Wright Daniel J, Day Felix R, Kerrison Nicola D, Zink Florian, Cardona Alexia, Sulem Patrick, Thompson Deborah J, Sigurjonsdottir Svanhvit, Gudbjartsson Daniel F, Helgason Agnar, Chapman J Ross, Jackson Steve P, Langenberg Claudia, Wareham Nicholas J, Scott Robert A, Thorsteindottir Unnur, Ong Ken K, Stefansson Kari, Perry John R B
MRC Epidemiology Unit, School of Clinical Medicine, University of Cambridge, Cambridge, UK.
deCODE Genetics-Amgen, Inc., Reykjavik, Iceland.
Nat Genet. 2017 May;49(5):674-679. doi: 10.1038/ng.3821. Epub 2017 Mar 27.
The Y chromosome is frequently lost in hematopoietic cells, which represents the most common somatic alteration in men. However, the mechanisms that regulate mosaic loss of chromosome Y (mLOY), and its clinical relevance, are unknown. We used genotype-array-intensity data and sequence reads from 85,542 men to identify 19 genomic regions (P < 5 × 10) that are associated with mLOY. Cumulatively, these loci also predicted X chromosome loss in women (n = 96,123; P = 4 × 10). Additional epigenome-wide methylation analyses using whole blood highlighted 36 differentially methylated sites associated with mLOY. The genes identified converge on aspects of cell proliferation and cell cycle regulation, including DNA synthesis (NPAT), DNA damage response (ATM), mitosis (PMF1, CENPN and MAD1L1) and apoptosis (TP53). We highlight the shared genetic architecture between mLOY and cancer susceptibility, in addition to inferring a causal effect of smoking on mLOY. Collectively, our results demonstrate that genotype-array-intensity data enables a measure of cell cycle efficiency at population scale and identifies genes implicated in aneuploidy, genome instability and cancer susceptibility.
Y染色体在造血细胞中经常丢失，这是男性中最常见的体细胞改变。然而，调节Y染色体镶嵌性丢失（mLOY）的机制及其临床相关性尚不清楚。我们使用来自85542名男性的基因型阵列强度数据和序列读数，确定了19个与mLOY相关的基因组区域（P < 5 × 10）。这些位点累积起来还预测了女性中的X染色体丢失（n = 96123；P = 4 × 10）。使用全血进行的全基因组甲基化分析突出了36个与mLOY相关的差异甲基化位点。鉴定出的基因集中在细胞增殖和细胞周期调控方面，包括DNA合成（NPAT）、DNA损伤反应（ATM）、有丝分裂（PMF1、CENPN和MAD1L1）和细胞凋亡（TP53）。除了推断吸烟对mLOY的因果效应外，我们还强调了mLOY与癌症易感性之间共享的遗传结构。总体而言，我们的结果表明，基因型阵列强度数据能够在群体规模上衡量细胞周期效率，并识别出与非整倍体、基因组不稳定和癌症易感性相关的基因。
