Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.
Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.
Genome Biol. 2021 Jan 29;22(1):52. doi: 10.1186/s13059-020-02257-z.
Mouse models have allowed for the direct interrogation of genetic effects on molecular, physiological, and behavioral brain phenotypes. However, it is unknown to what extent neurological or psychiatric traits may be human- or primate-specific and therefore which components can be faithfully recapitulated in mouse models.
We compare conservation of co-expression in 116 independent data sets derived from human, mouse, and non-human primate representing more than 15,000 total samples. We observe greater changes occurring on the human lineage than mouse, and substantial regional variation that highlights cerebral cortex as the most diverged region. Glia, notably microglia, astrocytes, and oligodendrocytes are the most divergent cell type, three times more on average than neurons. We show that cis-regulatory sequence divergence explains a significant fraction of co-expression divergence. Moreover, protein coding sequence constraint parallels co-expression conservation, such that genes with loss of function intolerance are enriched in neuronal, rather than glial modules. We identify dozens of human neuropsychiatric and neurodegenerative disease risk genes, such as COMT, PSEN-1, LRRK2, SHANK3, and SNCA, with highly divergent co-expression between mouse and human and show that 3D human brain organoids recapitulate in vivo co-expression modules representing several human cell types.
We identify robust co-expression modules reflecting whole-brain and regional patterns of gene expression. Compared with those that represent basic metabolic processes, cell-type-specific modules, most prominently glial modules, are the most divergent between species. These data and analyses serve as a foundational resource to guide human disease modeling and its interpretation.
小鼠模型允许直接研究遗传对分子、生理和行为脑表型的影响。然而，尚不清楚神经或精神特质在多大程度上是人类或灵长类动物特有的，因此哪些成分可以在小鼠模型中忠实地再现。
我们比较了来自人类、小鼠和非人类灵长类动物的 116 个独立数据集的共表达保守性，这些数据集代表了超过 15000 个总样本。我们观察到人类谱系比小鼠发生了更大的变化，并且存在大量的区域变异，突出了大脑皮层是最分化的区域。胶质细胞，特别是小胶质细胞、星形胶质细胞和少突胶质细胞，是最分化的细胞类型，平均是神经元的三倍。我们表明，顺式调控序列的差异解释了共表达差异的很大一部分。此外，蛋白质编码序列约束与共表达的保守性平行，因此功能丧失不耐受的基因在神经元模块中富集，而不是在神经胶质模块中富集。我们确定了几十个人类神经精神和神经退行性疾病风险基因，如 COMT、PSEN-1、LRRK2、SHANK3 和 SNCA，它们在小鼠和人类之间的共表达存在高度差异，并表明 3D 人类大脑类器官再现了代表几种人类细胞类型的体内共表达模块。
我们确定了反映全脑和区域基因表达模式的稳健共表达模块。与代表基本代谢过程的模块相比，细胞类型特异性模块，特别是神经胶质模块，在物种间的差异最大。这些数据和分析为人类疾病建模及其解释提供了基础资源。
