From Genes to Brains: Molecular Evolution and Mammalian Brain Cellular Diversity

Mammalian brains exhibit extensive diversity in size, cellular composition, and organization, yet the molecular evolutionary changes associated with this phenotypic diversification remain incompletely understood. Here, we investigated whether protein-sequence evolution covaries with quantitative differences in brain phenotypes across mammals. We integrated 29 brain and body traits with orthologous protein sequences from 18 mammalian species and obtained gene-specific molecular evolutionary measures for 10,395 genes. To reduce redundancy among strongly correlated phenotypes, we selected five representative traits that explained 88.12% of the standardized trait variance under linear reconstruction. Using RERconverge, we tested for associations between gene-specific relative evolutionary rates and evolutionary changes in these five representative traits. The primary analysis, based on log-transformed phenotypes, identified 25 significant gene--trait associations involving 23 genes, 19 of which were also recovered using untransformed phenotypes, indicating that a substantial subset of the associations was robust to phenotype transformation. Expression profiling of these shared candidate genes across adult human GTEx brain tissues revealed heterogeneous patterns ranging from broad expression across the examined tissues to low adult brain expression. Functional enrichment analysis further showed that the gene set retained for comparative analysis was enriched for diverse biological processes, including metabolic, cellular, and neural pathways. These results identify gene-specific evolutionary-rate associations with quantitative mammalian phenotypes and provide functional context for the genes represented in the comparative analysis. Our study provides a comparative framework linking relative evolutionary rates of protein-coding genes to quantitative variation in mammalian brain cellular architecture while accounting for shared evolutionary history.