Hotspots of Biased Nucleotide Substitutions in Human Genes

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 (dN/dS) 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.在近期进化过程中，人类谱系中进化速率加快的基因，是参与人类特异性适应的候选基因。为明确驱动特定基因进化速率升高的驱动力，我们对10238个人类基因与其在黑猩猩和猕猴中的直系同源基因（orthologue）的序列比对结果展开了分析。借助似然比检验（likelihood ratio test），我们鉴定出人类谱系中碱基替换速率加快的蛋白编码序列（protein-coding sequence）。在人类中进化较快的外显子，显著倾向于存在AT向GC（弱向强）偏好性碱基替换的簇状分布。这一特征同样在快速进化外显子侧翼的非编码序列中被观测到。加速进化的外显子所在区域的雄性重组率偏高，且相较于基因组平均水平，其非同义替换（nonsynonymous substitution）占比更高。随后我们进一步分析了两类基因：一类是人类谱系中碱基替换的非同义替换与同义替换速率之比（dN/dS）显著升高的基因，另一类是相较于人类群体多态性，氨基酸替换占比过量的基因。这两类基因同样呈现出弱向强偏好性碱基替换的簇状分布特征。上述研究结果表明，一类与重组相关的分子过程——如偏向性基因转换（biased gene conversion, BGC）——正在推动人类基因组中GC等位基因的固定。该过程可引发编码序列的进化加速以及过量的氨基酸替换，进而在正选择检验中得到具有统计学显著性的结果。