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研究揭示大规模全基因组中克隆造血的遗传原因
2020-10-16 15:26

近日,美国哈佛医学院Pradeep Natarajan、Sekar Kathiresan等研究人员合作揭示97,691个全基因组中克隆性造血的遗传原因。这一研究成果于2020年10月14日在线发表在《自然》上。

研究人员分析了来自美国国家心脏、肺和血液研究所精密医学转基因组学(TOPMed)计划的97691名参与者(来自不同祖先)的高覆盖全基因组序列,并确定了4229名克隆潜能不确定性(CHIP)患者。研究人员确定了与特定CHIP驱动程序基因的血细胞、脂质和炎症性状的关联。全基因组生殖系遗传变异集的关联使得能够鉴定与CHIP状况相关的三个遗传基因座,包括在TET2上一个特定于非洲血统个体的基因座。对TET2种系基因座进行计算机信息提供的体外评估,能够鉴定破坏TET2远端增强子的致病变异,从而导致造血干细胞的自我更新增加。
 
总的来说,研究人员观察到生殖系遗传变异会改变造血干细胞的功能,从而通过克隆造血的特异机制以及导致组织间体细胞突变的共有机制产生CHIP。
 
据介绍,年龄是大多数慢性人类疾病的主要风险因素,但衰老赋予这种风险的机制在很大程度上尚不清楚。与年龄相关的体细胞突变导致再生造血干细胞群体中的克隆扩增,最近与血液癌症和冠心病都相关。这种现象被称为CHIP。对种系和体细胞全基因组序列的同时分析提供了识别CHIP根本原因的机会。
 
附:英文原文

Title: Inherited causes of clonal haematopoiesis in 97,691 whole genomes

Author: Alexander G. Bick, Joshua S. Weinstock, Satish K. Nandakumar, Charles P. Fulco, Erik L. Bao, Seyedeh M. Zekavat, Mindy D. Szeto, Xiaotian Liao, Matthew J. Leventhal, Joseph Nasser, Kyle Chang, Cecelia Laurie, Bala Bharathi Burugula, Christopher J. Gibson, Amy E. Lin, Margaret A. Taub, Francois Aguet, Kristin Ardlie, Braxton D. Mitchell, Kathleen C. Barnes, Arden Moscati, Myriam Fornage, Susan Redline, Bruce M. Psaty, Edwin K. Silverman, Scott T. Weiss, Nicholette D. Palmer, Ramachandran S. Vasan, Esteban G. Burchard, Sharon L. R. Kardia, Jiang He, Robert C. Kaplan, Nicholas L. Smith, Donna K. Arnett, David A. Schwartz, Adolfo Correa, Mariza de Andrade, Xiuqing Guo, Barbara A. Konkle, Brian Custer, Juan M. Peralta, Hongsheng Gui, Deborah A. Meyers, Stephen T. McGarvey, Ida Yii-Der Chen, M. Benjamin Shoemaker, Patricia A. Peyser, Jai G. Broome, Stephanie M. Gogarten, Fei Fei Wang, Quenna Wong, May E. Montasser, Michelle Daya, Eimear E. Kenny, Kari E. North, Lenore J. Launer, Brian E. Cade, Joshua C. Bis, Michael H. Cho, Jessica Lasky-Su

Issue&Volume: 2020-10-14

Abstract: Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown1. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer2,3,4 and coronary heart disease5—this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP)6. Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.

DOI: 10.1038/s41586-020-2819-2

Source: https://www.nature.com/articles/s41586-020-2819-2

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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