Genome-wide quantification of rare somatic mutations in normal human tissues using massively parallel sequencing

Margaret L. Hoang, Isaac Kinde, Cristian Tomasetti, K. Wyatt McMahon, Thomas A. Rosenquist, Arthur P. Grollman, Kenneth W. Kinzler, Bert Vogelstein, Nickolas Papadopoulos

Research output: Contribution to journalArticlepeer-review

79 Scopus citations


We present the bottleneck sequencing system (BotSeqS), a nextgeneration sequencing method that simultaneously quantifies rare somatic point mutations across the mitochondrial and nuclear genomes. BotSeqS combines molecular barcoding with a simple dilution step immediately before library amplification. We use BotSeqS to show age- and tissue-dependent accumulations of rare mutations and demonstrate that somatic mutational burden in normal human tissues can vary by several orders of magnitude, depending on biologic and environmental factors. We further show major differences between the mutational patterns of the mitochondrial and nuclear genomes in normal tissues. Lastly, the mutation spectra of normal tissues were different from each other, but similar to those of the cancers that arose in them. This technology can provide insights into the number and nature of genetic alterations in normal tissues and can be used to address a variety of fundamental questions about the genomes of diseased tissues.

Original languageEnglish (US)
Pages (from-to)9846-9851
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number35
StatePublished - Aug 30 2016


  • Aging
  • Enomics
  • Next-generation sequencing
  • Somatic mutation

ASJC Scopus subject areas

  • General


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