High-Resolution Mapping of Complex Traits with a Four-Parent Advanced Intercross Yeast Population
High-Resolution Mapping of Complex Traits with a Four-Parent Advanced Intercross Yeast Population
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DOI：
10.1534/genetics.113.155515
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发表时间：
2013-11-01
期刊：
影响因子：
3.3
通讯作者：
Liti, Gianni
中科院分区：
文献类型：
--
作者：
Cubillos, Francisco A.;Parts, Leopold;Liti, Gianni
人类复杂性状遗传力的很大一部分是由于大量边际效应较小的变异及其与基因型和环境的相互作用造成的。此类等位基因更容易在模型生物体中进行研究，因为环境、基因组成和等位基因频率都可以控制。在这里，我们研究了来自多亲第 12 代杂交的大量面包酵母中自然遗传变异对遗传性状的影响。我们选择了四个有代表性的创始菌株来产生酵母基因组重测序计划 (SGRP)-4X 作图群体，并对 192 个分离子进行测序，以生成准确的遗传图谱。利用这些个体，我们绘制了 25 个与热应激、亚砷酸盐和百草枯下的生长性状相关的基因座，其中大多数基因座可以最好地解释为一种条件下单个等位基因引起的不同表型。通过对数百万在热应激下生长的分离子的汇集 DNA 进行测序，我们进一步鉴定了单倍体和二倍体池中分别选择的 34 和 39 个区域，其中大部分选择针对单个等位基因。虽然使用任一方法映射的大多数基因座的最简约模型是一个创始人私有的等位基因的效应，但我们可以验证基因座上多效性效应和复杂等位基因系列的示例。 SGRP-4X 是一种经过深入表征的资源，为酵母表型的强大且高分辨率的遗传分析提供了框架，并可作为测试攻击人类复杂性状的途径的试验台。
A large fraction of human complex trait heritability is due to a high number of variants with small marginal effects and their interactions with genotype and environment. Such alleles are more easily studied in model organisms, where environment, genetic makeup, and allele frequencies can be controlled. Here, we examine the effect of natural genetic variation on heritable traits in a very large pool of baker's yeast from a multiparent 12th generation intercross. We selected four representative founder strains to produce the Saccharomyces Genome Resequencing Project (SGRP)-4X mapping population and sequenced 192 segregants to generate an accurate genetic map. Using these individuals, we mapped 25 loci linked to growth traits under heat stress, arsenite, and paraquat, the majority of which were best explained by a diverging phenotype caused by a single allele in one condition. By sequencing pooled DNA from millions of segregants grown under heat stress, we further identified 34 and 39 regions selected in haploid and diploid pools, respectively, with most of the selection against a single allele. While the most parsimonious model for the majority of loci mapped using either approach was the effect of an allele private to one founder, we could validate examples of pleiotropic effects and complex allelic series at a locus. SGRP-4X is a deeply characterized resource that provides a framework for powerful and high-resolution genetic analysis of yeast phenotypes and serves as a test bed for testing avenues to attack human complex traits.