Evolution in neuropsychiatric cis-regulatory enhancers through human-specific neuronal mutations within transcription factor binding sites

cis-Regulatory elements (CREs) in multicellular genomes play a significant role in precise regulation of the genes. Increasing evidence has shown that alterations in CREs have had a drastic effect on the human brain evolution, neuronal cell adaptation and physiology. The human-specific sequence acceleration in CREs has not only changed the overall cognitive function of the human brain, but also seems to have strongly increased the risk of developing psychiatric disorders. Mapping the human-specific neuronal mutations within CREs remains to be a challenge and can largely impact the way DNA binding domain of the transcription factors interact with the CREs. In this study, we have identified human-specific neuronal mutations within transcription factor binding sites in neuropsychiatric enhancers of three major psychiatric disorders i.e. autism spectrum disorder, schizophrenia and bipolar disorder and studied the impact of human-specific neuronal mutations on binding affinities with the respective transcription factors via molecular dynamic simulation. Moreover, we have also identified signals of positive selection in the same set of empirically confirmed neuropsychiatric enhancers and correlated it with the way transcription factors bind with the human-specific and their counterpart ancestral allele harboring transcription factor binding sites.