Abstract
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.
Highlights
Mammalian species in general tend to have larger brain to body size ratios compared with other vertebrates and in some primate and cetacean species this relationship is pronounced [1]
We found that Gene ontology (GO) terms for immune response, chemotaxis, regulation of immune response, female pregnancy, cell– cell signalling, signal transduction, energy reserve metabolic processes, positive regulation of peptidyl-tyrosine phosphorylation and neuropeptide signalling pathways were significantly over-represented after Bonferroni correction
It is worth noting that the complementary GO enrichment analysis carried out on gene families with both the most significant association between MLSP and gene family size (GFS) (r . 0, p, 0.05) and a stronger association with MLSP than Ei (r(MLSP, GFS) . r(Ei, GFS), n 1⁄4 1321), resulted in no significant enrichment of any GO category. These results shows that enrichment of specific GO terms occurred only among gene families preferentially associated with degree of encephalization, whereas GFS variations potentially associated with increased MLSP showed no significant association with any particular functional category
Summary
Mammalian species in general tend to have larger brain to body size ratios compared with other vertebrates and in some primate and cetacean species this relationship is pronounced [1]. In some functional categories strongly suggests that changes in gene number within gene families may reflect evolutionary responses to specific adaptive demands [10]. In this regard, gene duplication events linked to distinct aspects of vertebrate evolution have been described. Whether changes in the number of copies of genes involved in distinct cellular and developmental functions has contributed to shaping the morphological, physiological and metabolic machinery supporting brain evolution in mammalian lineages is not known. Our results reveal a proportion of gene families displaying a positive association between GFS and level of encephalization significantly larger than expected by chance This bias occurs most prominently in families associated with specific biological functions. By examining expression data in human tissues, we further found that gene families displaying the highest association between encephalization and GFS are statistically enriched in genes that are prominently expressed in the brain, with maximal expression in the cortex and displaying an expression signature distinctly associated with cortical development
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