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).
Chromatin and Single-Cell RNA-Seq Profiling Reveal Dynamic Signaling and Metabolic Transitions during Human Spermatogonial Stem Cell Development.
Guo J. et al, (2017), Cell Stem Cell, 21, 533 - 546.e6
Whole-genome sequencing of spermatocytic tumors provides insights into the mutational processes operating in the male germline.
Giannoulatou E. et al, (2017), PLoS One, 12
Cellular correlates of selfish spermatogonial selection.
Maher GJ. et al, (2016), Andrology, 4, 550 - 553
Visualizing the origins of selfish de novo mutations in individual seminiferous tubules of human testes.
Maher GJ. et al, (2016), Proc Natl Acad Sci U S A, 113, 2454 - 2459
Autosomal-Dominant Corneal Endothelial Dystrophies CHED1 and PPCD1 Are Allelic Disorders Caused by Non-coding Mutations in the Promoter of OVOL2.
Davidson AE. et al, (2016), Am J Hum Genet, 98, 75 - 89