Coding sing le-nucleotide polymorphisms associated with complex vs. Mendelian disease: Evolutionary evidence for differences in molecular effects
Coding sing le-nucleotide polymorphisms associated with complex vs. Mendelian disease: Evolutionary evidence for differences in molecular effects
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DOI：
10.1073/pnas.0404380101
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发表时间：
2004-10-26
影响因子：
11.1
通讯作者：
Kejariwal, A
中科院分区：
文献类型：
--
作者：
Thomas, PD;Kejariwal, A
迄今为止研究的大多数孟德尔疾病都是由导致编码蛋白质中单个氨基酸变化的突变引起的。越来越多的复杂疾病也与氨基酸改变的单核苷酸多态性（编码SNPs，cSNPs）有关，这表明孟德尔和复杂疾病在分子水平上的潜在相似性。在这里，我们使用两种不同的进化分析来比较孟德尔和复杂疾病相关的cSNP。在第一，我们估计的可能性，在一个蛋白质中的特定氨基酸取代将影响蛋白质的功能，通过使用氨基酸取代得分来自相关的蛋白质序列的比对和统计数据从隐马尔可夫模型。在第二种方法中，我们使用标准Ka/Ks比率在基因而不是单个氨基酸水平上进行比较。我们发现，孟德尔疾病cSNPs有一个非常强烈的倾向，发生在高度保守的氨基酸位置的蛋白质，这表明他们通常有一个严重的影响蛋白质的功能。也许令人惊讶的是，复杂疾病cSNP的氨基酸取代评分的分布与孟德尔疾病cSNP的分布显著不同，并且与“正常”人类变异的分布无法区分。此外，人和小鼠直系同源物的Ka/Ks比的分布表明，平均而言，对复杂疾病相关基因的正选择压力更大（或负选择压力更小）。这些发现表明，当使用孟德尔疾病作为复杂疾病的模型时，至少在蛋白质功能的分子效应方面，应谨慎行事。
Most Mendelian diseases studied to date arise from mutations that lead to a single amino acid change in an encoded protein. An increasing number of complex diseases have also been associated with amino acid-changing single-nucleoticle polymorphisms (coding SNPs, cSNPs), suggesting potential similarities between Mendelian and complex diseases at the molecular level. Here, we use two different evolutionary analyses to compare Mendelian and complex disease-associated cSNPs. in the first, we estimate the likelihood that a specific amino acid substitution in a protein will affect the protein's function, by using amino acid substitution scores derived from an alignment of related protein sequences and statistics from hidden Markov models. In the second, we use standard Ka/Ks ratios to make comparisons at the gene, rather than the individual amino acid, level. We find that Mendelian disease cSNPs have a very strong tendency to occur at highly conserved amino acid positions in proteins, suggesting that they generally have a severe impact on the function of the protein. Perhaps surprisingly, the distribution of amino acid substitution scores for complex disease cSNPs is dramatically different from the distribution for Mendelian disease cSNPs, and is indistinguishable from the distribution for "normal" human variation. Further, the distributions of Ka/Ks ratios for human and mouse orthologs indicate greater positive selection (or less negative selection) pressure on complex disease-associated genes, on average. These findings suggest that caution should be exercised when using Mendelian disease as a model for complex disease, at least with respect to molecular effects on protein function.