughout the human genome and that positive selection is not required to explain these observations. While researchers have identified candidate genes that have evolved under positive Darwinian natural selection, less is known about how much of the human genome has been affected by natural selection or whether positive selection has had a greater role at shaping patterns of variation across the human genome than negative selection acting against deleterious mutations. To address these questions, we have combined patterns of genetic variation in three genome-wide resequencing datasets with population genetic models of natural selection. We find that genetic diversity and average minor allele frequency are reduced in regions of the genome with low recombination rate. Additionally, genetic diversity, human-chimp divergence, and average minor allele frequency have been reduced near genes. Overall, while we cannot exclude positive selection at a fraction of mutations, models that include many weakly deleterious mutations throughout the human genome better explain multiple aspects of the genome-wide resequencing data. This work points to negative selection as an important force for shaping patterns of variation and suggests that there are many weakly deleterious mutations at both coding and noncoding sites throughout the human genome. Understanding such mutations will be important for learning about human evolution and the genetic basis of common disease.
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