Changes in gene regulatory elements play critical roles in human phenotypic divergence. However, identifying the base-pair changes responsible for the distinctive morphology of remains challenging. Here, we report a noncoding single-nucleotide polymorphism (SNP), rs41298798, as a potential causal variant contributing to the morphology of the skull base and vertebral structures found in . Screening for differentially regulated genes between and extinct relatives revealed 13 candidate genes associated with basicranial development, with , implicated in DiGeorge syndrome, playing a pivotal role. Epigenetic markers and analyses prioritized rs41298798 within a intron for functional validation. CRISPR editing revealed that the 41-base-pair region surrounding rs41298798 modulates gene expression at 22q11.21. The derived allele of rs41298798 acts as an allele-specific enhancer mediated by E2F1, resulting in increased expression levels compared to the ancestral allele. -knockout mice exhibited skull base and vertebral abnormalities similar to those seen in DiGeorge syndrome. Phenotypic differences associated with deficiency are observed between and Neanderthals (). In conclusion, the regulatory divergence of contributes to the formation of skull base and vertebral structures found in .

中文翻译：

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影响 TBX1 表达的调控变异有助于智人的基本颅骨形态


基因调控元件的变化在人类表型分化中发挥着关键作用。然而，识别导致独特形态的碱基对变化仍然具有挑战性。在这里，我们报告了一个非编码单核苷酸多态性（SNP），rs41298798，作为一种潜在的因果变异，有助于发现的颅底和椎骨结构的形态。对已灭绝亲属之间差异调节基因的筛选揭示了 13 个与基础颅骨发育相关的候选基因，其中 与 DiGeorge 综合征有关，发挥着关键作用。表观遗传标记和分析优先考虑内含子内的 rs41298798，以进行功能验证。 CRISPR 编辑显示 rs41298798 周围的 41 个碱基对区域调节 22q11.21 的基因表达。 rs41298798 的衍生等位基因充当 E2F1 介导的等位基因特异性增强子，导致与祖先等位基因相比表达水平增加。 -基因敲除小鼠表现出与迪乔治综合征相似的颅底和椎骨异常。在尼安德特人和尼安德特人之间观察到与缺乏相关的表型差异（）。总之，调节分歧有助于颅底和椎骨结构的形成。