Figure 2.

Selfish spermatogonial selection (A) In selfish selection, rare specific mutations occur in genes involved in the homeostatic regulation of spermatogonial stem cells (SSCs), conferring gain-of-function properties to the encoded protein. This provides the SSCs with a selective advantage over the wild-type neighbors and results in their clonal expansion within individual seminiferous tubules. As a consequence of clonal growth, the relative proportion of mutant sperm increases over the course of time. Fertilization of an oocyte by a sperm carrying a selfish mutation results in a genetic disorder in the offspring. This process is akin to tumorigenesis but occurs in the germline with consequences for the next generation. (B) Single-cell transcriptomics has allowed the key signaling pathways active in SSCs to be identified. To date, all known selfishly selected genes (highlighted in red) cluster within the Receptor Tyrosine Kinase (RTK)-RAS-MAPK pathway (red box). Deciphering the role of these pathways/genes in controlling proliferation, growth and survival of SSCs allows us to focus on new promising candidates for selfishly selected genes within the testes. Note that most of these genes cause genetic disease when mutated. Adapted from refs 74-75. Figures created with BioRender.com. SSC = spermatogonial stem cell.