Department of Evolutionary Anthropology, Duke University, Durham, North Carolina, United States of America.
Department of Anthropology and Center for the Advanced Study of Human Paleobiology, The George Washington University, Washington, District of Columbia, United States of America.
PLoS Genet. 2021 May 6;17(5):e1009506. doi: 10.1371/journal.pgen.1009506. eCollection 2021 May.
Identifying the molecular underpinnings of the neural specializations that underlie human cognitive and behavioral traits has long been of considerable interest. Much research on human-specific changes in gene expression and epigenetic marks has focused on the prefrontal cortex, a brain structure distinguished by its role in executive functions. The cerebellum shows expansion in great apes and is gaining increasing attention for its role in motor skills and cognitive processing, including language. However, relatively few molecular studies of the cerebellum in a comparative evolutionary context have been conducted. Here, we identify human-specific methylation in the lateral cerebellum relative to the dorsolateral prefrontal cortex, in a comparative study with chimpanzees (Pan troglodytes) and rhesus macaques (Macaca mulatta). Specifically, we profiled genome-wide methylation levels in the three species for each of the two brain structures and identified human-specific differentially methylated genomic regions unique to each structure. We further identified which differentially methylated regions (DMRs) overlap likely regulatory elements and determined whether associated genes show corresponding species differences in gene expression. We found greater human-specific methylation in the cerebellum than the dorsolateral prefrontal cortex, with differentially methylated regions overlapping genes involved in several conditions or processes relevant to human neurobiology, including synaptic plasticity, lipid metabolism, neuroinflammation and neurodegeneration, and neurodevelopment, including developmental disorders. Moreover, our results show some overlap with those of previous studies focused on the neocortex, indicating that such results may be common to multiple brain structures. These findings further our understanding of the cerebellum in human brain evolution.
长期以来，确定导致人类认知和行为特征的神经特化的分子基础一直是人们非常感兴趣的话题。许多关于基因表达和表观遗传标记的人类特异性变化的研究都集中在前额叶皮层上，该大脑结构因其在执行功能中的作用而与众不同。小脑在大型猿类中出现扩张，并且由于其在运动技能和认知处理（包括语言）中的作用而受到越来越多的关注。但是，在比较进化背景下对小脑进行的分子研究相对较少。在这里，我们在与黑猩猩（Pan troglodytes）和恒河猴（Macaca mulatta）的比较研究中，确定了相对于背外侧前额叶皮层，人类外侧小脑中特异性的甲基化。具体来说，我们针对两种大脑结构中的每一种，对三种物种的全基因组甲基化水平进行了分析，并鉴定了每个结构中独特的人类特异性差异甲基化基因组区域。我们进一步确定了哪些差异甲基化区域（DMR）与可能的调节元件重叠，并确定相关基因在基因表达方面是否存在相应的物种差异。我们发现小脑的人类特异性甲基化程度高于背外侧前额叶皮层，差异甲基化区域重叠涉及几个与人类神经生物学相关的条件或过程的基因，包括突触可塑性，脂质代谢，神经炎症和神经退行性变以及神经发育，包括发育障碍。此外，我们的结果与先前专注于新皮层的研究结果有些重叠，表明这些结果可能与多个大脑结构都相关。这些发现进一步加深了我们对人类大脑进化中小脑的理解。
