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

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’. Upon transmission of the mutant sperm 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. While we believe these observations supporting a close association between germline and brain development are compelling, research in this area is stymied by the relative scarcity of spermatogonia and the inherent stochasticity of the single-cell transcriptomic methods used to profile them. Accordingly, the molecular signatures of spermatogonia are incompletely understood, and their similarity with those of the brain difficult to assess. To support further work on the testis-brain relationship, 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 of thousands of proteins functionally associated with the brain, 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.