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Nature. 2018 Jul;559(7714):350-355. doi: 10.1038/s41586-018-0321-x. Epub 2018 Jul 11.

Insights into clonal haematopoiesis from 8,342 mosaic chromosomal alterations.

Author information

1
Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. poruloh@broadinstitute.org.
2
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. poruloh@broadinstitute.org.
3
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. giulio.genovese@gmail.com.
4
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. giulio.genovese@gmail.com.
5
Department of Genetics, Harvard Medical School, Boston, MA, USA. giulio.genovese@gmail.com.
6
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
7
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
8
Department of Genetics, Harvard Medical School, Boston, MA, USA.
9
Schmidt Fellows Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
10
Department of Computer Science, Harvard University, Cambridge, MA, USA.
11
Department of Statistics, University of Oxford, Oxford, UK.
12
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
13
Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
14
Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
15
Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
16
Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
17
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. mccarroll@genetics.med.harvard.edu.
18
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. mccarroll@genetics.med.harvard.edu.
19
Department of Genetics, Harvard Medical School, Boston, MA, USA. mccarroll@genetics.med.harvard.edu.
20
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. aprice@hsph.harvard.edu.
21
Departments of Epidemiology and Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA. aprice@hsph.harvard.edu.

Abstract

The selective pressures that shape clonal evolution in healthy individuals are largely unknown. Here we investigate 8,342 mosaic chromosomal alterations, from 50 kb to 249 Mb long, that we uncovered in blood-derived DNA from 151,202 UK Biobank participants using phase-based computational techniques (estimated false discovery rate, 6-9%). We found six loci at which inherited variants associated strongly with the acquisition of deletions or loss of heterozygosity in cis. At three such loci (MPL, TM2D3-TARSL2, and FRA10B), we identified a likely causal variant that acted with high penetrance (5-50%). Inherited alleles at one locus appeared to affect the probability of somatic mutation, and at three other loci to be objects of positive or negative clonal selection. Several specific mosaic chromosomal alterations were strongly associated with future haematological malignancies. Our results reveal a multitude of paths towards clonal expansions with a wide range of effects on human health.

PMID:
29995854
PMCID:
PMC6054542
[Available on 2019-01-11]
DOI:
10.1038/s41586-018-0321-x

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