Strength of the purifying selection against different categories of the point mutations in the coding regions of the human genome
Strength of the purifying selection against different categories of the point mutations in the coding regions of the human genome
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DOI：
10.1093/hmg/ddl029
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发表时间：
2006-04-01
影响因子：
3.5
通讯作者：
Amos, CI
中科院分区：
文献类型：
--
作者：
Gorlov, IP;Kimmel, M;Amos, CI
利用关于人类基因组编码区总绝对大小的可用信息、密码子使用数据和不同单核苷酸取代的假基因衍生突变率，我们估计了人类基因组能够产生的突变事件的潜在数量：（1）无意义； (2) 错义（激进和保守）； (3) 沉默； (4) 拼接； (5) 蛋白质延长（将野生型终止密码子改变为氨基酸编码密码子）突变。我们使用 NCBI dbSNP 数据库检索每个类别的观察到的多态性数量的数据。基因组中所有潜在事件中每个类别的多态性比例取决于选择的强度：多态性比率越高，选择越弱。我们使用无义突变作为参考组。与无义突变相比，我们发现针对蛋白质延伸突变的相对选择系数为21％，针对错义突变的相对选择系数为12％。研究发现，激进错义突变的危害性是保守突变的四倍。令人惊讶的是，我们发现沉默突变平均而言并不是中性的。无义突变的平均危害性为 3%。当沉默突变通过产生隐秘的供体-受体位点或干扰外显子剪接增强子（ESES）来影响剪接时，它们可能是有害的。针对剪接突变的平均选择系数是针对无义突变的 48%。使用酿酒酵母和秀丽隐杆线虫功能丧失突变的数据，或通过分析人类基因组中突变的预期频率，将相对选择系数转换为绝对选择系数，表明遗传漂变可能在保守错义和沉默突变的群体动态中发挥作用。
Using available Information on the total absolute size of the coding region of the human genome, data on codon usage and pseudogene-derived mutation rates for different single nucleotide substitutions we have estimated, for the human genome, the potential numbers of mutation events capable to produce: (1) nonsense; (2) missense (radical and conservative); (3) silent; (4) splice; and (5) protein-elongating (those changing wild-type stop codon into an amino acid encoding codon) mutations. We used the NCBI dbSNP database to retrieve data on the observed number of polymorphisms of each category. The fraction of polymorphisms in each category among all potential events in the genome depends on the strength of selection: the higher the rate of polymorphism, the weaker the selection. We used nonsense mutations as a referent group. Compared with nonsense mutations, we found that the relative selection coefficient against protein-elongating mutations was 21%, and the relative selection was 12% against missense mutations. Radical missense mutations were found to be four times more deleterious compared to conservative ones. Surprisingly, we found that silent mutations on average are not neutral; with the average harmfulness of 3% of nonsense mutations. Silent mutations may be deleterious when they affect splicing by creating cryptic donor-acceptor sites or by disturbing exonic splicing enhancers (ESESs). The average selection coefficient against splice mutations was 48% of that against nonsense mutations. Converting the relative selection coefficients into absolute ones using data on loss-of-function mutations in Saccharomyces cerevisiae and Caenorhabditis elegans, or by analysis of the expected frequency of mutations in the human genome, suggested that genetic drift could play a role in population dynamics of conservative missense and silent mutations.