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

PLoS Comput Biol. 2016 Apr 22;12(4):e1004413. doi: 10.1371/journal.pcbi.1004413. eCollection 2016 Apr.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Barrett Esophagus / genetics
  • Biopsy
  • Computational Biology
  • Computer Simulation
  • DNA Mutational Analysis
  • DNA, Neoplasm / genetics
  • Genotype
  • Humans
  • Models, Genetic
  • Mutation*
  • Neoplasms / genetics*
  • Selection, Genetic

Substances

  • DNA, Neoplasm