Regulatory and coding sequences of TRNP1 co-evolve with brain size and cortical folding in mammals

• Published in: bioRxiv
• Main Authors: Kliesmete, Zane, Lucas Esteban Wange, Vieth, Beate, Esgleas, Miriam, Radmer, Jessica, Huelsmann, Matthias, Geuder, Johanna, Richter, Daniel, Ohnuki, Mari, Goetz, Magdalena, Hellmann, Ines, Enard, Wolfgang
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 20.09.2022
• Subjects: Cell proliferation; Evolution; Mammals; Neural coding; Neural stem cells; Phenotypic variations; Protein folding; Species; Stem cells
• DOI: 10.1101/2021.02.05.429919

Brain size and cortical folding have increased and decreased recurrently during mammalian evolution. Identifying genetic elements whose sequence or functional properties co-evolve with these traits can provide unique information on evolutionary and developmental mechanisms. A good candidate for such a comparative approach is TRNP1, as it can control proliferation of neural progenitors in mice and ferrets. Here, we investigate the contribution of both regulatory and coding sequences of TRNP1 to brain size and cortical folding in over 30 mammals. We find that the rate of TRNP1 protein evolution (ω) significantly correlates with brain size, slightly less with cortical folding and much less with body size. This brain correlation is stronger than for >95% of random control proteins. This co-evolution is likely affecting TRNP1 activity, as we find that TRNP1 from species with larger brains and more cortical folding induce higher proliferation rates in neural stem cells. Furthermore, we compare the activity of putative cis-regulatory elements (CREs) of TRNP1 in a massively parallel reporter assay (MPRA) and identify one CRE that co-evolves with cortical folding in Old World Monkeys and Apes. Our analyses indicate that coding and regulatory changes that increased TRNP1 activity were positively selected either as a cause or a consequence of increases in brain size and cortical folding. They also provide an example how phylogenetic approaches can inform biological mechanisms, especially when combined with molecular phenotypes across several species. Competing Interest Statement The authors have declared no competing interest. Footnotes * In this manuscript version we added 125 control protein sequences from 30 mammalian species to estimate the average dN/dS correlation with brain size and folding. In addition, we resequenced the genomic region of Trnp1 in ferret, yielding a more complete coding-sequence.