识别与 orofacial 裂相关的功能非编码变异
bioRxiv : the preprint server for biology
|March 3, 2025
概括
研究人员确定了与口腔面部裂 (OFC) 相关的特定遗传变异或单核酸多态 (SNP). 靠近IRF6基因的这些功能性SNP显著增加了带有或没有裂 palates (CL/P) 的裂唇的风险.
科学领域:
- 遗传学和基因组学 遗传学和基因组学
- 发展生物学 发展生物学
- 人类疾病的发病因子人类疾病的发病因子
背景情况:
- 口腔面孔裂 (OFC) 是一种常见的出生缺陷,具有复杂的遗传和环境原因.
- 全基因组关联研究 (GWAS) 已经确定了许多与OFC相关的遗传位置,但功能变异在很大程度上仍然未知.
- IRF6基因位点是一个关键区域,与OFC风险有关.
研究的目的:
- 确定与八个特定遗传位置的口腔面孔裂 (OFC) 风险相关的功能单核酸多态 (SNP).
- 研究这些功能性SNP在胚胎口腔表皮中影响基因表达的机制.
- 确定已识别的功能性SNP对带有或没有裂口口唇 (CL/P) 风险的贡献.
主要方法:
- 在口腔上皮细胞系中利用大规模并行记者测试 (MPRA) 来选影响增强剂活性的SNP.
- 综合色素标记数据以优先考虑相关细胞类型中的增强剂.
- 使用传统的记者测定和基因组工程在诱导多能干细胞 (iPSCs) 中对口腔表皮分化进行验证的候选功能性SNP.
主要成果:
- 在五个位置确定了六个候选功能性SNP:1q32/IRF6,3q28/TP63,6p24.3/TFAP2A,20q12/MAFB和9q22.33/FOXE1.1.
- 在口腔上皮质中对已识别的SNP表现出基因特异性增强剂活性.
- 基因工程实验证实了两个SNP在IRF6附近和一个在FOXE1.1附近的监管作用.
- 对GWAS元分析的有条件分析表明,在IRF6附近的两个功能性SNP解释了与此位点相关的CL/P风险的大部分.
结论:
- 这项研究成功地确定了有助于口腔面部裂病变的功能遗传变异.
- 这些发现突显了IRF6位点和特定SNP在调节口腔发育关键基因表达方面的重要性.
- 将OFC中的遗传变异与潜在的分子机制联系起来,为未来的研究和潜在的治疗策略铺平了道路.
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