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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Genetic architecture of a complex trait and its implications for fitness and genome-wide association studies
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Genetic architecture of a complex trait and its implications for fitness and genome-wide association studies

机译：复杂性状的遗传结构及其对适应性和全基因组关联研究的意义

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摘要

A model is investigated in which mutations that affect a complex trait (e.g., heart disease) also affect fitness because the trait is a component of fitness or because the mutations have pleiotropic effects on fitness. The model predicts that the genetic variance, and hence the heritability, in the trait is contributed by mutations at low frequency in the population, unless the mean strength of selection of mutations that affect the trait is very small or weakly selected mutations tend to contribute disproportionately to the trait compared with strongly selected mutations. Furthermore, it is shown that each rare mutation tends to contribute more to the variance than each common mutation. These results may explain why most genome-wide association studies have failed to find associations that explain much of the variance. It is also shown that most of the variance in fitness contributed by new nonsynonymous mutations is caused by mutations at very low frequency in the population. This implies that most low-frequency SNPs, which are observed in current resequencing studies of, for example, 100 chromosomes, probably have little impact on the variance in fitness or traits. Finally, it is shown that the variance contributed by a category of mutations (e.g., coding or regulatory) depends largely upon the mean strength of selection; this has implications for understanding which types of mutations are likely to be responsible for the variance in fitness and inherited disease.
机译：研究了其中影响复杂性状（例如心脏病）的突变也影响适应性的模型，因为该性状是适应性的组成部分或因为突变对适应性具有多效性作用。该模型预测，该性状的遗传变异和遗传性是由群体中低频突变引起的，除非影响该性状的突变选择的平均强度很小或选择不当的突变倾向于不成比例地贡献与强烈选择的突变相比。此外，显示出每个稀有突变比每个常见突变对变异的贡献更大。这些结果可能解释了为什么大多数全基因组关联研究未能找到解释大部分差异的关联。还表明，由新的非同义突变引起的适应度的大部分差异是由人群中极低频率的突变引起的。这意味着，在当前的重新测序研究中，例如100条染色体中观察到的大多数低频SNP，可能对适应性或性状的变异几乎没有影响。最后，表明由一类突变（例如，编码或调控）引起的方差很大程度上取决于选择的平均强度。这对于了解哪种突变类型可能与适应性和遗传疾病的差异有关。

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