Systematic identification of cis-regulatory variants that cause gene expression differences in a yeast cross.
Systematic identification of cis-regulatory variants that cause gene expression differences in a yeast cross.
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DOI：
10.7554/elife.62669
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发表时间：
2020-11-12
期刊：
影响因子：
7.7
通讯作者：
Albert FW
中科院分区：
文献类型：
--
作者：
Renganaath K;Chong R;Day L;Kosuri S;Kruglyak L;Albert FW
调控DNA中的序列变异改变基因表达并形成遗传上复杂的性状。然而，识别个体的因果调节变体是具有挑战性的。在这里，我们使用了一个大规模的平行报告分析，以测量在酵母酿酒酵母中的2503个基因的启动子中的5832个天然DNA变体的顺式调控后果。我们确定了451个致病变异体，这些变异体是已知影响基因表达的遗传位点的基础。几个启动子携带多个致病变体。在五个启动子中，成对的变体表现出非加性的上位相互作用。致病变异在保守核苷酸处富集，倾向于具有低衍生等位基因频率，并且从必需基因的启动子中耗尽，这与负选择的作用一致。也富集了转录因子结合位点改变的因果变异。整合这些特征的模型提供了适度但具有统计学意义的预测因果变异的能力。这项工作揭示了一个复杂的顺式作用的调节变异的分子基础。
Sequence variation in regulatory DNA alters gene expression and shapes genetically complex traits. However, the identification of individual, causal regulatory variants is challenging. Here, we used a massively parallel reporter assay to measure the cis-regulatory consequences of 5832 natural DNA variants in the promoters of 2503 genes in the yeast Saccharomyces cerevisiae. We identified 451 causal variants, which underlie genetic loci known to affect gene expression. Several promoters harbored multiple causal variants. In five promoters, pairs of variants showed non-additive, epistatic interactions. Causal variants were enriched at conserved nucleotides, tended to have low derived allele frequency, and were depleted from promoters of essential genes, which is consistent with the action of negative selection. Causal variants were also enriched for alterations in transcription factor binding sites. Models integrating these features provided modest, but statistically significant, ability to predict causal variants. This work revealed a complex molecular basis for cis-acting regulatory variation.