Center for Human Genetics, Department of Genetics and Biochemistry, Clemson University, Greenwood, SC, 29646, USA.
Hum Genomics. 2024 Nov 4;18(1):119. doi: 10.1186/s40246-024-00689-3.
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.
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.
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.
4-甲基咪唑是一种普遍存在且潜在致癌的环境毒物。在人类群体中，评估导致其毒性作用易感性差异的遗传因素具有挑战性。我们使用黑腹果蝇遗传参考面板（DGRP），这是一个天然遗传变异的活体文库，来鉴定与对 4-甲基咪唑的易感性变化相关的具有人类同源物的基因。
我们对 204 条 DGRP 品系进行了 24 小时暴露于 4-甲基咪唑后的生存筛选。我们发现，生存存在广泛的遗传变异，广义遗传率为 0.82；同时也存在性别二态性的遗传变异，交叉性别遗传相关性为 0.59。全基因组关联分析总共确定了 273 个与生存相关的独特基因中的 241 个候选分子多态性。这些多态性具有性别特异性或性别拮抗作用，大多数具有潜在的调节作用。我们使用这些候选基因作为输入生成了相互作用网络，并通过计算招募了具有已知物理或遗传相互作用的基因。网络基因在涉及发育的各个方面（包括神经系统发育）以及细胞和生物体功能以及规范信号通路的基因本体论术语中显著过表达，并且大多数都具有人类同源物。
果蝇对急性暴露于 4-甲基咪唑的敏感性变化的遗传基础归因于已知对多种发育和细胞过程（包括可能的神经毒性）有影响的基因及其网络的变化。考虑到潜在基因和途径的进化保守性，这些见解可能适用于人类。
