Evolutionary conservation and divergence of the human brain transcriptome.
Evolutionary conservation and divergence of the human brain transcriptome.
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DOI：
10.1186/s13059-020-02257-z
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发表时间：
2021-01-29
期刊：
影响因子：
12.3
通讯作者：
Geschwind DH
中科院分区：
文献类型：
--
作者：
Pembroke WG;Hartl CL;Geschwind DH
小鼠模型已经允许直接询问遗传对分子、生理和行为脑表型的影响。然而，目前尚不清楚神经学或精神病学特征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概括出来。我们比较了116个独立的数据集中共表达的保守性，这些数据集来自人类、小鼠和非人类灵长类动物，代表了超过15,000个样本。我们观察到人类的血统发生了比老鼠更大的变化，并且大量的区域差异突出了大脑皮层作为最大的分歧区域。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，平均比神经元多三倍。我们发现，顺式调控序列的差异可以解释很大一部分共表达差异。此外，蛋白质编码序列限制平行于共表达保守，这样功能不耐受丧失的基因在神经元中丰富，而不是在神经胶质模块中。我们鉴定了数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存在高度差异的共表达，并表明3D人脑器官概括了代表几种人类细胞类型的活体共表达模块。我们确定了反映全脑和基因表达的区域模式的健壮的共表达模块。与那些代表基本代谢过程的模块相比，特定细胞类型的模块，最突出的是神经胶质模块，是物种之间差异最大的。这些数据和分析是指导人类疾病建模及其解释的基础资源。网上版载有补充材料，可在10.1186/s13059-020-02257-z查阅。
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. The online version contains supplementary material available at 10.1186/s13059-020-02257-z.
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影响因子：
25
作者：
Galatro, Thais F.;Holtman, Inge R.;Eggen, Bart J. L.
通讯作者：
Eggen, Bart J. L.
遗传对人体组织基因表达的影响。
影响因子：
64.8
作者：
GTEx Consortium;Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group;Statistical Methods groups—Analysis Working Group;Enhancing GTEx (eGTEx) groups;NIH Common Fund;NIH/NCI;NIH/NHGRI;NIH/NIMH;NIH/NIDA;Biospecimen Collection Source Site—NDRI;Biospecimen Collection Source Site—RPCI;Biospecimen Core Resource—VARI;Brain Bank Repository—University of Miami Brain Endowment Bank;Leidos Biomedical—Project Management;ELSI Study;Genome Browser Data Integration &Visualization—EBI;Genome Browser Data Integration &Visualization—UCSC Genomics Institute, University of California Santa Cruz;Lead analysts:;Laboratory, Data Analysis &Coordinating Center (LDACC):;NIH program management:;Biospecimen collection:;Pathology:;eQTL manuscript working group:;Battle A;Brown CD;Engelhardt BE;Montgomery SB
通讯作者：
Montgomery SB
影响因子：
9.8
作者：
Allen, Mariet;Carrasquillo, Minerva M.;Funk, Cory;Heavner, Benjamin D.;Zou, Fanggeng;Younkin, Curtis S.;Burgess, Jeremy D.;Chai, High-Seng;Crook, Julia;Eddy, James A.;Li, Hongdong;Logsdon, Ben;Peters, Mette A.;Dang, Kristen K.;Wang, Xue;Serie, Daniel;Wang, Chen;Thuy Nguyen;Lincoln, Sarah;Malphrus, Kimberly;Bisceglio, Gina;Li, Ma;Golde, Todd E.;Mangravite, Lara M.;Asmann, Yan;Price, Nathan D.;Petersen, Ronald C.;Graff-Radford, Neill R.;Dickson, Dennis W.;Younkin, Steven G.;Ertekin-Taner, Nilufer
通讯作者：
Ertekin-Taner, Nilufer
影响因子：
25
作者：
Fu H;Hardy J;Duff KE
通讯作者：
Duff KE
影响因子：
23.9
作者：
Han, Xiaoning;Chen, Michael;Wang, Fushun;Windrem, Martha;Wang, Su;Shanz, Steven;Xu, Qiwu;Oberheim, Nancy Ann;Bekar, Lane;Betstadt, Sarah;Silva, Alcino J.;Takano, Takahiro;Goldman, Steven A.;Nedergaard, Maiken
通讯作者：
Nedergaard, Maiken