Department of Ecology and Evolutionary Biology, University of California Irvine, Irvine, California 92697, USA.
Genome Res. 2012 Aug;22(8):1558-66. doi: 10.1101/gr.134031.111. Epub 2012 Apr 10.
Genetic dissection of complex, polygenic trait variation is a key goal of medical and evolutionary genetics. Attempts to identify genetic variants underlying complex traits have been plagued by low mapping resolution in traditional linkage studies, and an inability to identify variants that cumulatively explain the bulk of standing genetic variation in genome-wide association studies (GWAS). Thus, much of the heritability remains unexplained for most complex traits. Here we describe a novel, freely available resource for the Drosophila community consisting of two sets of recombinant inbred lines (RILs), each derived from an advanced generation cross between a different set of eight highly inbred, completely resequenced founders. The Drosophila Synthetic Population Resource (DSPR) has been designed to combine the high mapping resolution offered by multiple generations of recombination, with the high statistical power afforded by a linkage-based design. Here, we detail the properties of the mapping panel of >1600 genotyped RILs, and provide an empirical demonstration of the utility of the approach by genetically dissecting alcohol dehydrogenase (ADH) enzyme activity. We confirm that a large fraction of the variation in this classic quantitative trait is due to allelic variation at the Adh locus, and additionally identify several previously unknown modest-effect trans-acting QTL (quantitative trait loci). Using a unique property of multiparental linkage mapping designs, for each QTL we highlight a relatively small set of candidate causative variants for follow-up work. The DSPR represents an important step toward the ultimate goal of a complete understanding of the genetics of complex traits in the Drosophila model system.
对复杂的多基因性状变异进行遗传剖析是医学和进化遗传学的主要目标。试图鉴定复杂性状的遗传变异，受到传统连锁研究中映射分辨率低的困扰，并且无法识别能够累积解释全基因组关联研究（GWAS）中大部分遗传变异的变异。因此，大多数复杂性状的遗传率仍未得到解释。在这里，我们为果蝇社区描述了一个新颖的、免费的资源，该资源由两组重组近交系（RIL）组成，每组都来自于不同的八组高度近交、完全重测序的创始人之间的高级杂交。果蝇合成种群资源（DSPR）旨在结合多代重组提供的高映射分辨率，以及基于连锁的设计提供的高统计能力。在这里，我们详细介绍了超过 1600 个已分型 RIL 的映射面板的特性，并通过遗传剖析酒精脱氢酶（ADH）酶活性来提供该方法实用性的实证演示。我们证实，这个经典数量性状的大部分变异是由于 Adh 基因座的等位基因变异引起的，此外还鉴定了几个以前未知的中等效应的转录调控 QTL（数量性状位点）。利用多亲本连锁作图设计的一个独特特性，对于每个 QTL，我们都强调了一组相对较小的候选致病变异，供后续研究使用。DSPR 代表了朝着最终目标迈出的重要一步，即全面了解果蝇模型系统中复杂性状的遗传学。
