TRNP1 sequence, function and regulation co-evolve with cortical folding in mammals

Genomes can be seen as notebooks of evolution that contain unique information on successful genetic experiments. This allows to identify conserved genomic sequences and is very useful e.g. for finding disease-associated variants. Additional information from genome comparisons across species can be leveraged when considering phenotypic variance across species. Here, we exemplify such a cross-species association study for the gene TRNP1 that is important for mammalian brain development. We find that the rate of TRNP1 protein evolution is highly correlated with the rate of cortical folding across mammals and that TRNP1 proteins from species with more cortical folding induce higher proliferation rates in neural stem cells. Furthermore, we identify a regulatory element in TRNP1 whose activity correlates with cortical folding in Old World Monkeys and Apes. Our analyses indicate that coding and regulatory changes in TRNP1 have modulated its activity to adjust cortical folding during mammalian evolution and provide a blueprint for cross-species association studies.