Taylor Matthew B, Ehrenreich Ian M
Molecular and Computational Biology Section, Department of Biological Sciences, University of Southern California, Los Angeles, California, United States of America.
PLoS Genet. 2014 May 1;10(5):e1004324. doi: 10.1371/journal.pgen.1004324. eCollection 2014 May.
Recent research suggests that genetic interactions involving more than two loci may influence a number of complex traits. How these 'higher-order' interactions arise at the genetic and molecular levels remains an open question. To provide insights into this problem, we dissected a colony morphology phenotype that segregates in a yeast cross and results from synthetic higher-order interactions. Using backcrossing and selective sequencing of progeny, we found five loci that collectively produce the trait. We fine-mapped these loci to 22 genes in total and identified a single gene at each locus that caused loss of the phenotype when deleted. Complementation tests or allele replacements provided support for functional variation in these genes, and revealed that pre-existing genetic variants and a spontaneous mutation interact to cause the trait. The causal genes have diverse functions in endocytosis (END3), oxidative stress response (TRR1), RAS-cAMP signalling (IRA2), and transcriptional regulation of multicellular growth (FLO8 and MSS11), and for the most part have not previously been shown to exhibit functional relationships. Further efforts uncovered two additional loci that together can complement the non-causal allele of END3, suggesting that multiple genotypes in the cross can specify the same phenotype. Our work sheds light on the complex genetic and molecular architecture of higher-order interactions, and raises questions about the broader contribution of such interactions to heritable trait variation.
最近的研究表明，涉及两个以上基因座的基因相互作用可能会影响许多复杂性状。这些“高阶”相互作用如何在基因和分子水平上产生仍然是一个悬而未决的问题。为了深入了解这个问题，我们剖析了一种在酵母杂交中分离且由合成高阶相互作用导致的菌落形态表型。通过回交和对后代进行选择性测序，我们发现了五个共同产生该性状的基因座。我们将这些基因座精细定位到总共22个基因，并在每个基因座鉴定出一个基因，该基因缺失时会导致表型丧失。互补试验或等位基因替换为这些基因的功能变异提供了支持，并揭示了预先存在的遗传变异和一个自发突变相互作用导致了该性状。这些因果基因在内吞作用（END3）、氧化应激反应（TRR1）、RAS - cAMP信号传导（IRA2）以及多细胞生长的转录调控（FLO8和MSS11）中具有多种功能，并且在很大程度上以前尚未显示出具有功能关系。进一步的研究发现了另外两个基因座，它们共同可以互补END3的非因果等位基因，这表明杂交中的多种基因型可以指定相同的表型。我们的工作揭示了高阶相互作用复杂的遗传和分子结构，并提出了关于此类相互作用对可遗传性状变异更广泛贡献的问题。
