On the Prospects of Whole-Genome Association Mapping in Saccharomyces cerevisiae
On the Prospects of Whole-Genome Association Mapping in Saccharomyces cerevisiae
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DOI：
10.1534/genetics.112.141168
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发表时间：
2012-08-01
期刊：
影响因子：
3.3
通讯作者：
Akey, Joshua M.
中科院分区：
文献类型：
--
作者：
Connelly, Caitlin F.;Akey, Joshua M.
测序技术的进步使得能够从物种内的多个个体获得全基因组序列，特别是在具有紧凑基因组的模式生物中。例如，酿酒酵母的 36 个基因组序列现已公开，并且 SNP 数据可用于更大的菌株集合。这些资源的一种潜在用途是通过全基因组关联（GWA）研究绘制表型变异的遗传基础，其优点是可以比人类等远交群体更容易地通过实验研究相关变异。在这里，我们通过广泛的模拟和线粒体拷贝数的 GWA 研究来评估酿酒酵母菌株的 GWA 研究的前景。我们证明，酵母群体中存在的复杂且异质的群体结构模式可能导致数量性状 GWA 研究中的高 I 型错误率，并且通常用于控制群体分层的方法不能提供对 I 型错误率的充分控制。此外，我们表明，虽然根据研究的特定菌株组，对酿酒酵母数量性状进行 GWA 研究可能很困难，但绘制顺式作用数量性状基因座 (QTL) 和孟德尔表型的关联研究更为可行。我们还讨论了可以在酵母中进行 GWA 研究的采样策略，并说明了这种方法在奇异酵母中的实用性。因此，我们的结果为酵母和其他具有复杂群体结构模式的模式生物的 GWA 研究的设计和解释提供了重要的实用见解。
Advances in sequencing technology have enabled whole-genome sequences to be obtained from multiple individuals within species, particularly in model organisms with compact genomes. For example, 36 genome sequences of Saccharomyces cerevisiae are now publicly available, and SNP data are available for even larger collections of strains. One potential use of these resources is mapping the genetic basis of phenotypic variation through genome-wide association (GWA) studies, with the benefit that associated variants can be studied experimentally with greater ease than in outbred populations such as humans. Here, we evaluate the prospects of GWA studies in S. cerevisiae strains through extensive simulations and a GWA study of mitochondrial copy number. We demonstrate that the complex and heterogeneous patterns of population structure present in yeast populations can lead to a high type I error rate in GWA studies of quantitative traits, and that methods typically used to control for population stratification do not provide adequate control of the type I error rate. Moreover, we show that while GWA studies of quantitative traits in S. cerevisiae may be difficult depending on the particular set of strains studied, association studies to map cis-acting quantitative trait loci (QTL) and Mendelian phenotypes are more feasible. We also discuss sampling strategies that could enable GWA studies in yeast and illustrate the utility of this approach in Saccharomyces paradoxus. Thus, our results provide important practical insights into the design and interpretation of GWA studies in yeast, and other model organisms that possess complex patterns of population structure.