The role of GC-biased gene conversion in shaping the fastest evolving regions of the human genome.
The role of GC-biased gene conversion in shaping the fastest evolving regions of the human genome.
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DOI：
10.1093/molbev/msr279
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发表时间：
2012-03
影响因子：
10.7
通讯作者：
Pollard KS
中科院分区：
文献类型：
--
作者：
Kostka D;Hubisz MJ;Siepel A;Pollard KS
GC偏向基因转换（gBGC）是一个重组相关的进化过程，加速鸟嘌呤或胞嘧啶等位基因的固定，而不管它们对适应性的影响。gBGC可以增加取代的总体速率，这是正选择的标志。人类基因组中许多快速进化的基因和非编码序列具有GC偏向的取代模式，这表明gBGC-与适应过程相反-可能驱动了这些序列中的人类变化。为了研究这一假设，我们开发了一个DNA序列进化的替代模型，该模型量化了选择和gBGC对替代率和模式的非线性相互作用效应。基于该模型，我们使用了一系列谱系特异性似然比检验来评估序列比对，以获得选择模式、gBGC作用或两者的变化的证据。由于单个测试的假阳性率低于5%，我们发现大多数（76%）先前确定的人类加速区域在没有gBGC的情况下得到了最好的解释，而相当多的少数（19%）最好由gBGC单独的作用来解释。此外，超过一半（55%）的替代率显着超过当地估计的中性率，这表明这些地区可能是由积极的选择，而不是放松约束。通过区分gBGC，放松约束，积极选择的影响，我们提供了一个综合分析的进化力量，塑造了人类基因组的最快进化区域，这有利于设计有针对性的功能研究适应人类。
GC-biased gene conversion (gBGC) is a recombination-associated evolutionary process that accelerates the fixation of guanine or cytosine alleles, regardless of their effects on fitness. gBGC can increase the overall rate of substitutions, a hallmark of positive selection. Many fast-evolving genes and noncoding sequences in the human genome have GC-biased substitution patterns, suggesting that gBGC—in contrast to adaptive processes—may have driven the human changes in these sequences. To investigate this hypothesis, we developed a substitution model for DNA sequence evolution that quantifies the nonlinear interacting effects of selection and gBGC on substitution rates and patterns. Based on this model, we used a series of lineage-specific likelihood ratio tests to evaluate sequence alignments for evidence of changes in mode of selection, action of gBGC, or both. With a false positive rate of less than 5% for individual tests, we found that the majority (76%) of previously identified human accelerated regions are best explained without gBGC, whereas a substantial minority (19%) are best explained by the action of gBGC alone. Further, more than half (55%) have substitution rates that significantly exceed local estimates of the neutral rate, suggesting that these regions may have been shaped by positive selection rather than by relaxation of constraint. By distinguishing the effects of gBGC, relaxation of constraint, and positive selection we provide an integrated analysis of the evolutionary forces that shaped the fastest evolving regions of the human genome, which facilitates the design of targeted functional studies of adaptation in humans.
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