在具有高血缘关系的队列中进行人类淘汰和表型分析
Danish Saleheen1,2, Pradeep Natarajan3,4, Irina M Armean4,5
1Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Nature
|April 14, 2017
概括
研究人员在巴基斯坦发现了人类基因淘汰,通过表型分析揭示了特定的基因功能. 这项研究为人类淘汰项目提供了一个蓝图,
科学领域:
- 人类遗传学
- 基因组学
- 人类生理学
背景情况:
- 了解人类基因功能在生物医学中至关重要.
- 人类的功能丧失突变为基因功能提供了洞察力.
- 巴基斯坦高血缘关系增加了同卵性功能丧失突变的可能性.
研究的目的:
- 在南亚队列中识别具有同卵性预测功能丧失 (pLoF) 突变的个体.
- 对这些"人类淘汰"进行表型分析以了解基因功能.
- 建立一个全面的人类淘汰项目的路线图.
主要方法:
- 在巴基斯坦心肌梗塞风险研究 (PROMIS) 中,对10,503名成年参与者的蛋白质编码区域进行了测序.
- 识别罕见的 (小等位基因频率<1%) 同卵性pLoF突变.
- 在200个生物化学和疾病特征中对pLoF突变的个体进行表型分析.
- 招募和挑战具有口腔脂肪的同卵性APOC3淘汰载体.
主要成果:
- 鉴定出49138种罕见的pLoF突变, 估计至少在一个参与者中淘汰了1317个基因.
- 与酶活性 (PLA2G7),细胞因子度 (CYP2F1),脂蛋白水平 (TREH),胰岛素水平 (A3GALT2/NRG4) 和信号通路 (SLC9A3R1) 相关的特定pLoF突变.
- 与非携带者相比,同卵性APOC3淘汰显示出的食后甘油三反应.
结论:
- 特定基因的同卵性功能丧失突变具有明显的表型后果.
- 这项研究证明了研究人类淘汰的实用性,
- 为系统的人类淘汰项目提供框架,以将基因功能映射到表型.
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