Human Genetics

, Volume 127, Issue 5, pp 491–501 | Cite as

Selection and mutation in the “new” genetics: an emerging hypothesis

  • Bruce Gottlieb
  • Lenore K. Beitel
  • Carlos Alvarado
  • Mark A. Trifiro
Review Article


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.


Androgen Receptor Next Generation Sequencer Somatic Mutation Single Nucleotide Polymorphism Multifactorial Disease 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



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.


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Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Bruce Gottlieb
    • 1
    • 2
    • 3
  • Lenore K. Beitel
    • 1
    • 3
    • 4
  • Carlos Alvarado
    • 1
  • Mark A. Trifiro
    • 1
    • 2
    • 3
    • 4
  1. 1.Lady Davis Institute for Medical ResearchJewish General HospitalMontrealCanada
  2. 2.Segal Cancer CenterJewish General HospitalMontrealCanada
  3. 3.Department of Human GeneticsMcGill UniversityMontrealCanada
  4. 4.Department of MedicineMcGill UniversityMontrealCanada

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