Genetic architecture of complex traits: Large phenotypic effects and pervasive epistasis
Genetic architecture of complex traits: Large phenotypic effects and pervasive epistasis
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DOI：
10.1073/pnas.0810388105
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发表时间：
2008-12-16
影响因子：
11.1
通讯作者：
Nadeau, Joseph H.
中科院分区：
文献类型：
--
作者：
Shao, Haifeng;Burrage, Lindsay C.;Nadeau, Joseph H.
在大多数生物体中，生理和疾病背后的复杂性状的遗传结构仍然难以捉摸。我们仍然对这些特征背后的基因数量、它们的影响程度或它们相互作用的程度知之甚少。染色体替代株系（CSS）能够基于测试具有单一、独特和非重叠遗传差异的工程化近交系进行统计学上强大的研究，从而提供归因于单个染色体的表型效应的测量。在这里，我们报告了一项研究的表型效应和基因相互作用的90个血液，骨骼和代谢性状在小鼠CSS面板和54个性状在大鼠CSS面板。关于这些特征的遗传结构，出现了两个关键的观察结果。首先，这些性状往往是高度多基因的：在整个基因组中，许多单独的染色体替换，每一个都有显着的表型效应，在每一个研究的染色体中，发现了多个不同的基因座;其次，在单个染色体之间发现了强烈的上位性。具体而言，单个染色体取代通常赋予令人惊讶的大效应（通常是亲本菌株之间的整个表型差异的相当大的部分），结果是这些单个效应的总和通常显著超过亲本菌株之间的差异。我们认为，强大的，普遍的上位性可能反映了几个表型缓冲生理状态的存在。这些结果对识别复杂性状基因、表型变异的发育和生理研究以及在复杂生物系统中设计表型结果的机会具有意义。
The genetic architecture of complex traits underlying physiology and disease in most organisms remains elusive. We still know little about the number of genes that underlie these traits, the magnitude of their effects, or the extent to which they interact. Chromosome substitution strains (CSSs) enable statistically powerful studies based on testing engineered inbred strains that have single, unique, and nonoverlapping genetic differences, thereby providing measures of phenotypic effects that are attributable to individual chromosomes. Here, we report a study of phenotypic effects and gene interactions for 90 blood, bone, and metabolic traits in a mouse CSS panel and 54 traits in a rat CSS panel. Two key observations emerge about the genetic architecture of these traits. First, the traits tend to be highly polygenic: across the genome, many individual chromosome substitutions each had significant phenotypic effects and, within each of the chromosomes studied, multiple distinct loci were found. Second, strong epistasis was found among the individual chromosomes. Specifically, individual chromosome substitutions often conferred surprisingly large effects ( often a substantial fraction of the entire phenotypic difference between the parental strains), with the result that the sum of these individual effects often dramatically exceeded the difference between the parental strains. We suggest that strong, pervasive epistasis may reflect the presence of several phenotypically-buffered physiological states. These results have implications for identification of complex trait genes, developmental and physiological studies of phenotypic variation, and opportunities to engineer phenotypic outcomes in complex biological systems.