Advertisement

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

Abstract

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.

Keywords

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.

Notes

Acknowledgments

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.

References

  1. 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
  2. Alvarado C, Beitel LK, Sircar K, Aprikian A, Trifiro M, Gottlieb B (2005) Somatic mosaicism and cancer: a micro-genetic examination into the role of the androgen receptor gene in prostate cancer. Cancer Res 65:8514–8518CrossRefPubMedGoogle Scholar
  3. Ayala FJ (2009) One hundred years without Darwin are enough! Genome Res 19:693–699CrossRefPubMedGoogle Scholar
  4. Bielas JH, Loeb KR, Rubin BP, True LD, Loeb LA (2006) Human cancers express a mutator phenotype. Proc Natl Acad Sci USA 103:18238–18242CrossRefPubMedGoogle Scholar
  5. Bissell MJ, LaBarge MA (2005) Context, tissue plasticity, and cancer: are tumor stem cells also regulated by the microenvironment? Cancer Cell 7:17–23PubMedGoogle Scholar
  6. Brulde B (2001) The goals of medicine. Towards a unified theory. Health Care Anal 9:1–13CrossRefPubMedGoogle Scholar
  7. Campbell PJ, Pleasance ER, Stephens PJ, Dicks E, Rance R, Goodhead I, Follows GA, Green AR, Futreal PA, Stratton MR (2008) Subclonal phylogenetic structures in cancer revealed by ultra-deep pyrosequencing. PNAS 105:13081–13086CrossRefPubMedGoogle Scholar
  8. Cheng L, Jones TD, Pan C-X, Barbarin A, Eble JN, Koch MO (2005) Anatomic distribution and pathologic characterization of small-volume prostate cancer (<0.5 ml) in whole-mount prostatectomy specimens. Mod Pathol 18:1022–1026CrossRefPubMedGoogle Scholar
  9. Davis BR, Candotti F (2009) Revertant somatic mosaicism in the Wiskott-Aldrich syndrome. Immunol Res 44:127–131CrossRefPubMedGoogle Scholar
  10. Drake JW (2007) Too many mutants with multiple mutations. Crit Rev Biochem Mol Biol 42:247–258CrossRefPubMedGoogle Scholar
  11. Eldar A, Chary VK, Xenopoulos P, Fontes ME, Loson O, Dworkin J, Piggot PJ, Elowitz MB (2009) Partial penetrance facilitates developmental evolution in bacteria. Nature 460:510–515PubMedGoogle Scholar
  12. Erickson RP (2003) Somatic gene mutation and human disease other than cancer. Mutat Res 543:125–136CrossRefPubMedGoogle Scholar
  13. 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
  14. Gluckman P, Beedle A, Hanson M (2009) Principles of evolutionary medicine. Oxford University Press, OxfordGoogle Scholar
  15. Gottlieb B, Beitel LK, Trifiro M (2001) Somatic mosaicism and variable expressivity. Trends Genet 17:79–82CrossRefPubMedGoogle Scholar
  16. Gottlieb B, Beitel LK, Wu JH, Trifiro M (2004) The androgen receptor gene mutations database: 2004 update. Hum Mutat 23:527–533CrossRefPubMedGoogle Scholar
  17. Gottlieb B, Beitel LK, Trifiro M (2007) Will knowledge of human genome variation result in changing cancer paradigms? Bioessays 29:678–685CrossRefPubMedGoogle Scholar
  18. Gottlieb B, Chalifour LE, Mitmaker B, Sheiner N, Obrand D, Abraham C, Meilleur M, Sugahara T, Bkaily G, Schweitzer M (2009) BAK1 gene variations and abdominal aortic aneurysms. Hum Mutat 30:1043–1047CrossRefPubMedGoogle Scholar
  19. Haber DA, Settleman J (2007) Drivers and passengers. Nature 446:145–146CrossRefPubMedGoogle Scholar
  20. Happle R (2009) What is paradominant inheritance? J Med Genet 46:648CrossRefPubMedGoogle Scholar
  21. Harismendy O, Ng PC, Strausberg RL, Wang X, Stockwell TB, Beeson KY, Schork NJ, Murray SS, Toplo EJ, Levy S, Frazer KA (2009) Evaluation of next generation sequencing platforms for population targeted sequencing studies. Genome Biol 10:R32CrossRefPubMedGoogle Scholar
  22. Hutchinson MJ, Booth D (2004) Much ado about nothing…so far? J Evol Biol 17:1184–1186CrossRefGoogle Scholar
  23. 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
  24. Kazemi-Esfarjani P, Trifiro MA, Pinsky L (1995) Evidence for a repressive function of the long polyglutamine tract in the human androgen receptor: possible pathogenetic relevance for the (CAG)n-expanded neuronopathies. Hum Mol Genet 4:523–527CrossRefPubMedGoogle Scholar
  25. Laloi-Michelin M et al (2009) The clinical variability of maternally inherited diabetes and deafness is associated with the degree of heteroplasmy in blood leukocytes. J Clin Endocrinol Metab 94:3025–3030CrossRefPubMedGoogle Scholar
  26. Lander ES et al (2001) Initial sequencing and analysis of the human genome. Nature 409:860–921CrossRefPubMedGoogle Scholar
  27. Lee PH, Shatkay H (2008) F-SNP: computationally predicted functional SNPs for disease association studies. Nucl Acids Res 36:D820–D824CrossRefPubMedGoogle Scholar
  28. Losi L, Baisse B, Bouzourene H, Benhattar J (2005) Evolution of intratumoral genetic heterogeneity during colorectal cancer progression. Carcinogenesis 26:916–922CrossRefPubMedGoogle Scholar
  29. Lutskiy MI, Park JY, Renold SK, Remold-O’Donnell E (2008) Evolution of highly polymorphic T cell populations in siblings with the Wiskott-Aldrich syndrome. PLoS One 3:e3444CrossRefPubMedGoogle Scholar
  30. 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
  31. McKernan KJ et al (2009) Sequence and structural variation in a human genome uncovered by short-read, massively parallel ligation sequencing using two-base encoding. Genome Res 19:1527–1541CrossRefPubMedGoogle Scholar
  32. Molderings GJ, Kolck UW, Scheurlin C, Bruss M, Homann J, Von Kugelgen I (2007) Multiple novel alterations in Kit tyrosine kinase in patients with gastrointestinally pronounced systemic mast cell activation disorder. Scan J Gasteroenterol 42:1045–1053CrossRefGoogle Scholar
  33. Pannell JR, Eppley SM (2004) Intraorganismal genetic heterogeneity: is it a useful concept? J Evol Biol 17:1180–1181CrossRefPubMedGoogle Scholar
  34. Pineda-Krch M, Lehtila K (2004) Costs and benefits of genetic heterogeneity within organisms. J Evol Biol 17:1167–1177CrossRefPubMedGoogle Scholar
  35. Pleasance ED et al (2009a) A small-cell lung cancer genome with complex signatures of tobacco exposure. Nature. doi: 10.1038/nature08629
  36. Pleasance ED et al (2009b) A comprehensive catalogue of somatic mutations from a human cancer genome. Nature. doi: 10.1038/nature08658
  37. Pushkarev D, Neff NF, Quake SR (2009) Single-molecule sequencing of an individual human genome. Nat Biotech 27(9):847–852Google Scholar
  38. Rohlin A, Wenersson J, Engwall Y, Wiklund L, Bjork J, Nordling M (2009) Parallel sequencing used in detection of mosaic mutations: comparison with four diagnostic DNA screening techniques. Hum Mutat 30:1012–1020CrossRefPubMedGoogle Scholar
  39. Sale JE, Batters C, Edmunds CE, Philips LG, Simpson LJ, Szuts D (2009) Timing matters: error-prone gap filling and translesion synthesis in immunoglobin gene hypermutation. Philos Trans R Soc B 364:595–603CrossRefGoogle Scholar
  40. Salk JJ, Fox EJ, Loeb LA (2010) Mutational heterogeneity in human cancers: origin and consequences. Annu Rev Path Mech Dis 5:51–75CrossRefGoogle Scholar
  41. Sircar K, Gottlieb B, Alvarado C, Aprikian A, Beitel LK, Alam-Fahmy M, Begin L, Trifiro M (2007) Androgen receptor CAG repeat length contraction in diseased and non-diseased prostatic tissues. Prostate Cancer Prostatic Dis 10:360–368CrossRefPubMedGoogle Scholar
  42. 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
  43. Takenaka S, McCormick S, Safroneeva E, Xing Z, Gauldie J (2009) Influence of the tissue microenvironment on Toll-like receptor expression by CD11+ antigen-presenting cells isolated from mucosal tissues. Clin Vaccine Immunol 16:1615–1623CrossRefPubMedGoogle Scholar
  44. Thorisson GA, Muliu J, Brookes AJ (2009) Genotype-phenotype databases: challenges and solutions for the post-genomic era. Nat Rev Genet 10:9–18CrossRefPubMedGoogle Scholar
  45. Venter JC et al (2001) The sequence of the human genome. Science 291:1304–1351CrossRefPubMedGoogle Scholar
  46. Vineis P, Berwick M (2006) The population dynamics of cancer: a Darwinian perspective. Int J Epidemiol 35:1151–1159CrossRefPubMedGoogle Scholar
  47. Wang C, Mitsuya Y, Gharizadeh B, Ronanghi M, Shafer RW (2007) Characterization of mutation spectra with ultra-deep pyrosequencing: application to HIV-1 drug resistance. Genome Res 17:1195–1201CrossRefPubMedGoogle Scholar
  48. Zlotogora J (2007) Multiple mutations responsible for frequent genetic diseases in isolated population. Eur J Hum Genet 15:272–278CrossRefPubMedGoogle Scholar

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

Personalised recommendations