Selection and mutation in the “new” genetics: an emerging hypothesis
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It has been anticipated that new, much more sensitive, next generation sequencing (NGS) techniques, using massively parallel sequencing, will likely provide radical insights into the genetics of multifactorial diseases. While NGS has been used initially to analyze individual human genomes, and has revealed considerable differences between healthy individuals, we have used NGS to examine genetic variation within individuals, by sequencing tissues “in depth”, i.e., oversequencing many thousands of times. Initial studies have revealed intra-tissue genetic heterogeneity, in the form of multiple variants of a single gene that exist as distinct “majority and “minority” variants. This highly specialized form of somatic mosaicism has been found within both cancer and normal tissues. If such genetic variation within individual tissues is widespread, it will need to be considered as a significant factor in the ontogeny of many multifactorial diseases, including cancer. The discovery of majority and minority gene variants and the resulting somatic cell heterogeneity in both normal and diseased tissues suggests that selection, as opposed to mutation, might be the critical event in disease ontogeny. We, therefore, are proposing a hypothesis to explain multifactorial disease ontogeny in which pre-existing multiple somatic gene variants, which may arise at a very early stage of tissue development, are eventually selected due to changes in tissue microenvironments.
KeywordsAndrogen Receptor Next Generation Sequencer Somatic Mutation Single Nucleotide Polymorphism Multifactorial Disease
Dr. Bruce Gottlieb and Dr. Mark Trifiro acknowledge the support of grants from the Canadian Institutes of Health Research and the Weekend to End Breast Cancer.
- Ahn SM, Kim TH, Lee S, Kim D, Ghang H, Kim D-S, Kim B-H, Kim S-Y, Kim W-Y, Kim C, Park D, Lee YS, Kim S, Reja R, Jho S, Kim CG, Cha J-Y, Kim K-H, Lee B, Bhak J, Kim S-J (2009) The first Korean genome sequence and analysis: full genome sequencing for a socio-ethnic group. Genome Res 19:1622–1629CrossRefPubMedGoogle Scholar
- Frank SA (2010) Somatic evolutionary genomics: Mutations during development cause highly variable genetic mosaicism with risk of cancer and neurodegeneration. PNAS (in press)Google Scholar
- Gluckman P, Beedle A, Hanson M (2009) Principles of evolutionary medicine. Oxford University Press, OxfordGoogle Scholar
- Irwin JA, Saunier JL, Niederstatter H, Strous KM, Sturk KA, Diegoli TM, Brandstatter A, Parson W, Parsons TJ (2009) Investigation of heteroplasmy in the human mitochondrial DNA control region: a synthesis of observations from more than 5000 global population samples. J Mol Evol 68:516–527CrossRefPubMedGoogle Scholar
- Marva F, Lopez-Rodas V, Rouco M, Navarro M, Toro FJ, Costas E, Flores-Moya A (2009) Adaptation of green microalgae to the herbicides simazine and diquat as result of pre-selective mutations. Aquat Toxicol. doi: 10.1016/j.aquatox.2009.10.009
- Pleasance ED et al (2009a) A small-cell lung cancer genome with complex signatures of tobacco exposure. Nature. doi: 10.1038/nature08629
- Pleasance ED et al (2009b) A comprehensive catalogue of somatic mutations from a human cancer genome. Nature. doi: 10.1038/nature08658
- Pushkarev D, Neff NF, Quake SR (2009) Single-molecule sequencing of an individual human genome. Nat Biotech 27(9):847–852Google Scholar
- Steinkamp MP, O’Mahoney OA, Brogley M, Rehman H, LaPensee EW, Dhannasekaran S, Hofer MD, Kuefer R, Chinnaiyan A, Rubin MA, Pienta KJ, Robins DM (2009) Treatment-dependent androgen receptor mutations in prostate cancer exploit multiple mechanisms to evade therapy. Cancer Res 69:4434–4442CrossRefPubMedGoogle Scholar