Higher intensity of purifying selection on >90% of the human genes revealed by the intrinsic replacement mutation rates
Higher intensity of purifying selection on >90% of the human genes revealed by the intrinsic replacement mutation rates
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DOI：
10.1093/molbev/msl123
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发表时间：
2006-12-01
影响因子：
10.7
通讯作者：
Kumar, Sudhir
中科院分区：
文献类型：
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作者：
Subramanian, Sankar;Kumar, Sudhir
在过去的30年里，替换突变的速率一直被假设为等于，并从非编码区和沉默密码子位置中的“严格”中性序列趋异的速率估计，其中突变不改变编码的氨基酸。这一假设对于估计有害蛋白质突变的比例以及识别个体密码子和蛋白质的适应性进化是至关重要的。我们表明，假设是不合理的，因为一个更大的比例的密码子位置是参与高变CpG二核苷酸相比，内含子，导致更高的预期置换突变率，每个站点在绝大多数的基因。考虑到这一差异，我们发现自然选择的净化强度比以前在人类基因中推断的要高。我们还表明，一个更少的基因预计将与积极的选择比预测使用在人类基因组中的内含子和沉默位置的序列分歧。这些模式表明需要使用新的方法来估计氨基酸改变突变的速率，以便在含有高变CpG的基因组中找到正选择的基因和密码子。
For over 3 decades, the rate of replacement mutations has been assumed to be equal to, and estimated from, the rate of "strictly" neutral sequence divergence in noncoding regions and in silent-codon positions where mutations do not alter the amino acid encoded. This assumption is fundamental to estimating the fraction of harmful protein mutations and to identifying adaptive evolution at individual codons and proteins. We show that the assumption is not justifiable because a much larger fraction of codon positions is involved in hypermutable CpG dinucleotides as compared with the introns, leading to a higher expected replacement mutation rate per site in a vast majority of the genes. Consideration of this difference reveals a higher intensity of purifying natural selection than previously inferred in human genes. We also show that a much smaller number of genes are expected to be evolving with positive selection than that predicted using sequence divergence at intron and silent positions in the human genome. These patterns indicate the need for using new approaches for estimating rates of amino acid-altering mutations in order to find positively selected genes and codons in genomes that contain hypermutable CpG's.