A regulatory variant impacting TBX1 expression contributes to basicranial morphology in Homo sapiens

Area of Science:

• Evolutionary biology
• Human genetics
• Developmental biology

Background:

• Gene regulatory element changes drive human phenotypic divergence.
• Identifying specific genetic variants impacting human morphology is challenging.

Purpose of the Study:

• To identify causal genetic variants contributing to Homo sapiens skull base and vertebral morphology.
• To investigate the role of a specific single-nucleotide polymorphism (SNP), rs41298798, in human evolution.

Main Methods:

• Screening for differentially regulated genes between Homo sapiens and extinct hominins.
• Prioritizing candidate SNPs using epigenetic markers and in silico analysis.
• Functional validation using CRISPR editing and gene expression analysis in mice.

Main Results:

• rs41298798 was identified as a potential causal variant within a TBX1 intron.
• CRISPR editing confirmed rs41298798 modulates gene expression at 22q11.21.
• The derived allele of rs41298798 acts as an enhancer, increasing TBX1 expression via E2F1.

Conclusions:

• Regulatory divergence of TBX1 contributes to the distinct skull base and vertebral structures of Homo sapiens.
• TBX1 plays a pivotal role in basicranial development, with deficiency causing abnormalities similar to DiGeorge syndrome.