Drosophila Toxicogenomics: genetic variation and sexual dimorphism in susceptibility to 4-Methylimidazole.

IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Human Genomics Pub Date : 2024-11-04 DOI:10.1186/s40246-024-00689-3
Katelynne M Collins, Elisabeth Howansky, Sarah C Macon-Foley, Maria E Adonay, Vijay Shankar, Richard F Lyman, Nestor Octavio Nazario-Yepiz, Jordyn K Brooks, Rachel A Lyman, Trudy F C Mackay, Robert R H Anholt
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Abstract

Background: 4-methylimidazole is a ubiquitous and potentially carcinogenic environmental toxicant. Genetic factors that contribute to variation in susceptibility to its toxic effects are challenging to assess in human populations. We used the Drosophila melanogaster Genetic Reference Panel (DGRP), a living library of natural genetic variation, to identify genes with human orthologs associated with variation in susceptibility to 4-methylimidazole.

Results: We screened 204 DGRP lines for survival following 24-hour exposure to 4-methylimidazole. We found extensive genetic variation for survival, with a broad sense heritability of 0.82; as well as genetic variation in sexual dimorphism, with a cross-sex genetic correlation of 0.59. Genome-wide association analyses identified a total of 241 candidate molecular polymorphisms in or near 273 unique genes associated with survival. These polymorphisms had either sex-specific or sex-antagonistic effects, and most had putative regulatory effects. We generated interaction networks using these candidate genes as inputs and computationally recruited genes with known physical or genetic interactions. The network genes were significantly over-represented for gene ontology terms involving all aspects of development (including nervous system development) and cellular and organismal functions as well as canonical signaling pathways, and most had human orthologs.

Conclusions: The genetic basis of variation in sensitivity to acute exposure to 4-methylimidazole in Drosophila is attributable to variation in genes and networks of genes known for their effects on multiple developmental and cellular processes, including possible neurotoxicity. Given evolutionary conservation of the underlying genes and pathways, these insights may be applicable to humans.

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果蝇毒物基因组学:4-甲基咪唑易感性的遗传变异和性双态性。
背景:4 甲基咪唑是一种无处不在的潜在致癌环境毒物。在人类群体中评估导致对其毒性作用易感性变异的遗传因素具有挑战性。我们利用黑腹果蝇遗传参照组(DGRP)--一个活的自然遗传变异库--来鉴定与4-甲基咪唑易感性变异相关的人类直向同源基因:我们对 204 个 DGRP 株系进行了筛选,以检测它们在暴露于 4-甲基咪唑 24 小时后的存活率。我们发现了存活率的广泛遗传变异,广义遗传率为 0.82;以及性二态的遗传变异,跨性别遗传相关性为 0.59。全基因组关联分析在与存活率相关的 273 个独特基因中或其附近共发现了 241 个候选分子多态性。这些多态性要么具有性别特异性效应,要么具有性别拮抗效应,而且大多数具有假定的调控效应。我们利用这些候选基因作为输入,并通过计算招募了具有已知物理或遗传相互作用的基因,从而生成了相互作用网络。网络基因在涉及发育(包括神经系统发育)、细胞和生物体功能以及典型信号通路的基因本体术语中的代表性明显偏高,而且大多数基因都有人类直向同源物:果蝇对急性暴露于 4-甲基咪唑的敏感性差异的遗传基础可归因于基因和基因网络的差异,已知这些基因和基因网络对多个发育和细胞过程具有影响,包括可能的神经毒性。鉴于基本基因和途径的进化保护,这些见解可能适用于人类。
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来源期刊
Human Genomics
Human Genomics GENETICS & HEREDITY-
CiteScore
6.00
自引率
2.20%
发文量
55
审稿时长
11 weeks
期刊介绍: Human Genomics is a peer-reviewed, open access, online journal that focuses on the application of genomic analysis in all aspects of human health and disease, as well as genomic analysis of drug efficacy and safety, and comparative genomics. Topics covered by the journal include, but are not limited to: pharmacogenomics, genome-wide association studies, genome-wide sequencing, exome sequencing, next-generation deep-sequencing, functional genomics, epigenomics, translational genomics, expression profiling, proteomics, bioinformatics, animal models, statistical genetics, genetic epidemiology, human population genetics and comparative genomics.
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