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A spermatogonial perspective on the expansion of the mammalian brain

Publicado
Servidor
bioRxiv
DOI
10.1101/2025.09.15.676184

The brain and testis share many molecular similarities, yet the evolutionary implications of this overlap remain unclear. We have previously hypothesised that, throughout evolution, some genetic variants contributing to brain size expansion first arose in spermatogonia where they conferred a selective advantage to the male germline stem cells via ‘selfish spermatogonial selection’, a process analogous to oncogenesis. Once transmitted to the next generation, these selfish variants became constitutive, disproportionately accumulating in signalling pathways active in both spermatogenesis and neurogenesis and which regulate stem cell proliferation. However, testing this hypothesis is stymied by the relative scarcity of spermatogonia and the inherent stochasticity of single-cell transcriptomic profiling. Accordingly, the molecular signatures of spermatogonia are incompletely understood, and their similarity with neural programs difficult to assess. To address this, we combine single-cell testis and brain transcriptomic datasets with multi-tissue proteomic data to show that genes associated with brain-expansion phenotypes, and neurodevelopment generally, are not only widely expressed in the male germline but particularly enriched in spermatogonia, an observation consistent across mammalian evolutionary history. We contextualise these results with an extensive literature survey and conclude that enquiry into the testis-brain connection may yield novel insight into the evolutionary processes that shaped the human condition.

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