Can the male germline offer insight into mammalian brain size expansion?

Abstract

Recent advances in single-cell transcriptomic data have greatly expanded our understanding of both spermatogenesis and the molecular mechanisms of male infertility. However, this growing wealth of data could also shed light on a seemingly unrelated biological problem: the genetic basis of mammalian brain size expansion throughout evolution. It is now increasingly recognized that the testis and brain share many cellular and molecular similarities including pivotal roles for the RAS/MAPK and PI3K/AKT/mTOR pathways, mutations in which are known to have a pronounced impact on cell proliferation. Most notably, in the stem cell lineages of both organs, new mutations have been shown to increase cellular output over time. These include 'selfish' mutations in spermatogonial stem cells, which disproportionately increase the proportion of mutant sperm, and-to draw a parallel-human-specific mutations in neural stem cells which, by increasing the number of neurons, have been implicated in neocortical expansion. Here we speculate that the origin for many 'expansion'-associated mutations is the male germline and that as such, a deeper understanding of the mechanisms controlling testicular turnover may yield fresh insight into the biology and evolution of the brain.