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Nature DOI:10.1038/s41586-018-0321-x

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

Publication TypeJournal Article
Year of Publication2018
AuthorsLoh, P-R, Genovese, G, Handsaker, RE, Finucane, HK, Reshef, YA, Palamara, PFrancesco, Birmann, BM, Talkowski, ME, Bakhoum, SF, McCarroll, SA, Price, AL
Date Published2018 07
KeywordsAdult, Aged, Alleles, Biological Specimen Banks, Chromosome Aberrations, Chromosome Breakage, Chromosome Fragile Sites, Chromosomes, Human, Pair 10, Clone Cells, Female, Health, Hematologic Neoplasms, Hematopoiesis, Humans, Male, Middle Aged, Mosaicism, Penetrance, United Kingdom

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.


Alternate JournalNature
PubMed ID29995854
PubMed Central IDPMC6054542
Grant ListMC_QA137853 / MRC_ / Medical Research Council / United Kingdom
T32 GM007753 / GM / NIGMS NIH HHS / United States
R21 HG009513 / HG / NHGRI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
R01 HD081256 / HD / NICHD NIH HHS / United States
R01 HG006855 / HG / NHGRI NIH HHS / United States
R01 GM105857 / GM / NIGMS NIH HHS / United States
R01 HG006399 / HG / NHGRI NIH HHS / United States
DP5 OD026395 / OD / NIH HHS / United States
MC_PC_17228 / MRC_ / Medical Research Council / United Kingdom
R01 MH101244 / MH / NIMH NIH HHS / United States