Drosophila Toxicogenomics: genetic variation and sexual dimorphism in susceptibility to 4-Methylimidazole
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 (...
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2024-11-01
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| Online Access: | https://doi.org/10.1186/s40246-024-00689-3 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Katelynne M. Collins |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-e59933fe43b04c80965ccab72c2b6d57 |
| institution | DOAJ |
| issn | 1479-7364 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Human Genomics |
| spelling | doaj-art-e59933fe43b04c80965ccab72c2b6d572025-08-20T02:49:59ZengBMCHuman Genomics1479-73642024-11-0118111410.1186/s40246-024-00689-3Drosophila Toxicogenomics: genetic variation and sexual dimorphism in susceptibility to 4-MethylimidazoleKatelynne M. Collins0Elisabeth Howansky1Sarah C. Macon-Foley2Maria E. Adonay3Vijay Shankar4Richard F. Lyman5Nestor Octavio Nazario-Yepiz6Jordyn K. Brooks7Rachel A. Lyman8Trudy F. C. Mackay9Robert R. H. Anholt10Center for Human Genetics, Department of Genetics and Biochemistry, Clemson UniversityCenter for Human Genetics, Department of Genetics and Biochemistry, Clemson UniversityCenter for Human Genetics, Department of Genetics and Biochemistry, Clemson UniversityCenter for Human Genetics, Department of Genetics and Biochemistry, Clemson UniversityCenter for Human Genetics, Department of Genetics and Biochemistry, Clemson UniversityCenter for Human Genetics, Department of Genetics and Biochemistry, Clemson UniversityCenter for Human Genetics, Department of Genetics and Biochemistry, Clemson UniversityCenter for Human Genetics, Department of Genetics and Biochemistry, Clemson UniversityCenter for Human Genetics, Department of Genetics and Biochemistry, Clemson UniversityCenter for Human Genetics, Department of Genetics and Biochemistry, Clemson UniversityCenter for Human Genetics, Department of Genetics and Biochemistry, Clemson UniversityAbstract 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.https://doi.org/10.1186/s40246-024-00689-3Quantitative geneticsgenome wide association analysesDrosophila Genetic Reference Panelsex-specific effectssexually antagonistic effectsnetwork associations with complex traits |
| spellingShingle | 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 Drosophila Toxicogenomics: genetic variation and sexual dimorphism in susceptibility to 4-Methylimidazole Human Genomics Quantitative genetics genome wide association analyses Drosophila Genetic Reference Panel sex-specific effects sexually antagonistic effects network associations with complex traits |
| title | Drosophila Toxicogenomics: genetic variation and sexual dimorphism in susceptibility to 4-Methylimidazole |
| title_full | Drosophila Toxicogenomics: genetic variation and sexual dimorphism in susceptibility to 4-Methylimidazole |
| title_fullStr | Drosophila Toxicogenomics: genetic variation and sexual dimorphism in susceptibility to 4-Methylimidazole |
| title_full_unstemmed | Drosophila Toxicogenomics: genetic variation and sexual dimorphism in susceptibility to 4-Methylimidazole |
| title_short | Drosophila Toxicogenomics: genetic variation and sexual dimorphism in susceptibility to 4-Methylimidazole |
| title_sort | drosophila toxicogenomics genetic variation and sexual dimorphism in susceptibility to 4 methylimidazole |
| topic | Quantitative genetics genome wide association analyses Drosophila Genetic Reference Panel sex-specific effects sexually antagonistic effects network associations with complex traits |
| url | https://doi.org/10.1186/s40246-024-00689-3 |
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