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

Abstract

AbstractGenomes can be seen as notebooks of evolution that contain unique information on successful genetic experiments (Wright 2001). This allows to identify conserved genomic sequences (Zoonomia Consortium 2020) and is very useful e.g. for finding disease-associated variants (Kircher et al. 2014). Additional information from genome comparisons across species can be leveraged when considering phenotypic variance across species. Here, we exemplify this principle in a cross-species association study by testing whether structural or regulatory changes in TRNP1 correlate with changes in brain size and cortical folding in mammals. We find that the rate of TRNP1 protein evolution (ω) correlates best with the rate of cortical folding and that TRNP1 proteins from species with more cortical folding induce higher proliferation rates in neural stem cells from murine cerebral cortex. Furthermore, we compare the activity of putative cis-regulatory elements of TRNP1 in a massively parallel reporter assay and identify one element that correlates with cortical folding in Old World Monkeys and Apes. Our analyses indicate that coding and regulatory changes in TRNP1 modulated its activity to adjust cortical folding during mammalian evolution and exemplify how evolutionary information can be leveraged by cross-species association studies.