Genetic predisposition to mosaic Y chromosome loss in blood
Genetic predisposition to mosaic Y chromosome loss in blood
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DOI：
10.1038/s41586-019-1765-3
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发表时间：
2019-11-28
期刊：
影响因子：
64.8
通讯作者：
Perry, John R. B.
中科院分区：
文献类型：
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作者：
Thompson, Deborah J.;Genovese, Giulio;Perry, John R. B.
循环白细胞中Y染色体的镶嵌缺失（LOY）是克隆镶嵌最常见的形式（1-5），但我们对其原因和后果的了解有限。在这里，使用计算方法，我们估计在英国生物银行研究中，20%的男性人口（n = 205,011）有可检测的LOY。我们确定了LOY的156个常染色体遗传决定因素，我们在757,114名欧洲和日本血统的男性中进行了复制。这些基因座突出了参与细胞周期调节和癌症易感性的基因，以及肿瘤生长的体细胞驱动因素和癌症治疗的靶标。我们证明，对LOY的遗传易感性与男性和女性对健康的非血液学影响有关，这支持了克隆造血是其他组织基因组不稳定性的生物标志物的假设。单细胞RNA测序鉴定了LOY白细胞中常染色体基因的表达失调，并提供了这些细胞克隆扩增可能发生的原因。总的来说，这些数据突出了研究克隆嵌合体的价值，揭示了癌症和其他衰老相关疾病的基本机制。
Mosaic loss of chromosome Y (LOY) in circulating white blood cells is the most common form of clonal mosaicism(1-5), 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.