Clonal haematopoiesis harbouring AML-associated mutations is ubiquitous in healthy adults

Nat Commun. 2016 Aug 22;7:12484. doi: 10.1038/ncomms12484.


Clonal haematopoiesis is thought to be a rare condition that increases in frequency with age and predisposes individuals to haematological malignancy. Recent studies, utilizing next-generation sequencing (NGS), observed haematopoietic clones in 10% of 70-year olds and rarely in younger individuals. However, these studies could only detect common haematopoietic clones->0.02 variant allele fraction (VAF)-due to the error rate of NGS. To identify and characterize clonal mutations below this threshold, here we develop methods for targeted error-corrected sequencing, which enable the accurate detection of clonal mutations as rare as 0.0003 VAF. We apply these methods to study serially banked peripheral blood samples from healthy 50-60-year-old participants in the Nurses' Health Study. We observe clonal haematopoiesis, frequently harbouring mutations in DNMT3A and TET2, in 95% of individuals studied. These clonal mutations are often stable longitudinally and present in multiple haematopoietic compartments, suggesting a long-lived haematopoietic stem and progenitor cell of origin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Aged
  • Clone Cells / metabolism
  • Cohort Studies
  • DNA (Cytosine-5-)-Methyltransferases / genetics
  • DNA Methyltransferase 3A
  • DNA-Binding Proteins / genetics
  • Dioxygenases
  • Female
  • Gene Frequency
  • Genetic Predisposition to Disease / genetics*
  • Genetic Variation*
  • Hematopoiesis / genetics*
  • High-Throughput Nucleotide Sequencing / methods
  • Humans
  • Leukemia, Myeloid / genetics*
  • Middle Aged
  • Mutation*
  • Proto-Oncogene Proteins / genetics


  • DNA-Binding Proteins
  • DNMT3A protein, human
  • Proto-Oncogene Proteins
  • Dioxygenases
  • TET2 protein, human
  • DNA (Cytosine-5-)-Methyltransferases
  • DNA Methyltransferase 3A