School of Medicine, Universidad San Francisco de Quito, Quito, Ecuador.
BMC Genomics. 2022 Dec 22;23(1):849. doi: 10.1186/s12864-022-09071-w.
Modern human brains and skull shapes differ from other hominids. Brain growth disorders as micro- (ASPM, MCPH1) and macrocephaly (NFIX, GLI3) have been highlighted as relevant for the evolution in humans due to the impact in early brain development. Genes associated with macrocephaly have been reported to cause this change, for example NSD1 which causes Sotos syndrome.
In this study we performed a systematic literature review, located the reported variants associated to Sotos syndrome along the gene domains, compared the sequences with close primates, calculated their similarity, Ka/Ks ratios, nucleotide diversity and selection, and analyzed the sequence and structural conservation with distant primates. We aimed to understand if NSD1 in humans differs from other primates since the evolution of NSD1 has not been analyzed in primates, nor if the localization of the mutations is limited to humans. Our study found that most variations causing Sotos syndrome are in exon 19, 22 and 10. In the primate comparison we did not detect Ka/Ks ratios > 1, but a high nucleotide diversity with non-synonymous variations in exons 10, 5, 9, 11 and 23, and sites under episodic selection in exon 5 and 23, and human, macaque/colobus/tarsier/galago and tarsier/lemur/colobus. Most of the domains are conserved in distant primates with a particular progressive development from a simple PWWP1 in O. garnetti to a complex structure in Human.
NSD1 is a chromatin modifier that suggests that the selection could influence brain development during modern human evolution and is not present in other primates; however, nowadays the nucleotide diversity is associated with Sotos syndrome.
现代人类的大脑和颅骨形状与其他原始人类不同。由于对早期大脑发育的影响，脑生长障碍（如微小头畸形（ASPM，MCPH1）和大头畸形（NFIX，GLI3））已被认为与人类进化有关。与大头畸形相关的基因已被报道会导致这种变化，例如 NSD1 会引起 Sotos 综合征。
在这项研究中，我们进行了系统的文献回顾，在基因区域中找到了与 Sotos 综合征相关的报告变体，比较了与近亲灵长类动物的序列，计算了它们的相似性、Ka/Ks 比值、核苷酸多样性和选择，并分析了与远亲灵长类动物的序列和结构保守性。我们旨在了解人类的 NSD1 是否与其他灵长类动物不同，因为 NSD1 的进化在灵长类动物中尚未得到分析，也不知道突变的定位是否仅限于人类。我们的研究发现，导致 Sotos 综合征的大多数变异都在外显子 19、22 和 10 中。在灵长类动物比较中，我们没有检测到 Ka/Ks 比值>1，但在外显子 10、5、9、11 和 23 中存在高度的核苷酸多样性和非同义变异，以及在外显子 5 和 23 中存在阶段性选择的位点，以及在人类、猕猴/疣猴/原猴/夜猴和原猴/狐猴/猕猴/疣猴中存在。大多数结构域在远亲灵长类动物中是保守的，从 O. garnetti 中的简单 PWWP1 到人类中的复杂结构，呈现出一种渐进的发展。
NSD1 是一种染色质修饰因子，这表明选择可能会影响现代人类进化过程中的大脑发育，并且在其他灵长类动物中不存在；然而，如今核苷酸多样性与 Sotos 综合征有关。
