The Gene scb-1 Underlies Variation in Caenorhabditis elegans Chemotherapeutic Responses
The Gene scb-1 Underlies Variation in Caenorhabditis elegans Chemotherapeutic Responses
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DOI：
10.1534/g3.120.401310
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发表时间：
2020-07-01
影响因子：
2.6
通讯作者：
Andersen, Erik C.
中科院分区：
文献类型：
--
作者：
Evans, Kathryn S.;Andersen, Erik C.
多效性，即单个基因控制多个不同特征的概念，在大多数生物体中普遍存在，并对医学和农业具有广泛的影响。多效性背后的分子机制的鉴定有能力揭示看似无关的特征之间以前未知的生物联系。此外，多效性基因的发现通过表征新的基因功能增加了我们对遗传和表型复杂性的理解。数量性状基因座(QTL)定位已被用来确定许多生物体中的几个多效区。然而，需要进行基因敲除研究，以消除紧密连锁的非多效性基因座的可能性。在这里，我们使用一组296个秀丽线虫的重组近交系和高通量适合度分析来确定位于V染色体中心的单个大效应QTL，该QTL与8种化疗药物的反应变化有关。我们用近等基因系验证这个QTL，并将全基因组的基因表达数据与药物反应性状配对进行中介分析，从而识别出八种化疗药物中的一些药物的多效性候选基因。使用通过基因组编辑创建的缺失菌株，我们表明，以前被认为与博莱霉素的反应有关的基因，也是对其他双链DNA断裂诱导化疗药物的反应的基础。这一发现为线虫药物反应中的作用提供了新的证据，并强调了中介分析在识别致病基因方面的力量。
Pleiotropy, the concept that a single gene controls multiple distinct traits, is prevalent in most organisms and has broad implications for medicine and agriculture. The identification of the molecular mechanisms underlying pleiotropy has the power to reveal previously unknown biological connections between seemingly unrelated traits. Additionally, the discovery of pleiotropic genes increases our understanding of both genetic and phenotypic complexity by characterizing novel gene functions. Quantitative trait locus (QTL) mapping has been used to identify several pleiotropic regions in many organisms. However, gene knockout studies are needed to eliminate the possibility of tightly linked, non-pleiotropic loci. Here, we use a panel of 296 recombinant inbred advanced intercross lines of Caenorhabditis elegans and a high-throughput fitness assay to identify a single large-effect QTL on the center of chromosome V associated with variation in responses to eight chemotherapeutics. We validate this QTL with near-isogenic lines and pair genome-wide gene expression data with drug response traits to perform mediation analysis, leading to the identification of a pleiotropic candidate gene,, for some of the eight chemotherapeutics. Using deletion strains created by genome editing, we show that, which was previously implicated in response to bleomycin, also underlies responses to other double-strand DNA break-inducing chemotherapeutics. This finding provides new evidence for the role of in the nematode drug response and highlights the power of mediation analysis to identify causal genes.