A small number of human lineage mutations regulated RNA-protein binding of conserved genes and promoted human evolution

Abstract

Whether human lineage mutations (HLM) have contributed to human evolution via post-transcriptional modification remained unknown. We applied deep learning models Seqweaver to predict how HLM impacts RNA-binding protein affinity (RBP). At the threshold of the top 1% of human common variation, only 0.27% of HLM had large impacts on RBP. These HLMs enriched in a set of conserved genes that are highly expressed in adult excitatory neurons and prenatal Purkinje neurons, and involved in synapse organization and the GTPase pathway. These genes also carried excess damaging coding mutations that caused neurodevelopmental disorders, ataxia, and Schizophrenia. Among these genes, NTRK2 and ITPR1 had the most aggregated evidence of functional importance, pointing to an essential role in cognition and bipedalism. We concluded that a very small number of human-specific mutations have contributed to human speciation via impacts on post-transcriptional modification of critical brain-related genes. Author summaryPost-transcriptional modification has important functions in biological systems, but its role in evolution has long been a mystery due to the difficulty in predicting how a mutation could impact this process. Here we applied the newly developed deep learning model Seqweaver on human lineage mutations (HLM) to predict their effect on RNA-protein binding affinity profile (RBP). We found that only a very small number HLM are influential to RBP. Influential HLMs enriched in a set of conserved genes that are enriched in cells and functions critical for cognition and bipedal walking, and severe mutations on these genes cause the disruption of cognition (neurodevelopmental disorders) and bipedalism (ataxia). NTRK2 and ITPR1 had the most aggregated pieces of evidence of functional importance, pointing to an important role in cognition and bipedal walking. Taken together, our result demonstrated that there is a small number of human lineage mutations that modified the post-transcriptional modifications of conserved neuronal genes, which contributed to human speciation.