The human brain differs from that of other primates, but the genetic basis of these differences remains unclear. We investigated the evolutionary pressures acting on almost all human protein-coding genes (N=11,667; 1:1 orthologs in primates) based on their divergence from those of early hominins, such as Neanderthals, and non-human primates. We confirm that genes encoding brain-related proteins are among the most strongly conserved protein-coding genes in the human genome. Combining our evolutionary pressure metrics for the protein-coding genome with recent datasets, we found that this conservation applied to genes functionally associated with the synapse and expressed in brain structures such as the prefrontal cortex and the cerebellum. Conversely, several genes presenting signatures commonly associated with positive selection appear as causing brain diseases or conditions, such as micro/macrocephaly, Joubert syndrome, dyslexia, and autism. Among those, a number of DNA damage response genes associated with microcephaly in humans such as BRCA1, NHEJ1, TOP3A, and RNF168 show strong signs of positive selection and might have played a role in human brain size expansion during primate evolution. We also showed that cerebellum granule neurons express a set of genes also presenting signatures of positive selection and that may have contributed to the emergence of fine motor skills and social cognition in humans. This resource is available online and can be used to estimate evolutionary constraints acting on a set of genes and to explore their relative contributions to human traits.

中文翻译：

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灵长类动物进化过程中阳性选择下脑蛋白编码基因的系统检测及其在认知中的作用

人脑不同于其他灵长类动物，但是这些差异的遗传基础仍然不清楚。我们研究了作用于几乎所有人类蛋白质编码基因（N = 11,667；灵长类动物中的1：1直向同源物）的进化压力，基于它们与早期人类素（如尼安德特人和非人类灵长类动物）的差异。我们证实，编码脑相关蛋白的基因是人类基因组中最保守的蛋白编码基因。结合我们的蛋白质编码基因组的进化压力度量标准和最新数据集，我们发现这种保守性适用于与突触功能相关并在脑结构（如前额叶皮层和小脑）中表达的基因。反过来，表现出通常与阳性选择相关的特征的几个基因会引起脑部疾病或状况，例如微头畸形，巨头畸形，乔伯特综合症，诵读困难和自闭症。其中，与人类小头畸形相关的许多DNA损伤反应基因，例如BRCA1，NHEJ1，TOP3A和RNF168，都显示出强烈的阳性选择迹象，并且可能在灵长类动物进化过程中对人脑大小的扩展起作用。我们还表明，小脑颗粒神经元表达了一组基因，这些基因也呈现出阳性选择的特征，这可能有助于人类精细运动技能和社会认知的出现。该资源可在线获得，并可用于估计作用于一组基因的进化限制，并探索它们对人类特征的相对贡献。