Structural Genetic Variation in the Context of Somatic Mosaicism

  • Jan P. DumanskiEmail author
  • Arkadiusz Piotrowski
Part of the Methods in Molecular Biology book series (MIMB, volume 838)


Somatic mosaicism is the result of postzygotic de novo mutation occurring in a portion of the cells making up an organism. Structural genetic variation is a very heterogeneous group of changes, in terms of numerous types of aberrations that are included in this category, involvement of many mechanisms behind the generation of structural variants, and because structural variation can encompass genomic regions highly variable in size. Structural variation rapidly evolved as the dominating type of changes behind human genetic diversity, and the importance of this variation in biology and medicine is continuously increasing. In this review, we combine the evidence of structural variation in the context of somatic cells. We discuss the normal and disease-related somatic structural variation. We review the recent advances in the field of monozygotic twins and other models that have been studied for somatic mutations, including other vertebrates. We also discuss chromosomal mosaicism in a few prime examples of disease genes that contributed to understanding of the importance of somatic heterogeneity. We further highlight challenges and opportunities related to this field, including methodological and practical aspects of detection of somatic mosaicism. The literature devoted to interindividual variation versus papers reporting on somatic variation suggests that the latter is understudied and underestimated. It is important to increase our awareness about somatic mosaicism, in particular, related to structural variation. We believe that further research of somatic mosaicism will prove beneficial for better understanding of common sporadic disorders.

Key words

Copy number variation Heterogeneity Mosaicism Chimerism Aneuploidy Somatic cell Monozygotic twins Mitochondrial genome Nuclear genome Uniparental disomy 



We thank Drs. Nils-Göran Larsson, Lars Forsberg, Patrick Buckley, Teresita Diaz de Ståhl, and Kenneth Nilsson for review of the ­manuscript. This work was supported by the Ellison Medical Foundation, the Swedish Cancer Society, the Swedish Research Council to JPD; and by the Foundation for Polish Science, the Foundation for the Development of Polish Pharmacy and Medicine to A.P.


  1. 1.
    Redon R, Ishikawa S, Fitch KR, et al. (2006) Global variation in copy number in the human genome. Nature;444:444–54.PubMedCrossRefGoogle Scholar
  2. 2.
    Conrad DF, Pinto D, Redon R, et al. (2010) Origins and functional impact of copy number variation in the human genome. Nature;464:704–712.Google Scholar
  3. 3.
    Hastings PJ, Lupski JR, Rosenberg SM, Ira G. (2009) Mechanisms of change in gene copy number. Nat Rev Genet;10:551–64.PubMedCrossRefGoogle Scholar
  4. 4.
    Feinberg AP. (2002) Genomic imprinting and cancer. In: Vogelstein B, Kinzler KW, eds. The genetic basis of human cancer. Second ed. New York: McGraw-Hill.Google Scholar
  5. 5.
    Engel E. (2006) A fascination with chromosome rescue in uniparental disomy: Mendelian recessive outlaws and imprinting copyrights infringements. Eur J Hum Genet;14:1158–69.PubMedCrossRefGoogle Scholar
  6. 6.
    Kotzot D. (2008) Prenatal testing for uniparental disomy: indications and clinical relevance. Ultrasound Obstet Gynecol;31:100–5.PubMedCrossRefGoogle Scholar
  7. 7.
    Kotzot D. (2008) Complex and segmental uniparental disomy updated. J Med Genet;45:545–56.PubMedCrossRefGoogle Scholar
  8. 8.
    Ballif BC, Rorem EA, Sundin K, et al. (2006) Detection of low-level mosaicism by array CGH in routine diagnostic specimens. Am J Med Genet A;140:2757–67.PubMedGoogle Scholar
  9. 9.
    Cheung SW, Shaw CA, Scott DA, et al. (2007) Microarray-based CGH detects chromosomal mosaicism not revealed by conventional cytogenetics. Am J Med Genet A;143A:1679–86.PubMedCrossRefGoogle Scholar
  10. 10.
    Conlin LK, Thiel BD, Bonnemann CG, et al. (2010) Mechanisms of mosaicism, chimerism and uniparental disomy identified by SNP array analysis. Human Molecular Genetics;19 1263–75.PubMedCrossRefGoogle Scholar
  11. 11.
    Strain L, Warner JP, Johnston T, Bonthron DT. (1995) A human parthenogenetic chimaera. Nat Genet;11:164–9.PubMedCrossRefGoogle Scholar
  12. 12.
    Hall JG. (1996) Twinning: mechanisms and genetic implications. Curr Opin Genet Dev;6:343–7.PubMedCrossRefGoogle Scholar
  13. 13.
    van Dijk BA, Boomsma DI, de Man AJ. (1996) Blood group chimerism in human multiple births is not rare. Am J Med Genet;61:264–8.PubMedCrossRefGoogle Scholar
  14. 14.
    Bianchi DW, Lo YM. (2001) Fetomaternal cellular and plasma DNA trafficking: the Yin and the Yang. Ann N Y Acad Sci;945:119–31.PubMedCrossRefGoogle Scholar
  15. 15.
    Quaini F, Urbanek K, Beltrami AP, et al. (2002) Chimerism of the transplanted heart. N Engl J Med;346:5–15.PubMedCrossRefGoogle Scholar
  16. 16.
    Malan V, Vekemans M, Turleau C. (2006) Chimera and other fertilization errors. Clin Genet;70:363–73.PubMedCrossRefGoogle Scholar
  17. 17.
    Vogelstein B, Kinzler KW. (2002) The genetic basis of human cancer. Second Edition ed. New York: McGrawh-Hill.Google Scholar
  18. 18.
    Vogelstein B, Kinzler KW. (2004) Cancer genes and the pathways they control. Nature medicine;10:789–99.PubMedCrossRefGoogle Scholar
  19. 19.
    Stratton MR, Campbell PJ, Futreal PA. (2009) The cancer genome. Nature;458:719–24.PubMedCrossRefGoogle Scholar
  20. 20.
    Salk JJ, Fox EJ, Loeb LA. (2010) Mutational heterogeneity in human cancers: origin and consequences. Annu Rev Pathol;5:51–75.PubMedCrossRefGoogle Scholar
  21. 21.
    Frank S. (2010) Somatic evolutionary genomics: Mutations during development cause highly variable genetic mosaicism with risk of cancer and neurodegeneration. PNAS USA;107:1725–30.PubMedCrossRefGoogle Scholar
  22. 22.
    Rubin H. (2002) The disparity between human cell senescence in vitro and lifelong replication in vivo. Nat Biotechnol;20:675–81.PubMedCrossRefGoogle Scholar
  23. 23.
    Takubo K, Izumiyama-Shimomura N, Honma N, et al. (2002) Telomere lengths are characteristic in each human individual. Exp Gerontol;37:523–31.PubMedCrossRefGoogle Scholar
  24. 24.
    Nakamura K, Izumiyama-Shimomura N, Sawabe M, et al. (2002) Comparative analysis of telomere lengths and erosion with age in human epidermis and lingual epithelium. J Invest Dermatol;119:1014–9.PubMedCrossRefGoogle Scholar
  25. 25.
    Baird DM. (2008) Telomere dynamics in human cells. Biochimie;90:116–21.PubMedCrossRefGoogle Scholar
  26. 26.
    Baird DM, Britt-Compton B, Rowson J, Amso NN, Gregory L, Kipling D. (2006) Telomere instability in the male germline. Hum Mol Genet;15:45–51.PubMedCrossRefGoogle Scholar
  27. 27.
    Strachan T, Read A. (2004) Human Molecular Genetics 3. Third edition ed. New York: Garland Publishing.Google Scholar
  28. 28.
    Buckley P, Mantripragada K, Díaz de Ståhl T, et al. (2005) Identification of genetic aberrations on chromosome 22 outside the NF2 locus in schwannomatosis and neurofibromatosis type 2. Hum Mut;26:540–9.PubMedCrossRefGoogle Scholar
  29. 29.
    Terzioglu M, Larsson NG. (2007) Mitochondrial dysfunction in mammalian ageing. Novartis Found Symp;287:197–208; discussion 13.Google Scholar
  30. 30.
    Trifunovic A, Larsson NG. (2008) Mitochondrial dysfunction as a cause of ageing. J Intern Med;263:167–78.PubMedCrossRefGoogle Scholar
  31. 31.
    Holt IJ, Harding AE, Morgan-Hughes JA. (1988) Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature;331:717–9.PubMedCrossRefGoogle Scholar
  32. 32.
    Wallace DC, Singh G, Lott MT, et al. (1988) Mitochondrial DNA mutation associated with Leber’s hereditary optic neuropathy. Science;242:1427–30.PubMedCrossRefGoogle Scholar
  33. 33.
    DiMauro S, Hirano M. (2005) Mitochondrial encephalomyopathies: an update. Neuromuscul Disord;15:276–86.PubMedCrossRefGoogle Scholar
  34. 34.
    Larsson NG, Clayton DA. (1995) Molecular genetic aspects of human mitochondrial disorders. Annu Rev Genet;29:151–78.PubMedCrossRefGoogle Scholar
  35. 35.
    Mohamed SA, Hanke T, Erasmi AW, et al. (2006) Mitochondrial DNA deletions and the aging heart. Exp Gerontol;41:508–17.PubMedCrossRefGoogle Scholar
  36. 36.
    Lee HC, Pang CY, Hsu HS, Wei YH. (1994) Differential accumulations of 4,977 bp deletion in mitochondrial DNA of various tissues in human ageing. Biochim Biophys Acta;1226:37–43.PubMedGoogle Scholar
  37. 37.
    van Ommen GJ. (2005) Frequency of new copy number variation in humans. Nat Genet;37:333–4.PubMedCrossRefGoogle Scholar
  38. 38.
    Lupski JR. (2007) Genomic rearrangements and sporadic disease. Nat Genet;39:S43–7.PubMedCrossRefGoogle Scholar
  39. 39.
    Hall JG. (2003) Twinning. Lancet;362:735–43.PubMedCrossRefGoogle Scholar
  40. 40.
    Martin JA, Hamilton BE, Sutton PD, et al. (2007) Births: Final Data for 2005. National Vital Statistics Reports;56.Google Scholar
  41. 41.
    Gringras P, Chen W. (2001) Mechanisms for differences in monozygous twins. Early Hum Dev;64:105–17.PubMedCrossRefGoogle Scholar
  42. 42.
    Busjahn A, Hur YM. (2006) Twin registries: an ongoing success story. Twin Res Hum Genet;9:705.PubMedCrossRefGoogle Scholar
  43. 43.
    Merriman C. (1924) The intellectual resemblance of twins. Psycological Monographs;33:1–58.Google Scholar
  44. 44.
    Siemens H. (1924) Zwillingspathologie: Ihre Bedeutung; ihre Methodik; ihre bisherigen Ergebnisse. Berlin: Springer Verlag.Google Scholar
  45. 45.
    Nystad W, Roysamb E, Magnus P, Tambs K, Harris JR. (2005) A comparison of genetic and environmental variance structures for asthma, hay fever and eczema with symptoms of the same diseases: a study of Norwegian twins. International journal of epidemiology;34:1302–9.PubMedCrossRefGoogle Scholar
  46. 46.
    Harris JR, Magnus P, Samuelsen SO, Tambs K. (1997) No evidence for effects of family environment on asthma. A retrospective study of Norwegian twins. American journal of respiratory and critical care medicine;156:43–9.PubMedGoogle Scholar
  47. 47.
    Ahmadi KR, Lanchbury JS, Reed P, et al. (2003) Novel association suggests multiple independent QTLs within chromosome 5q21–33 region control variation in total humans IgE levels. Genes and immunity;4:289–97.PubMedCrossRefGoogle Scholar
  48. 48.
    Faraone SV, Perlis RH, Doyle AE, et al. (2005) Molecular genetics of attention-deficit/hyperactivity disorder. Biological psychiatry;57:1313–23.PubMedCrossRefGoogle Scholar
  49. 49.
    Folstein S, Rutter M. (1977) Genetic influences and infantile autism. Nature;265:726–8.PubMedCrossRefGoogle Scholar
  50. 50.
    Grjibovski AM, Olsen AO, Magnus P, Harris JR. (2007) Psoriasis in Norwegian twins: contribution of genetic and environmental effects. J Eur Acad Dermatol Venereol;21:1337–43.PubMedCrossRefGoogle Scholar
  51. 51.
    Heflin LH, Meyerowitz BE, Hall P, et al. (2005) Cancer as a risk factor for long-term cognitive deficits and dementia. Journal of the National Cancer Institute;97:854–6.PubMedCrossRefGoogle Scholar
  52. 52.
    Lichtenstein P, Holm NV, Verkasalo PK, et al. (2000) Environmental and heritable factors in the causation of cancer–analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med;343:78–85.PubMedCrossRefGoogle Scholar
  53. 53.
    Strachan DP, Wong HJ, Spector TD. (2001) Concordance and interrelationship of atopic diseases and markers of allergic sensitization among adult female twins. The Journal of allergy and clinical immunology;108:901–7.PubMedCrossRefGoogle Scholar
  54. 54.
    Stunkard AJ, Foch TT, Hrubec Z. (1986) A twin study of human obesity. Jama;256:51–4.PubMedCrossRefGoogle Scholar
  55. 55.
    Joseph J. (2002) Twin studies in psychiatry and psychology: science or pseudoscience? The Psychiatric quarterly;73:71–82.PubMedCrossRefGoogle Scholar
  56. 56.
    Kondo S, Schutte BC, Richardson RJ, et al. (2002) Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes. Nat Genet;32:285–9.PubMedCrossRefGoogle Scholar
  57. 57.
    Bruder C, Piotrowski A, Gijsbers A, et al. (2008) Phenotypically Concordant and Discordant Monozygotic Twins Display Different DNA Copy-Number-Variation Profiles. Am J Hum Genet;82:763–71.PubMedCrossRefGoogle Scholar
  58. 58.
    Machin GA. (1996) Some causes of genotypic and phenotypic discordance in monozygotic twin pairs. Am J Med Genet;61:216–28.PubMedCrossRefGoogle Scholar
  59. 59.
    Fraga MF, Ballestar E, Paz MF, et al. (2005) Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci USA;102:10604–9.PubMedCrossRefGoogle Scholar
  60. 60.
    Kaminsky ZA, Tang T, Wang SC, et al. (2009) DNA methylation profiles in monozygotic and dizygotic twins. Nat Genet;41:240–5.PubMedCrossRefGoogle Scholar
  61. 61.
    Petronis A, Gottesman, II, Kan P, et al. (2003) Monozygotic twins exhibit numerous epigenetic differences: clues to twin discordance? Schizophrenia bulletin;29:169–78.PubMedGoogle Scholar
  62. 62.
    Petronis A. (2006) Epigenetics and twins: three variations on the theme. Trends Genet;22:347–50.PubMedCrossRefGoogle Scholar
  63. 63.
    Summersgill B, Thornton P, Atkinson S, et al. (2002) Chromosomal imbalances in familial chronic lymphocytic leukaemia: a comparative genomic hybridisation analysis. Leukemia;16:1229–32.PubMedCrossRefGoogle Scholar
  64. 64.
    Ripolles L, Ortega M, Ortuno F, et al. (2006) Genetic abnormalities and clinical outcome in chronic lymphocytic leukemia. Cancer Genet Cytogenet;171:57–64.PubMedCrossRefGoogle Scholar
  65. 65.
    Korbel JO, Urban AE, Affourtit JP, et al. (2007) Paired-End Mapping Reveals Extensive Structural Variation in the Human Genome. Science;318:420–6.PubMedCrossRefGoogle Scholar
  66. 66.
    Tsujita T, Niikawa N, Yamashita H, et al. (1998) Genomic discordance between monozygotic twins discordant for schizophrenia. The American journal of psychiatry;155:422–4.PubMedGoogle Scholar
  67. 67.
    Machin G. (2009) Non-identical monozygotic twins, intermediate twin types, zygosity testing, and the non-random nature of monozygotic twinning: a review. Am J Med Genet C Semin Med Genet;151 C:110–27.PubMedCrossRefGoogle Scholar
  68. 68.
    Razzaghian HR, Shahi MH, Forsberg LA, et al. (2010) Somatic mosaicism for chromosome X and Y aneuploidies in monozygotic twins heterozygous for sickle cell disease mutation. Am J Med Genet A;152A:2595–2598.Google Scholar
  69. 69.
    Stumm M, Musebeck J, Tonnies H, et al. (2002) Partial trisomy 9p12p21.3 with a normal phenotype. J Med Genet; 39:141–4.PubMedCrossRefGoogle Scholar
  70. 70.
    McAuliffe F, Winsor EJ, Chitayat D. (2005) Tetrasomy 9p mosaicism associated with a normal phenotype. Fetal Diagn Ther;20:219–22.PubMedCrossRefGoogle Scholar
  71. 71.
    Di Giacomo MC, Susca FC, Resta N, Bukvic N, Vimercati A, Guanti G. (2007) Trisomy 13 mosaicism in a phenotypically normal child: description of cytogenetic and clinical findings from early pregnancy beyond 2 years of age. Am J Med Genet A;143:518–20.PubMedGoogle Scholar
  72. 72.
    Sung PL, Chang SP, Wen KC, et al. (2009) Small supernumerary marker chromosome originating from chromosome 10 associated with an apparently normal phenotype. Am J Med Genet A;149A:2768–74.PubMedCrossRefGoogle Scholar
  73. 73.
    Venci A, Bettio D. (2009) Tetrasomy 5p mosaicism due to an additional isochromosome 5p in a man with normal phenotype. Am J Med Genet A;149A:2889–91.PubMedCrossRefGoogle Scholar
  74. 74.
    Pack SD, Weil RJ, Vortmeyer AO, et al. (2005) Individual adult human neurons display aneuploidy: detection by fluorescence in situ hybridization and single neuron PCR. Cell cycle;4:1758–60.PubMedCrossRefGoogle Scholar
  75. 75.
    Iourov IY, Liehr T, Vorsanova SG, Kolotii AD, Yurov YB. (2006) Visualization of interphase chromosomes in postmitotic cells of the human brain by multicolour banding (MCB). Chromosome Res;14:223–9.PubMedCrossRefGoogle Scholar
  76. 76.
    Yurov YB, Iourov IY, Vorsanova SG, et al. (2007) Aneuploidy and confined chromosomal mosaicism in the developing human brain. PLoS ONE;2:e558.PubMedCrossRefGoogle Scholar
  77. 77.
    Piotrowski A, Bruder C, Andersson R, et al. (2008) Somatic mosaicism for copy number variation in differentiated human tissues. Human Mutation;29:1118–24.PubMedCrossRefGoogle Scholar
  78. 78.
    Eichler EE, Clark RA, She X. (2004) An assessment of the sequence gaps: unfinished business in a finished human genome. Nat Rev Genet;5:345–54.PubMedCrossRefGoogle Scholar
  79. 79.
    Bovee D, Zhou Y, Haugen E, et al. (2008) Closing gaps in the human genome with fosmid resources generated from multiple individuals. Nat Genet;40:96–101.PubMedCrossRefGoogle Scholar
  80. 80.
    Garber M, Zody MC, Arachchi HM, et al. (2009) Closing gaps in the human genome using sequencing by synthesis. Genome Biol;10:R60.PubMedCrossRefGoogle Scholar
  81. 81.
    Tapia-Paez I, Kost-Alimova M, Hu P, et al. (2001) The position of t(11;22)(q23;q11) constitutional translocation breakpoint is conserved among its carriers. Hum Genet;109:167–77.PubMedCrossRefGoogle Scholar
  82. 82.
    Coufal NG, Garcia-Perez JL, Peng GE, et al. (2009) L1 retrotransposition in human neural progenitor cells. Nature;460:1127–31.PubMedCrossRefGoogle Scholar
  83. 83.
    Kormoczi GF, Dauber EM, Haas OA, et al. (2007) Mosaicism due to myeloid lineage restricted loss of heterozygosity as cause of spontaneous Rh phenotype splitting. Blood;110:2148–57.PubMedCrossRefGoogle Scholar
  84. 84.
    Lam KW, Jeffreys AJ. (2006) Processes of copy-number change in human DNA: the dynamics of {alpha}-globin gene deletion. Proc Natl Acad Sci USA;103:8921–7.PubMedCrossRefGoogle Scholar
  85. 85.
    Flores M, Morales L, Gonzaga-Jauregui C, et al. (2007) Recurrent DNA inversion rearrangements in the human genome. Proc Natl Acad Sci USA;104:6099–106.PubMedCrossRefGoogle Scholar
  86. 86.
    Hall JG. (1988) Review and hypotheses: somatic mosaicism: observations related to clinical genetics. Am J Hum Genet;43:355–63.PubMedGoogle Scholar
  87. 87.
    Gottlieb B, Beitel LK, Trifiro MA. (2001) Somatic mosaicism and variable expressivity. Trends Genet;17:79–82.PubMedCrossRefGoogle Scholar
  88. 88.
    Youssoufian H, Pyeritz RE. (2002) Mechanisms and consequences of somatic mosaicism in humans. Nat Rev Genet;3:748–58.PubMedCrossRefGoogle Scholar
  89. 89.
    Erickson RP. (2003) Somatic gene mutation and human disease other than cancer. Mutat Res;543:125–36.PubMedCrossRefGoogle Scholar
  90. 90.
    Hirschhorn R. (2003) In vivo reversion to normal of inherited mutations in humans. J Med Genet;40:721–8.PubMedCrossRefGoogle Scholar
  91. 91.
    Notini AJ, Craig JM, White SJ. (2008) Copy number variation and mosaicism. Cytogenet Genome Res;123:270–7.PubMedCrossRefGoogle Scholar
  92. 92.
    Lutskiy MI, Park JY, Remold SK, Remold-O’Donnell E. (2008) Evolution of highly polymorphic T cell populations in siblings with the Wiskott-Aldrich Syndrome. PLoS One;3:e3444.PubMedCrossRefGoogle Scholar
  93. 93.
    Gottlieb B, Chalifour LE, Mitmaker B, et al. (2009) BAK1 gene variation and abdominal aortic aneurysms. Hum Mutat;30:1043–7.PubMedCrossRefGoogle Scholar
  94. 94.
    Mandel JL. (1989) Dystrophin. The gene and its product. Nature;339:584–6.PubMedCrossRefGoogle Scholar
  95. 95.
    Den Dunnen JT, Grootscholten PM, Dauwerse JG, et al. (1992) Reconstruction of the 2.4 Mb human DMD-gene by homologous YAC recombination. Hum Mol Genet;1:19–28.CrossRefGoogle Scholar
  96. 96.
    Roberts RG, Coffey AJ, Bobrow M, Bentley DR. (1993) Exon structure of the human dystrophin gene. Genomics;16:536–8.PubMedCrossRefGoogle Scholar
  97. 97.
    White SJ, den Dunnen JT. (2006) Copy number variation in the genome; the human DMD gene as an example. Cytogenet Genome Res;115:240–6.PubMedCrossRefGoogle Scholar
  98. 98.
    Passos-Bueno MR, Bakker E, Kneppers AL, et al. (1992) Different mosaicism frequencies for proximal and distal Duchenne muscular dystrophy (DMD) mutations indicate difference in etiology and recurrence risk. Am J Hum Genet;51:1150–5.PubMedGoogle Scholar
  99. 99.
    White SJ, Aartsma-Rus A, Flanigan KM, et al. (2006) Duplications in the DMD gene. Hum Mutat;27:938–45.PubMedCrossRefGoogle Scholar
  100. 100.
    Kvittingen EA, Rootwelt H, Berger R, Brandtzaeg P. (1994) Self-induced correction of the genetic defect in tyrosinemia type I. The Journal of clinical investigation;94:1657–61.PubMedCrossRefGoogle Scholar
  101. 101.
    Ellis NA, Lennon DJ, Proytcheva M, Alhadeff B, Henderson EE, German J. (1995) Somatic intragenic recombination within the mutated locus BLM can correct the high sister-chromatid exchange phenotype of Bloom syndrome cells. Am J Hum Genet;57:1019–27.PubMedGoogle Scholar
  102. 102.
    Gregory JJ, Jr., Wagner JE, Verlander PC, et al. (2001) Somatic mosaicism in Fanconi anemia: evidence of genotypic reversion in lymphohematopoietic stem cells. Proc Natl Acad Sci USA;98:2532–7.PubMedCrossRefGoogle Scholar
  103. 103.
    Cawthon RM, Weiss R, Xu GF, et al. (1990) A major segment of the neurofibromatosis type 1 gene: cDNA sequence, genomic structure, and point mutations. Cell;62:193–201.PubMedCrossRefGoogle Scholar
  104. 104.
    Viskochil D, Buchberg AM, Xu G, et al. (1990) Deletions and translocation interrupt a cloned gene at the neurofibromatosis type 1 locus. Cell;62:187–92.PubMedCrossRefGoogle Scholar
  105. 105.
    Wallace MR, Marchuk DA, Andersen LB, et al. (1990) Type 1 neurofibromatosis gene: Identification of a large transcript disrupted in three NF1 patients. Science;249:181–6.PubMedCrossRefGoogle Scholar
  106. 106.
    Kehrer-Sawatzki H, Kluwe L, Sandig C, et al. (2004) High frequency of mosaicism among patients with neurofibromatosis type 1 (NF1) with microdeletions caused by somatic recombination of the JJAZ1 gene. Am J Hum Genet;75:410–23.PubMedCrossRefGoogle Scholar
  107. 107.
    Mantripragada KK, Thuresson AC, Piotrowski A, et al. (2006) Identification of novel deletion breakpoints bordered by segmental duplications in the NF1 locus using high resolution array-CGH. J Med Genet;43:28–38.PubMedCrossRefGoogle Scholar
  108. 108.
    Rasmussen SA, Colman SD, Ho VT, et al. (1998) Constitutional and mosaic large NF1 gene deletions in neurofibromatosis type 1. J Med Genet;35:468–71.PubMedCrossRefGoogle Scholar
  109. 109.
    Petek E, Jenne DE, Smolle J, et al. (2003) Mitotic recombination mediated by the JJAZF1 (KIAA0160) gene causing somatic mosaicism and a new type of constitutional NF1 microdeletion in two children of a mosaic female with only few manifestations. J Med Genet;40:520–5.PubMedCrossRefGoogle Scholar
  110. 110.
    Steinmann K, Cooper DN, Kluwe L, et al. (2007) Type 2 NF1 deletions are highly unusual by virtue of the absence of nonallelic homologous recombination hotspots and an apparent preference for female mitotic recombination. Am J Hum Genet;81:1201–20.PubMedCrossRefGoogle Scholar
  111. 111.
    Bielanska M, Tan SL, Ao A. (2002) Chromosomal mosaicism throughout human preimplantation development in vitro: incidence, type, and relevance to embryo outcome. Human reproduction (Oxford, England);17:413–9.Google Scholar
  112. 112.
    Munne S, Bahce M, Sandalinas M, et al. (2004) Differences in chromosome susceptibility to aneuploidy and survival to first trimester. Reprod Biomed Online;8:81–90.PubMedCrossRefGoogle Scholar
  113. 113.
    Delhanty JD. (2005) Mechanisms of aneuploidy induction in human oogenesis and early embryogenesis. Cytogenet Genome Res;111:237–44.PubMedCrossRefGoogle Scholar
  114. 114.
    Munne S. (2006) Chromosome abnormalities and their relationship to morphology and development of human embryos. Reprod Biomed Online;12:234–53.PubMedCrossRefGoogle Scholar
  115. 115.
    Kalousek DK. (2000) Pathogenesis of chromosomal mosaicism and its effect on early human development. Am J Med Genet;91:39–45.PubMedCrossRefGoogle Scholar
  116. 116.
    Hassold T, Hall H, Hunt P. (2007) The origin of human aneuploidy: where we have been, where we are going. Hum Mol Genet;16 Spec No. 2:R203–8.Google Scholar
  117. 117.
    Vanneste E, Voet T, Le Caignec C, et al. (2009) Chromosome instability is common in human cleavage-stage embryos. Nature medicine;15:577–83.PubMedCrossRefGoogle Scholar
  118. 118.
    Hassold TJ, Jacobs PA. (1984) Trisomy in man. Annu Rev Genet;18:69–97.PubMedCrossRefGoogle Scholar
  119. 119.
    Reeser SL, Wenger SL. (1992) Failure of PHA-stimulated i(12p) lymphocytes to divide in Pallister-Killian syndrome. Am J Med Genet;42:815–9.PubMedCrossRefGoogle Scholar
  120. 120.
    Priest JH, Rust JM, Fernhoff PM. (1992) Tissue specificity and stability of mosaicism in Pallister-Killian  +  i(12p) syndrome: relevance for prenatal diagnosis. Am J Med Genet;42:820–4.PubMedCrossRefGoogle Scholar
  121. 121.
    Kingston HM, Nicolini U, Haslam J, Andrews T. (1993) 46,XY/47,XY, + 17p  +  mosaicism in amniocytes associated with fetal abnormalities despite normal fetal blood karyotype. Prenat Diagn;13:637–42.PubMedCrossRefGoogle Scholar
  122. 122.
    Magenis E, Webb MJ, Spears B, Opitz JM. (1999) Blaschkolinear malformation syndrome in complex trisomy-7 mosaicism. Am J Med Genet;87:375–83.PubMedCrossRefGoogle Scholar
  123. 123.
    Kayser M, Henderson LB, Kreutzman J, Schreck R, Graham JM, Jr. (2000) Blaschkolinear skin pigmentary variation due to trisomy 7 mosaicism. Am J Med Genet;95:281–4.PubMedCrossRefGoogle Scholar
  124. 124.
    Iourov IY, Vorsanova SG, Liehr T, Yurov YB. (2009) Aneuploidy in the normal, Alzheimer’s disease and ataxia-telangiectasia brain: differential expression and pathological meaning. Neurobiology of disease;34:212–20.PubMedCrossRefGoogle Scholar
  125. 125.
    Yurov YB, Vorsanova SG, Iourov IY, et al. (2007) Unexplained autism is frequently associated with low-level mosaic aneuploidy. J Med Genet;44:521–5.PubMedCrossRefGoogle Scholar
  126. 126.
    Kakinuma H, Ozaki M, Sato H, Takahashi H. (2008) Variation in GABA-A subunit gene copy number in an autistic patient with mosaic 4 p duplication (p12p16). Am J Med Genet B Neuropsychiatr Genet;147B:973–5.PubMedCrossRefGoogle Scholar
  127. 127.
    Saito T, Nishii Y, Yasuda T, et al. (2009) Familial hypophosphatemic rickets caused by a large deletion in PHEX gene. European journal of endocrinology / European Federation of Endocrine Societies;161:647–51.PubMedCrossRefGoogle Scholar
  128. 128.
    Wilson M, Peters G, Bennetts B, et al. (2008) The clinical phenotype of mosaicism for genome-wide paternal uniparental disomy: two new reports. Am J Med Genet A;146A:137–48.PubMedCrossRefGoogle Scholar
  129. 129.
    Smith AC, Shuman C, Chitayat D, et al. (2007) Severe presentation of Beckwith-Wiedemann syndrome associated with high levels of constitutional paternal uniparental disomy for chromosome 11p15. Am J Med Genet A;143A:3010–5.PubMedCrossRefGoogle Scholar
  130. 130.
    Rehen SK, McConnell MJ, Kaushal D, Kingsbury MA, Yang AH, Chun J. (2001) Chromosomal variation in neurons of the developing and adult mammalian nervous system. Proc Natl Acad Sci USA;98:13361–6.PubMedCrossRefGoogle Scholar
  131. 131.
    Rajendran RS, Zupanc MM, Losche A, Westra J, Chun J, Zupanc GK. (2007) Numerical chromosome variation and mitotic segregation defects in the adult brain of teleost fish. Developmental neurobiology;67:1334–47.PubMedCrossRefGoogle Scholar
  132. 132.
    Cervantes RB, Stringer JR, Shao C, Tischfield JA, Stambrook PJ. (2002) Embryonic stem cells and somatic cells differ in mutation frequency and type. Proc Natl Acad Sci USA;99:3586–90.PubMedCrossRefGoogle Scholar
  133. 133.
    Liang Q, Conte N, Skarnes WC, Bradley A. (2008) Extensive genomic copy number variation in embryonic stem cells. Proc Natl Acad Sci USA;105:17453–6.PubMedCrossRefGoogle Scholar
  134. 134.
    Kano H, Godoy I, Courtney C, et al. (2009) L1 retrotransposition occurs mainly in embryogenesis and creates somatic mosaicism. Genes & development;23:1303–12.CrossRefGoogle Scholar
  135. 135.
    Geigl JB, Obenauf AC, Waldispuehl-Geigl J, et al. (2009) Identification of small gains and losses in single cells after whole genome amplification on tiling oligo arrays. Nucleic Acids Res;37:e105.PubMedCrossRefGoogle Scholar
  136. 136.
    Nilsson K, Ponten J. (1975) Classification and biological nature of established human hematopoietic cell lines. Int J Cancer;15:321–41.PubMedCrossRefGoogle Scholar
  137. 137.
    Giovanella B, Nilsson K, Zech L, Yim O, Klein G, Stehlin JS. (1979) Growth of diploid, Epstein-Barr virus-carrying human lymphoblastoid cell lines heterotransplanted into nude mice under immunologically privileged conditions. Int J Cancer;24:103–13.PubMedCrossRefGoogle Scholar
  138. 138.
    Gottlieb B, Beitel LK, Alvarado C, et al. (2010) Selection and mutation in the “new” genetics: an emerging hypothesis. Hum Genet;127:491–501.Google Scholar
  139. 139.
    Blouin JL, Avramopoulos D, Pangalos C, Antonarakis SE. (1993) Normal phenotype with paternal uniparental isodisomy for chromosome 21. Am J Hum Genet;53:1074–8.PubMedGoogle Scholar
  140. 140.
    Bernardini L, Sinibaldi L, Ceccarini C, Novelli A, Dallapiccola B. (2005) Reproductive history of a healthy woman with mosaic duplication of chromosome 4p. Prenat Diagn;25:283–5.PubMedCrossRefGoogle Scholar
  141. 141.
    Loitzsch A, Bartsch O. (2006) Healthy 12-year-old boy with mosaic inv dup(15)(q13). Am J Med Genet A;140:640–3.PubMedGoogle Scholar
  142. 142.
    Santos M, Mrasek K, Rigola MA, Starke H, Liehr T, Fuster C. (2007) Identification of a “cryptic mosaicism” involving at least four different small supernumerary marker chromosomes derived from chromosome 9 in a woman without reproductive success. Fertility and sterility;88:969 e11–7.Google Scholar
  143. 143.
    Frey NV, Leid CE, Nowell PC, et al. (2008) Trisomy 8 in an allogeneic stem cell transplant recipient representative of a donor-derived constitutional abnormality. Am J Hematol;83:846–9.PubMedCrossRefGoogle Scholar
  144. 144.
    Hockner M, Utermann B, Erdel M, Fauth C, Utermann G, Kotzot D. (2008) Molecular characterization of a de novo ring chromosome 6 in a growth retarded but otherwise healthy woman. Am J Med Genet A;146:925–9.PubMedGoogle Scholar
  145. 145.
    Liehr T, Ewers E, Kosyakova N, et al. (2009) Handling small supernumerary marker chromosomes in prenatal diagnostics. Expert Rev Mol Diagn;9:317–24.PubMedCrossRefGoogle Scholar
  146. 146.
    Iwarsson E, Sahlen S, Nordgren A. (2009) Jumping translocation in a phenotypically normal male: A study of mosaicism in spermatozoa, lymphocytes, and fibroblasts. Am J Med Genet A;149A:1706–11.PubMedCrossRefGoogle Scholar
  147. 147.
    Yang D, McCrann DJ, Nguyen H, et al. (2007) Increased polyploidy in aortic vascular smooth muscle cells during aging is marked by cellular senescence. Aging cell;6:257–60.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Department of Immunology Genetics and PathologyUppsala UniversityUppsalaSweden
  2. 2.Department of Biology and Pharmaceutical BotanyMedical University of GdanskGdanskPoland

Personalised recommendations