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As the key organ that separates humans from non-human primates, the brain has continuously evolved to adapt to the changes of environments and climates. Although human shares most genetic, molecular, and cellular features with other primates such as macaques, there are significant differences in the structure and function of the brain between humans and these species. Thus, exploring the differences between the brains of human and non-human primates in the context of evolution will provide insights into the development, functionality, and diseases of the human nervous system. Since the genes involved in many aspects of the human brain are under common pressures of natural selection, their evolutionary features can be analyzed collectively at the pathway-level. In this study, the molecular mechanisms underlying human brain capabilities were explored by comparing the evolutionary features of pathways enriched in genes expressed in the human brain and the macaque brain. 31 differentially expressed evolutionary pathways were identified in the brains of humans and macaques, among which included those related to neurological diseases, signal transduction, immunological response, and metabolic processes. By analyzing differentially expressed genes in brain regions or development stages between humans and macaques, 10 pathways and 4 pathways were found to have evolutionary distinctions, respectively. We further performed crosstalk analysis of pathways in order to obtain an intuitive correlation between the pathways, of which is helpful in understanding the mechanisms of interaction between pathways. Our results shed light on a comprehensive view of the evolutionary pathways of the human nervous system and provide a reference for the study of human brain development.

The nicotinic acetylcholine receptors (nAChR) belong to a large family of ligand-gated ion channels and are involved in the mediation of fast synaptic transmission. Each receptor is made up of five subunits that arrange symmetrically around a central pore. Despite the similarity in their sequences and structures, the properties of these subunits vary significantly. Thus, identifying the function-related sites specific to each subunit is essential for understanding the characteristics of the subunits and the receptors assembled by them. In this study, we examined the sequence features of the nine neuronal nAChRs subunits from twelve representative vertebrate species. Analysis revealed that all the subunits were subject to strong purifying selection in evolution, and each was under a unique pattern of selection pressures. At the same time, the functional constraints were not uniform within each subunit, with different domains in the molecule being subject to different selection pressures. Via evolutionary analyses, we also detected potential positive selection events in the subunits or subunit clusters, and identified the sites might be associated with the function specificity of each subunit. Furthermore, positive selection at some domains might contributed to the diversity of subunit function; for example, the β9 strand might be related to the agonist specificity of α subunit in heteromeric receptor and β4-β5 linker could be involved in Ca2+ permeability. Subunits α7, α4 and β2 subunits possess a strong adaptability in vertebrates. Our results highlighted the importance of tracking functional differentiation in protein sequence underlying functional properties of nAChRs. In summary, our work may provide clues on understanding the diversity and the function specificity of the nAChR subunits, as well as the receptors co-assembled by them.