Genomics, variation, and evolution of cerebellar circuits linked to higher cognitive functions in humans

摘要 人类进化过程中不断增长的认知需求塑造了人脑的适应 对于日益复杂的高级认知功能，如执行控制、社会认知、注意力和 语言。对这些高级认知功能的研究主要集中在新皮质的部分区域。 以及相关的皮质下区域，这些区域组成了与特定认知功能相关的前脑网络。近期 然而，研究表明，这些前脑网络中的每一个在功能上都与不同的 小脑的区域。令人惊讶的是，进化论研究进一步表明，正是小脑的这些部分 与非人类灵长类动物相比，这显示出人类最戏剧性的扩张，甚至在现代 把人类比作尼安德特人。在今天生活的人类中，个体在大小或功能上的差异 这些小脑区域的连接与影响高级认知功能的障碍有关，如 如自闭症谱系障碍(ASD)、注意力缺陷/多动障碍(ADHD)和精神分裂症。这些 聚合结果有力地表明，控制发育和发育的分子和细胞机制 人类小脑的功能组织经历了系统性的变化，这已经证明 在现代人类中具有重要的功能。拟议的研究开始绘制出这些变化的地图，从 一项全基因组相关性研究(GWAS)，使用现有的来自中国的小脑结构MRI图像数据集 30,000名人类参与者进行基因分型，以确定与整个小脑相关的基因和基因组变异 不同区域的体积和个体的相对大小和灰质厚度的差异 小脑皮质(目标1)。一项平行研究(AIM 2)将使用人类、猕猴和 小鼠小脑FKURPDWLQ DFFHVVLELOLW基因表达的可能差异 人类和其他动物之间小脑固有回路的细胞类型组成(目标2)。一起， 这些研究解决了一个基本但尚未解决的问题，即人类小脑的扩张 表示基本小脑电路模块容量的简单增加，否则该模块在 人类，或者小脑扩大区域的局部回路是否在功能上经历了 重大修改。在这项研究的最后部分(目标3)，进化分析将确定具体的 在前两个目的中确定的基因中的调控元件显示了加速的替代速度 或在人类进化过程中积极、净化或平衡选择的证据，以及 进化选择是否倾向于增加或减少这些地点的多样性 现代人与其他灵长类动物的分化。这些研究将使我们能够确定具体的监管 在与小脑相关的基因中作为自然选择目标的元素或其他变体 或成人小脑功能的发育，并将这些进化选择的目标与特定的 现代人中与个体变异或重大精神疾病风险增加相关的变异 人口。

ABSTRACT Growing cognitive demands over the course of human evolution have shaped the adaptation of human brains for increasingly complex higher cognitive functions, like executive control, social cognition, attention, and language. Research on those higher cognitive functions has focused predominantly on parts of the neocortex and related subcortical areas that comprise forebrain networks linked to specific cognitive functions. Recent research makes it clear, however, that each of those forebrain networks is functionally connected to distinct regions of the cerebellum. Surprisingly, evolutionary studies show further that it is those parts of the cerebellum that show the most dramatic expansion in humans compared to non-human primates, and even in modern humans compared to Neanderthals. In humans living today, individual variation in the size or functional connectivity of those cerebellar regions has been linked to disorders affecting higher cognitive functions, such as autism spectrum disorder (ASD), attention-deficit/hyperactive disorder (ADHD), and schizophrenia. These converging results suggest strongly that molecular and cellular mechanisms controlling the development and functional organization of the human cerebellum have undergone systematic changes that have proven functionally important in modern humans. The proposed studies begin to map out those changes, beginning with a genome-wide association study (GWAS) using an existing dataset of structural MRI images of cerebellum from 30,000 genotyped human participants to identify genes and genomic variants associated with overall cerebellar volume and individual differences in relative size and gray matter thickness across different regions of the cerebellar cortex (Aim 1). A parallel study (Aim 2) will use single-cell genomics of human, macaque, and mouse cerebellum to investigate possible differences in gene expression FKURPDWLQ DFFHVVLELOLW\ and the cell type composition of intrinsic cerebellar circuits between humans and other animals (Aim 2). Together, those studies address an essential but unresolved issue, whether expansion of the cerebellum in humans represents a simple increase in capacity of a basic cerebellar circuit module that is otherwise unchanged in humans, or whether the local circuitry in expanded regions of the cerebellum has undergone functionally significant modifications. In the final part of this research (Aim 3), evolutionary analysis will identify specific regulatory elements within the genes identified in the first two aims that show accelerated rates of substitution in humans or evidence of positive, purifying, or balancing selection over the course of human evolution, and whether evolutionary selection has tended to increase or decrease diversity at these sites in since the divergence of modern humans from other primates. These studies will allow us to identify specific regulatory elements or other variants that have been targets of natural selection within the genes involved in cerebellar development or adult cerebellar functions, and to compare those targets of evolutionary selection to specific variants associated with individual variation or increased risk for major psychiatric disorders in modern human populations.