Zemke Nathan R, Armand Ethan J, Wang Wenliang, Lee Seoyeon, Zhou Jingtian, Li Yang Eric, Liu Hanqing, Tian Wei, Nery Joseph R, Castanon Rosa G, Bartlett Anna, Osteen Julia K, Li Daofeng, Zhuo Xiaoyu, Xu Vincent, Miller Michael, Krienen Fenna M, Zhang Qiangge, Taskin Naz, Ting Jonathan, Feng Guoping, McCarroll Steven A, Callaway Edward M, Wang Ting, Behrens M Margarita, Lein Ed S, Ecker Joseph R, Ren Bing
bioRxiv. 2023 Apr 8:2023.04.08.536119. doi: 10.1101/2023.04.08.536119.
Sequence divergence of regulatory elements drives species-specific traits, but how this manifests in the evolution of the neocortex at the molecular and cellular level remains to be elucidated. We investigated the gene regulatory programs in the primary motor cortex of human, macaque, marmoset, and mouse with single-cell multiomics assays, generating gene expression, chromatin accessibility, DNA methylome, and chromosomal conformation profiles from a total of over 180,000 cells. For each modality, we determined species-specific, divergent, and conserved gene expression and epigenetic features at multiple levels. We find that cell type-specific gene expression evolves more rapidly than broadly expressed genes and that epigenetic status at distal candidate -regulatory elements (cCREs) evolves faster than promoters. Strikingly, transposable elements (TEs) contribute to nearly 80% of the human-specific cCREs in cortical cells. Through machine learning, we develop sequence-based predictors of cCREs in different species and demonstrate that the genomic regulatory syntax is highly preserved from rodents to primates. Lastly, we show that epigenetic conservation combined with sequence similarity helps uncover functional -regulatory elements and enhances our ability to interpret genetic variants contributing to neurological disease and traits.
调控元件的序列差异驱动物种特异性性状，但这在新皮层进化中如何在分子和细胞水平上表现仍有待阐明。我们通过单细胞多组学分析研究了人类、猕猴、狨猴和小鼠初级运动皮层中的基因调控程序，从总共超过180,000个细胞中生成了基因表达、染色质可及性、DNA甲基化组和染色体构象图谱。对于每种模式，我们在多个水平上确定了物种特异性、差异和保守的基因表达及表观遗传特征。我们发现细胞类型特异性基因表达的进化比广泛表达的基因更快，并且远端候选调控元件（cCREs）处的表观遗传状态比启动子进化得更快。引人注目的是，转座元件（TEs）在皮质细胞中占人类特异性cCREs的近80%。通过机器学习，我们开发了不同物种中基于序列的cCREs预测器，并证明从啮齿动物到灵长类动物，基因组调控语法高度保守。最后，我们表明表观遗传保守性与序列相似性相结合有助于发现功能性调控元件，并增强我们解释导致神经疾病和性状的遗传变异的能力。
