About the Project
Germ cells (which make sperm or oocytes) are tasked with passing genetic information from one generation to the next. It is therefore of paramount importance that the genome of these cells remain free from errors. Our DNA is constantly damaged however we have evolved mechanisms to detect and repair this damage. If this process goes wrong then errors (mutations) are introduced into the genome with devastating consequences. The majority of mutations that passed between generations arise in the father’s germ cells. Furthermore, the number of mutations increases with increasing age of the father.
The aim of this project will be to identify when during sperm production DNA damage occurs and how this damage is normally repaired. The project will employ mouse models to study the consequences of DNA repair deficiency on sperm production and spermatogonial stem cell maintenance. We will generate new reporter mice to allow us to isolate and study this rare population of stem cells. This will be coupled with studying the nature of mutations that arise in the gametes of these DNA repair deficient mice using next generation sequencing.
The project will provide insights into how the genome that we pass on to our children is threatened and maintained free from errors.
References
Garaycoechea, JI, Crossan, GP, Langevin, F, Daly, M., Arends, MJ, Patel, K J. (2012)
Genotoxic consequences of endogenous aldehydes on mouse haematopoietic stem cell function.
Nature; 489, 571-5.
Garaycoechea JI, Crossan GP, Langevin F, Mulderrig L, Gibaud G, Gomes S, Yang F, Roerink S, Nik-Zainal S, Stratton M and Patel KJ. (2018)
Alcohol-derived and endogenous aldehydes rearrange chromosomes and mutate stem cell genomes.
Nature 553, 171-177
Kong, A. et al. (2012)
Rate of de novo mutations and the importance of father's age to disease risk.
Nature 488, 471-5.
Campbell, C.D. et al. (2012)
Estimating the human mutation rate using autozygosity in a founder population.
Nat Genet 44, 1277-81.
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