Sunyaev Shamil, Kondrashov Fyodor A, Bork Peer, Ramensky Vasily
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Hum Mol Genet. 2003 Dec 15;12(24):3325-30. doi: 10.1093/hmg/ddg359. Epub 2003 Oct 21.
The accumulation of genome-wide information on single nucleotide polymorphisms in humans provides an unprecedented opportunity to detect the evolutionary forces responsible for heterogeneity of the level of genetic variability across loci. Previous studies have shown that history of recombination events has produced long haplotype blocks in the human genome, which contribute to this heterogeneity. Other factors, however, such as natural selection or the heterogeneity of mutation rates across loci, may also lead to heterogeneity of genetic variability. We compared synonymous and non-synonymous variability within human genes with their divergence from murine orthologs. We separately analyzed the non-synonymous variants predicted to damage protein structure or function and the variants predicted to be functionally benign. The predictions were based on comparative sequence analysis and, in some cases, on the analysis of protein structure. A strong correlation between non-synonymous, benign variability and non-synonymous human-mouse divergence suggests that selection played an important role in shaping the pattern of variability in coding regions of human genes. However, the lack of correlation between deleterious variability and evolutionary divergence shows that a substantial proportion of the observed non-synonymous single-nucleotide polymorphisms reduces fitness and never reaches fixation. Evolutionary and medical implications of the impact of selection on human polymorphisms are discussed.
人类全基因组单核苷酸多态性信息的积累，为检测导致各基因座遗传变异水平存在异质性的进化力量提供了前所未有的契机。以往研究表明，重组事件的历史在人类基因组中产生了长单倍型块，这导致了这种异质性。然而，其他因素，如自然选择或各基因座突变率的异质性，也可能导致遗传变异的异质性。我们将人类基因内的同义变异和非同义变异与其与小鼠直系同源基因的差异进行了比较。我们分别分析了预测会破坏蛋白质结构或功能的非同义变异以及预测为功能良性的变异。这些预测基于比较序列分析，在某些情况下还基于蛋白质结构分析。非同义、良性变异与非同义人鼠差异之间的强相关性表明，选择在塑造人类基因编码区变异模式中发挥了重要作用。然而，有害变异与进化差异之间缺乏相关性，这表明观察到的相当一部分非同义单核苷酸多态性会降低适应性，且从未达到固定状态。文中讨论了选择对人类多态性影响的进化和医学意义。
