Bulk Genotyping of Biopsies Can Create Spurious Evidence for Hetereogeneity in Mutation Content

Rumen Kostadinov, Carlo Maley, Mary K. Kuhner

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

When multiple samples are taken from the neoplastic tissues of a single patient, it is natural to compare their mutation content. This is often done by bulk genotyping of whole biopsies, but the chance that a mutation will be detected in bulk genotyping depends on its local frequency in the sample. When the underlying mutation count per cell is equal, homogenous biopsies will have more high-frequency mutations, and thus more detectable mutations, than heterogeneous ones. Using simulations, we show that bulk genotyping of data simulated under a neutral model of somatic evolution generates strong spurious evidence for non-neutrality, because the pattern of tissue growth systematically generates differences in biopsy heterogeneity. Any experiment which compares mutation content across bulk-genotyped biopsies may therefore suggest mutation rate or selection intensity variation even when these forces are absent. We discuss computational and experimental approaches for resolving this problem.

Original languageEnglish (US)
Article numbere1004413
JournalPLoS Computational Biology
Volume12
Issue number4
DOIs
StatePublished - Apr 1 2016
Externally publishedYes

Fingerprint

Biopsy
genotyping
biopsy
mutation
Mutation
Mutation Rate
Tissue
Clonal Evolution
selection intensity
Cell Count
Evidence
Count
Growth
Experiments
sampling
Cell
simulation
Experiment
Simulation

ASJC Scopus subject areas

  • Computational Theory and Mathematics
  • Modeling and Simulation
  • Ecology, Evolution, Behavior and Systematics
  • Genetics
  • Molecular Biology
  • Ecology
  • Cellular and Molecular Neuroscience

Cite this

Bulk Genotyping of Biopsies Can Create Spurious Evidence for Hetereogeneity in Mutation Content. / Kostadinov, Rumen; Maley, Carlo; Kuhner, Mary K.

In: PLoS Computational Biology, Vol. 12, No. 4, e1004413, 01.04.2016.

Research output: Contribution to journalArticle

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