Revealing the genetic structure of a trait by sequencing a population under selection
Revealing the genetic structure of a trait by sequencing a population under selection
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DOI：
10.1101/gr.116731.110
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发表时间：
2011-07-01
期刊：
影响因子：
7
通讯作者：
Liti, Gianni
中科院分区：
文献类型：
--
作者：
Parts, Leopold;Cubillos, Francisco A.;Liti, Gianni
了解性状遗传基础的一种方法是研究它们在表型不同的亲本后代之间的遗传模式。以前，这种分析受到低映射分辨率、高人工成本和检测适度效应所需的大样本量的限制。在此，我们提出了一种利用人工选择绘制性状位点的新方法。首先，我们将两个耐热性不同的芽殖酵母菌杂交12代，产生了1000 -1亿个单倍体和二倍体分离群体。然后，我们将这些大的分离池置于热胁迫下长达12天，以丰富有益的等位基因。最后，我们在选择前和选择过程中对来自池中的总DNA进行测序，以测量亲本等位基因频率的变化。我们绘制了21个遗传背景因选择而发生显著变化的区间，这是传统连锁方法发现的数倍。这些区域中有9个包含两个或更少的基因，比以前的基因组连锁研究产生了更高的分辨率。RAS/cAMP信号通路的多个成员，以及以前未被注释为热应激反应功能的基因都涉及其中。令人惊讶的是，在大多数选择的基因座中，等位基因频率在选择实验结束前停止变化，但等位基因并没有固定下来。此外，我们能够以相似的能力和分辨率在二倍体个体群体中检测到相同的一组性状位点，并观察到主要的加性效应，类似于在其他二倍体生物（如人类）中看到的复杂性状遗传。
One approach to understanding the genetic basis of traits is to study their pattern of inheritance among offspring of phenotypically different parents. Previously, such analysis has been limited by low mapping resolution, high labor costs, and large sample size requirements for detecting modest effects. Here, we present a novel approach to map trait loci using artificial selection. First, we generated populations of 10-100 million haploid and diploid segregants by crossing two budding yeast strains of different heat tolerance for up to 12 generations. We then subjected these large segregant pools to heat stress for up to 12 d, enriching for beneficial alleles. Finally, we sequenced total DNA from the pools before and during selection to measure the changes in parental allele frequency. We mapped 21 intervals with significant changes in genetic background in response to selection, which is several times more than found with traditional linkage methods. Nine of these regions contained two or fewer genes, yielding much higher resolution than previous genomic linkage studies. Multiple members of the RAS/cAMP signaling pathway were implicated, along with genes previously not annotated with heat stress response function. Surprisingly, at most selected loci, allele frequencies stopped changing before the end of the selection experiment, but alleles did not become fixed. Furthermore, we were able to detect the same set of trait loci in a population of diploid individuals with similar power and resolution, and observed primarily additive effects, similar to what is seen for complex trait genetics in other diploid organisms such as humans.