Evolution of Human Brain Size-Associated NOTCH2NL Genes Proceeds toward Reduced Protein Levels
Evolution of Human Brain Size-Associated NOTCH2NL Genes Proceeds toward Reduced Protein Levels
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DOI：
10.1093/molbev/msaa104
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发表时间：
2020-09-01
影响因子：
10.7
通讯作者：
Jacobs, Frank M. J.
中科院分区：
文献类型：
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作者：
Lodewijk, Gerrald A.;Fernandes, Diana P.;Jacobs, Frank M. J.
自从尼安德特人、丹尼索瓦人和古人类的基因组出现以来，进化基因组学领域一直在寻找蛋白质编码变体，这些变体可能包含我们人类在过去大约60万年里是如何进化的线索。在这项研究中，我们在人类特有的NOTCH2NL基因家族中发现了这些变体，最近被发现可能对人脑的进化扩张做出贡献。我们发现了在尼安德特人和丹尼索瓦人中存在独特的编码蛋白质的NOTCH2NL变体的证据，这可能会影响他们激活Notch信号的能力。此外，在尼安德特人和丹尼索瓦人的基因组中，我们发现了不寻常的NOTCH2NL配置，这在所分析的任何现代人类基因组中都没有发现。最后，对古代人和现代人的遗传分析揭示了现代人NOTCH2NL基因正在进行的适应性进化，确定了三种结构变体，它们起互补作用，驱动我们的基因组产生较低剂量的NOTCH2NL蛋白。由于包含NOTCH2NL基因的1q21.1基因座的拷贝数变异与严重的神经疾病有关，这种似乎相互矛盾的低水平NOTCH2NL蛋白驱动表明，NOTCH2NL的最佳剂量可能尚未在人类群体中得到解决。
Ever since the availability of genomes from Neanderthals, Denisovans, and ancient humans, the field of evolutionary genomics has been searching for protein-coding variants that may hold clues to how our species evolved over the last similar to 600,000 years. In this study, we identify such variants in the human-specific NOTCH2NL gene family, which were recently identified as possible contributors to the evolutionary expansion of the human brain. We find evidence for the existence of unique protein-coding NOTCH2NL variants in Neanderthals and Denisovans which could affect their ability to activate Notch signaling. Furthermore, in the Neanderthal and Denisovan genomes, we find unusual NOTCH2NL configurations, not found in any of the modern human genomes analyzed. Finally, genetic analysis of archaic and modern humans reveals ongoing adaptive evolution of modern human NOTCH2NL genes, identifying three structural variants acting complementary to drive our genome to produce a lower dosage of NOTCH2NL protein. Because copy-number variations of the 1q21.1 locus, encompassing NOTCH2NL genes, are associated with severe neurological disorders, this seemingly contradicting drive toward low levels of NOTCH2NL protein indicates that the optimal dosage of NOTCH2NL may have not yet been settled in the human population.