Increased brain size in mammals is associated with size variations in gene families with cell signalling, chemotaxis and immune-related functions.

Genomic determinants underlying increased encephalization across mammalian lineages are unknown. Whole genome comparisons have revealed large and frequent changes in the size of gene families, and it has been proposed that these variations could play a major role in shaping morphological and physiological differences among species. Using a genome-wide comparative approach, we examined changes in gene family size (GFS) and degree of encephalization in 39 fully sequenced mammalian species and found a significant over-representation of GFS variations in line with increased encephalization in mammals. We found that this relationship is not accounted for by known correlates of brain size such as maximum lifespan or body size and is not explained by phylogenetic relatedness. Genes involved in chemotaxis, immune regulation and cell signalling-related functions are significantly over-represented among those gene families most highly correlated with encephalization. Genes within these families are prominently expressed in the human brain, particularly the cortex, and organized in co-expression modules that display distinct temporal patterns of expression in the developing cortex. Our results suggest that changes in GFS associated with encephalization represent an evolutionary response to the specific functional requirements underlying increased brain size in mammals.