Hotspots of biased nucleotide substitutions in human genes.
Hotspots of biased nucleotide substitutions in human genes.
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DOI：
10.1371/journal.pbio.1000026
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发表时间：
2009-01-27
期刊：
影响因子：
9.8
通讯作者：
Webster, Matthew T.
中科院分区：
文献类型：
--
作者：
Berglund, Jonas;Pollard, Katherine S.;Webster, Matthew T.
在最近的进化过程中，人类谱系中经历了加速进化的基因是参与人类特异性适应的候选者。为了确定导致某些基因进化速度加快的力量，我们分析了10，238个人类基因与黑猩猩和猕猴的直系同源物的比对。使用似然比检验，我们确定了蛋白质编码序列与加速率的碱基替换沿着人类谱系。外显子在人类中以快速的速度进化，具有包含AT到GC（弱到强）偏向性取代簇的显著趋势。这种模式也观察到非编码序列侧翼快速演变的外显子。加速外显子发生在男性重组率升高的区域，并表现出相对于基因组平均水平的过量非同义替换。接下来，我们分析了人类谱系沿着非同义与同义碱基置换率（d N /d S）显著升高的基因，以及相对于人类多态性具有过量氨基酸置换置换的基因。这些基因也显示出弱到强的偏向性取代簇的证据。这些发现表明，重组相关的过程，如偏向基因转换（BGC），是驱动固定的GC等位基因在人类基因组中。该过程可导致编码序列的加速进化和过量的氨基酸置换取代，从而产生阳性选择测试的显著结果。人类基因组中那些似乎进化迅速的区域可能受到了强烈的正选择，可能包含了导致我们物种独特性的遗传变化。然而，中性（非适应性）进化过程可能会产生一些信号，这些信号可能被误认为是选择的迹象。在这篇文章中，我们确定了在人类中经历了加速变化的编码序列，影响了它们编码的蛋白质的差异。通过分析这些基因的分子进化模式及其在基因组中的分布，我们发现变化最快的基因中的许多蛋白质编码变化并不是选择作用于基因的结果，而是AT到GC突变的偏倚固定的结果。我们的研究结果是一致的重组驱动偏置基因转换的模型。这导致了一个挑衅性的假设，即许多导致人类特有特征的遗传变化可能是由有害突变的固定引起的。自然选择通常被认为是功能性遗传变化的主要引擎，但与重组相关的独立中性进化过程可能对人类蛋白质的分化做出了重大贡献。
Genes that have experienced accelerated evolutionary rates on the human lineage during recent evolution are candidates for involvement in human-specific adaptations. To determine the forces that cause increased evolutionary rates in certain genes, we analyzed alignments of 10,238 human genes to their orthologues in chimpanzee and macaque. Using a likelihood ratio test, we identified protein-coding sequences with an accelerated rate of base substitutions along the human lineage. Exons evolving at a fast rate in humans have a significant tendency to contain clusters of AT-to-GC (weak-to-strong) biased substitutions. This pattern is also observed in noncoding sequence flanking rapidly evolving exons. Accelerated exons occur in regions with elevated male recombination rates and exhibit an excess of nonsynonymous substitutions relative to the genomic average. We next analyzed genes with significantly elevated ratios of nonsynonymous to synonymous rates of base substitution (d N /d S) along the human lineage, and those with an excess of amino acid replacement substitutions relative to human polymorphism. These genes also show evidence of clusters of weak-to-strong biased substitutions. These findings indicate that a recombination-associated process, such as biased gene conversion (BGC), is driving fixation of GC alleles in the human genome. This process can lead to accelerated evolution in coding sequences and excess amino acid replacement substitutions, thereby generating significant results for tests of positive selection. Regions of the human genome that appear to evolve rapidly may have been under strong positive selection and could contain the genetic changes responsible for the uniqueness of our species. However, neutral (nonadaptive) evolutionary processes can give rise to signals that can be mistaken as signs of selection. In this article, we identify coding sequences that have undergone accelerated rates of change in humans, affecting the divergence of the proteins they encode. By analyzing patterns of molecular evolution in these genes and their distribution in the genome, we show that many protein-coding changes in the fastest-changing genes are not a result of selection operating on the genes, but instead result from biased fixation of AT-to-GC mutations. Our findings are consistent with a model of recombination-driven biased gene conversion. This leads to the provocative hypothesis that many of the genetic changes leading to human-specific characters may have been prompted by fixation of deleterious mutations. Natural selection is commonly believed to be the main engine of functional genetic change, but a separate neutral evolutionary process linked to recombination may have contributed significantly to the divergence of human proteins.
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7
作者：
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通讯作者：
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影响因子：
4.5
作者：
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作者：
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Zwieg, Ann S.
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y