I am a postdoctoral researcher with an interest in the origins of de novo mutations and their links with male germ cell biology. De novo point mutations, a major cause of developmental disorders, predominantly originate in the male germline and increase in frequency with age, attributed to the accumulation of copy errors that occur during the regular division of spermatogonial stem cells.
My research focuses on selfish spermatogonial selection, a phenomenon that explains why specific mutations associated with some severe congenital disorders are the most frequently observed spontaneous mutations in the human germline. These 'selfish' mutations confer a selective advantage to the spermatogonial stem cells in which they arise, leading to clonal expansion and an increased risk of transmission to the next generation.
To study this process I developed methods to visualise the mutant clones directly in normal human testes and by subsequently isolating the clones, facilitate broad-scale genetic testing. This combination of immunohistochemistry and next-generation sequencing approaches extended the range of documented selfish mutations and revealed insights into the cellular basis of the mutant clones. These events occur in the testes of all men with their number and size increasing with age, which has implications for ageing reproductive populations.
By improving the sensitivity and scalability of approaches to detect these mutant spermatogonial clones, I aim to assess the full-spectrum of mutations under positive selection in the male germline and to study the effect of these mutations on the germ cells in which they arise. In addition, I am also investigating the link between these common benign growths and the rare testicular tumour spermatocytic seminoma (spermatocytic tumour).
Teasing apart the multiple roles of Shp2 (Ptpn11) in spermatogenesis.
Maher GJ. and Goriely A., (2020), Asian J Androl, 22
amplimap: a versatile tool to process and analyze targeted NGS data.
Koelling N. et al, (2019), Bioinformatics, 35, 5349 - 5350
The impact of chemo- and radiotherapy treatments on selfish de novo FGFR2 mutations in sperm of cancer survivors.
Maher GJ. et al, (2019), Hum Reprod
CRISPR/Cas9-targeted enrichment and long-read sequencing of the Fuchs endothelial corneal dystrophy-associated TCF4 triplet repeat.
Hafford-Tear NJ. et al, (2019), Genet Med
Selfish mutations dysregulating RAS-MAPK signaling are pervasive in aged human testes.
Maher GJ. et al, (2018), Genome Res, 28, 1779 - 1790