Genetic architecture of a complex trait and its implications for fitness and genome-wide association studies
Genetic architecture of a complex trait and its implications for fitness and genome-wide association studies
复制标题
DOI：
10.1073/pnas.0906182107
复制
发表时间：
2010-01-26
影响因子：
11.1
通讯作者：
Eyre-Walker, Adam
中科院分区：
文献类型：
--
作者：
Eyre-Walker, Adam
研究了一个模型，在该模型中，影响复杂性状（例如心脏病）的突变也会影响适合度，因为该性状是适合度的一个组成部分，或者因为这些突变对适合度具有多效性影响。该模型预测，该性状的遗传方差以及因此的遗传力是由群体中低频的突变所贡献的，除非影响该性状的突变的平均选择强度非常小，或者与强选择的突变相比，弱选择的突变往往对该性状有不成比例的贡献。此外，研究表明，每个罕见突变往往比每个常见突变对方差的贡献更大。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能解释大部分方差的关联。还表明，新的非同义突变对适合度贡献的大部分方差是由群体中极低频率的突变引起的。这意味着，在当前例如对100条染色体的重测序研究中观察到的大多数低频单核苷酸多态性（SNP）可能对适合度或性状的方差影响很小。最后，研究表明，一类突变（例如编码或调控突变）所贡献的方差在很大程度上取决于平均选择强度；这对理解哪些类型的突变可能对适合度和遗传性疾病的方差负责具有启示意义。
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.