Joshy Dennis, Santpere Gabriel, Yi Soojin V
Department of Mechanical Engineering, University of California, Santa Barbara, CA 93106.
Neuroscience Research Institute, University of California, Santa Barbara, CA 93106.
Proc Natl Acad Sci U S A. 2024 Dec 24;121(52):e2411918121. doi: 10.1073/pnas.2411918121. Epub 2024 Dec 16.
The molecular basis of human brain evolution is a key piece in understanding the evolution of human-specific cognitive and behavioral traits. Comparative studies have suggested that human brain evolution was accompanied by accelerated changes of gene expression (referred to as "regulatory evolution"), especially those leading to an increase of gene products involved in energy production and metabolism. However, the signals of accelerated regulatory evolution were not always consistent across studies. One confounding factor is the diversity of distinctive cell types in the human brain. Here, we leveraged single-cell human and nonhuman primate transcriptomic data to investigate regulatory evolution at cell-type resolution. We relied on six well-established major cell types: excitatory and inhibitory neurons, astrocytes, microglia, oligodendrocytes, and oligodendrocyte precursor cells. We found pervasive signatures of accelerated regulatory evolution in the human brains compared to the chimpanzee brains in the major six cell types, as well as across multiple neuronal subtypes. Moreover, regulatory evolution is highly cell type specific rather than shared between cell types and strongly associated with cellular-level epigenomic features. Evolutionarily differentially expressed genes (DEGs) exhibit greater cell-type specificity than other genes, suggesting their role in the functional specialization of individual cell types in the human brain. As we continue to unfold the cellular complexity of the brain, the actual scope of DEGs in the human brain appears to be much broader than previously estimated. Our study supports the acceleration of cell-type-specific functional programs as an important feature of human brain evolution.
人类大脑进化的分子基础是理解人类特有的认知和行为特征进化的关键环节。比较研究表明，人类大脑进化伴随着基因表达的加速变化（称为“调控进化”），尤其是那些导致参与能量产生和代谢的基因产物增加的变化。然而，不同研究中加速调控进化的信号并不总是一致的。一个混杂因素是人类大脑中独特细胞类型的多样性。在此，我们利用单细胞人类和非人类灵长类动物的转录组数据，以细胞类型分辨率研究调控进化。我们依据六种成熟的主要细胞类型：兴奋性和抑制性神经元、星形胶质细胞、小胶质细胞、少突胶质细胞和少突胶质细胞前体细胞。我们发现，与黑猩猩大脑相比，人类大脑在这六种主要细胞类型以及多种神经元亚型中存在广泛的加速调控进化特征。此外，调控进化具有高度的细胞类型特异性，而非细胞类型之间共享，并且与细胞水平的表观基因组特征密切相关。进化上差异表达的基因（DEGs）比其他基因表现出更大的细胞类型特异性，这表明它们在人类大脑中单个细胞类型的功能特化中发挥作用。随着我们不断揭示大脑的细胞复杂性，人类大脑中DEGs的实际范围似乎比先前估计的要广泛得多。我们的研究支持细胞类型特异性功能程序的加速是人类大脑进化的一个重要特征。
