A role for the male germline in the expansion of the mammalian brain

Preprint

The brain and testis share a surprisingly high number of molecular and cellular similarities. We have previously hypothesised that, throughout evolution, many genetic variants contributing to brain size expansion first arose in spermatogonia where they conferred a selective advantage to the male germline stem cells via a process analogous to oncogenesis – known as ‘selfish spermatogonial selection’. 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. Although the evidence supporting a close molecular relationship between the germline and brain is compelling, research in this area 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 re-analyses of 34 adult human single-cell testis datasets with data from the Human Protein Atlas to assess the extent to which genes functionally associated with brain growth and development are expressed within testicular cell types. Consistent with our hypothesis, we find that among thousands of proteins with brain-associated functions, the majority are not only expressed in male germ cells, but show particular enrichment in spermatogonia. We contextualise these results with an extensive literature survey and conclude that further enquiry into the testis-brain connection may yield novel insight into the evolutionary processes that shaped the human condition.

Significance statement The human brain and testis share unexpected molecular similarities, yet the evolutionary and biomedical implications of this overlap remain poorly understood. By integrating single-cell transcriptomic datasets with large-scale proteomic data, we show that genes implicated in neurodevelopment are widely expressed in the male germline and particularly enriched in spermatogonia. These findings support the idea that ‘selfish’ mutations arising in spermatogonial stem cells not only promote their own propagation in the testis but may also influence neural progenitor biology once inherited. Our results provide a systematic foundation for understanding how male germline-specific evolutionary forces could have contributed to the emergence of the large and complex human brain, while also offering insight into the origins of susceptibility to some congenital neurodevelopmental diseases.

Authors: Bush, SJ; Goriely, A

• Publication status: Published
• Preprint server: bioRxiv
• Publication date: 2026-02-10
• DOI: 10.1101/2025.09.15.676184
• Server owner: Cold Spring Harbor Laboratory
• Language: English
• Keywords: generic health relevance; genetics; contraception; urologic diseases; stem cell research; non-human nonembryonic stem cell research; human genome; reproduction