Format

Send to

Choose Destination
Nature. 2019 Nov;575(7784):652-657. doi: 10.1038/s41586-019-1765-3. Epub 2019 Nov 20.

Genetic predisposition to mosaic Y chromosome loss in blood.

Author information

1
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
2
Department of Genetics, Harvard Medical School, Boston, MA, USA.
3
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
4
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
5
Department of Immunology, Genetics and Pathology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
6
Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA, USA.
7
MRC Epidemiology Unit, School of Clinical Medicine, University of Cambridge, Cambridge, UK.
8
Open Targets Core Genetics, Wellcome Sanger Institute, Hinxton, UK.
9
Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.
10
Clinical Research Center, Shizuoka General Hospital, Shizuoka, Japan.
11
Department of Applied Genetics, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
12
Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.
13
deCODE Genetics, Amgen, Reykjavík, Iceland.
14
Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
15
23andMe, Mountain View, CA, USA.
16
Colon Cancer Genetics Group, Medical Research Council Human Genetics Unit and CRUK Cancer Research Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK.
17
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
18
Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
19
Geriatrics Research Group, Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden.
20
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
21
Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
22
Division of Molecular Pathology, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
23
Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK.
24
Faculty of Pharmacy, Medical University of Gdansk, Gdansk, Poland.
25
Faculty of Medicine, University of Iceland, Reykjavík, Iceland.
26
Cancer Genetics and Evolution Laboratory, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
27
William Harvey Research Institute, Queen Mary University, London, UK.
28
School of Engineering and Natural Sciences, University of Iceland, Reykjavík, Iceland.
29
Kyoto-McGill International Collaborative School in Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
30
DNRF Center for Chromosome Stability, Department of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
31
Department of Biochemistry, University of Cambridge, Cambridge, UK.
32
Wellcome Trust and Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, UK.
33
Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
34
Beijer Laboratory of Genome Research, Uppsala University, Uppsala, Sweden.
35
MRC Epidemiology Unit, School of Clinical Medicine, University of Cambridge, Cambridge, UK. john.perry@mrc-epid.cam.ac.uk.
36
Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. john.perry@mrc-epid.cam.ac.uk.

Abstract

Mosaic loss of chromosome Y (LOY) in circulating white blood cells is the most common form of clonal mosaicism1-5, 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.

PMID:
31748747
PMCID:
PMC6887549
[Available on 2020-05-20]
DOI:
10.1038/s41586-019-1765-3

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center