找私服-Y染色体镶嵌丢失的遗传易感性

时间:2019-11-21 17:36 来源: www.seosem.ws

本期文章:《自然》:Online/在线发表

英国剑桥大学John R. B. Perry等研究人员合作揭示血液中Y染色体镶嵌丢失(LOY)的遗传易感性。 2019年11月20日,《自然》在线发表了这项成果。

研究人员使用一种计算方法,估计了英国生物银行研究中代表的男性人口中有20%(n = 205011)检测到LOY。研究人员确定了LOY的156个常染色体遗传决定因素,并在757114名欧洲和日本血统的男人中进行了重复验证。这些基因座突出了参与细胞周期调控和癌症易感性的基因,以及肿瘤生长的体细胞驱动力和癌症治疗的靶标。研究人员证明对LOY的遗传易感性与对男性和女性健康的非血液学影响有关,这支持了克隆性造血是其他组织基因组不稳定性的生物标记的假设。单细胞RNA测序可通过LOY识别白细胞中常染色体基因的表达失调,并提供了为何可能发生这些细胞克隆扩增的新见解。总体而言,这些数据凸显了研究克隆镶嵌的价值,从而得以揭示癌症和其他与衰老相关的疾病的基本机制。

据了解,循环白细胞中Y染色体的镶嵌丢失是克隆镶嵌的最常见形式,但是我们对此的成因和后果的认知有限。

附:英文原文

Title: Genetic predisposition to mosaic Y chromosome loss in blood

Author: Deborah J. Thompson, Giulio Genovese, Jonatan Halvardson, Jacob C. Ulirsch, Daniel J. Wright, Chikashi Terao, Olafur B. Davidsson, Felix R. Day, Patrick Sulem, Yunxuan Jiang, Marcus Danielsson, Hanna Davies, Joe Dennis, Malcolm G. Dunlop, Douglas F. Easton, Victoria A. Fisher, Florian Zink, Richard S. Houlston, Martin Ingelsson, Siddhartha Kar, Nicola D. Kerrison, Ben Kinnersley, Ragnar P. Kristjansson, Philip J. Law, Rong Li, Chey Loveday, Jonas Mattisson, Steven A. McCarroll, Yoshinori Murakami, Anna Murray, Pawel Olszewski, Edyta Rychlicka-Buniowska, Robert A. Scott, Unnur Thorsteinsdottir, Ian Tomlinson, Behrooz Torabi Moghadam, Clare Turnbull, Nicholas J. Wareham, Daniel F. Gudbjartsson, Yoichiro Kamatani, Eva R. Hoffmann, Steve P. Jackson, Kari Stefansson, Adam Auton, Ken K. Ong, Mitchell J. Machiela, Po-Ru Loh, Jan P. Dumanski, Stephen J. Chanock, Lars A. Forsberg, John R. B. Perry

Issue&Volume: 2019-11-20

Abstract: Mosaic loss of chromosome Y (LOY) in circulating white blood cells is the most common form of clonal mosaicism1,2,3,4,5, yet our knowledge of the causes and consequences of this is limited. Here, using a computational approach, we estimate that 20% of the male population represented in the UK Biobank study (n = 205,011) has detectable LOY. We identify 156 autosomal genetic determinants of LOY, which we replicate in 757,114 men of European and Japanese ancestry. These loci highlight genes that are involved in cell-cycle regulation and cancer susceptibility, as well as somatic drivers of tumour growth and targets of cancer therapy. We demonstrate that genetic susceptibility to LOY is associated with non-haematological effects on health in both men and women, which supports the hypothesis that clonal haematopoiesis is a biomarker of genomic instability in other tissues. Single-cell RNA sequencing identifies dysregulated expression of autosomal genes in leukocytes with LOY and provides insights into why clonal expansion of these cells may occur. Collectively, these data highlight the value of studying clonal mosaicism to uncover fundamental mechanisms that underlie cancer and other ageing-related diseases.

DOI: 10.1038/s41586-019-1765-3

Source: https://www.nature.com/articles/s41586-019-1765-3

期刊信息

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:
投稿链接: