Funding period: 2019-2024
Lead: Francesco Marchetti
Total GRDI funding: $1,050,000
New mutations occur at each cell division either because of random errors or because of exposure to a toxic agent. When mutations happen in tissues, they may give rise to cancer. When mutations happen in sperm or eggs, they can result in a variety of genetic diseases if transmitted to the offspring. Existing tests have limitations as they measure mutations in a single gene (the human genome has ~20,000 genes) or use genetically modified laboratory rodents where mutations are measured in a bacterial gene. The key objectives of this project are to establish the latest next generation sequencing technologies to quantify and characterize chemically-induced mutations over the entire genome. This project is generating foundational data to modernize and improve regulatory testing for mutagenicity, contribute to effectively and efficiently assessing the potential adverse health effects of chemicals and provide regulatory knowledge to help prevent cancer and other genetic diseases. The application of Next Generation Sequencing approaches for mutagenicity testing is an international priority and knowledge generated by this project contributes to ongoing discussions on how to incorporate these methods in the guidelines of the Organisation for the Economic Co-operation and Development.
Publications
- Axelsonn J, Shojaeisaadi H, Marchetti F, Yauk, CL. 2023. How do paternal factors such as diet, smoking, stress and environmental chemical exposure affects germ cell mutations. Robaire B, Chan P (eds). Handbook of Andrology. Third Edition. The American Society of Andrology, pp. 179-184. Chapter-29-Axelsson-Shojaeisaadi-Marchetti-and-Yauk.pdf (secureserver.net)
- Beal MA, Meier MJ, LeBlanc D, Maurice C, O'Brien JM, Yauk CL, Marchetti F. 2020. Chemically induced mutations in a MutaMouse reporter gene inform mechanisms underlying human cancer mutational signatures. Commun. Biol. 3(1):438. https://doi.org/10.1038/s42003-020-01174-y
- Beal MA, Meier MJ, Williams A, Rowan-Carroll A, Gagné R, Lindsay SJ, Fitzgerald T, Hurles ME, Marchetti F, Yauk CL. 2019. Paternal exposure to benzo(a)pyrene induces genome-wide mutations in offspring. Commun. Biol. 2:e228. https://doi.org/10.1038/s42003-019-0476-5
- Leblanc DPM, Meier M, Lo FY, Schmidt E, Valentine C, Williams A, Salk JJ, Yauk CL, Marchetti F. 2022. Duplex sequencing identifies genomic features that determine susceptibility to mutation induction in the bone marrow of MutaMouse males exposed to benzo(a)pyrene. BMC Genomics, 23:542. https://doi.org/10.1186/s12864-022-08752-w
- Marchetti F, Cardoso R, Chen CL, Custer L, Douglas GR, Elloway J, Escobar PA, Harper Jr T, Heflich RH, Kidd D, Lynch AM, Myers MB, Parsons BL, Salk JJ, Settivary RS, Smith-Roe SL, Witt KL, Yauk CL, Young RR, Zhang S, Minocherhomji S. 2023. Error-corrected next-generation sequencing to advance nonclinical genotoxicity and carcinogenicity testing. Nature Reviews Drug Discovery 22:165-166. https://doi.org/10.1038/d41573-023-00014-y
- Marchetti F, Douglas GR, Yauk CL. 2020. A return to the origin of the EMGS: rejuvenating the quest for human germ cell mutagens and determining the risk to future generations. Environ. Mol. Mutagen. 61(1):42-54. https://doi.org/10.1002/em.22327
- Meier MJ, Beal MA, Schoenrock A, Yauk CL, Marchetti F. 2019. Whole genome sequencing of the MutaMouse model reveals strain- and colony-level variation, and genomic features of the transgene integration site. Sci. Rep.. 9:e13775. https://doi.org/10.1038/s41598-019-50302-0
Contact us
For additional information, please contact:
Genomics R&D Initiative
Email: info@grdi-irdg.collaboration.gc.ca