Bulk Genotyping of Biopsies Can Create Spurious Evidence for Hetereogeneity in Mutation Content.
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.
Pediatric Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America.
Rumen
R
Kostadinov
Center for Evolution and Cancer, University of California, San Francisco, San Francisco, California, United States of America.
Carlo C
CC
Maley
Department of Genome Sciences, University of Washington, Seattle, Washington, United States of America.
Mary K
MK
Kuhner
D001471:Barrett Esophagus / Q000235:genetics; D001706:Biopsy; D019295:Computational Biology; D003198:Computer Simulation; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D005838:Genotype; D006801:Humans; D008957:Models, Genetic; D009154:Mutation; D009369:Neoplasms / Q000235:genetics*; D012641:Selection, Genetic
D004273:DNA, Neoplasm