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Structural Genetic Variation in the Context of Somatic Mosaicism

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Genomic Structural Variants

Part of the book series: Methods in Molecular Biology ((MIMB,volume 838))

Abstract

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.

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References

  1. Redon R, Ishikawa S, Fitch KR, et al. (2006) Global variation in copy number in the human genome. Nature;444:444–54.

    Article  PubMed  CAS  Google Scholar 

  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. Hastings PJ, Lupski JR, Rosenberg SM, Ira G. (2009) Mechanisms of change in gene copy number. Nat Rev Genet;10:551–64.

    Article  PubMed  CAS  Google Scholar 

  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. 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.

    Article  PubMed  CAS  Google Scholar 

  6. Kotzot D. (2008) Prenatal testing for uniparental disomy: indications and clinical relevance. Ultrasound Obstet Gynecol;31:100–5.

    Article  PubMed  CAS  Google Scholar 

  7. Kotzot D. (2008) Complex and segmental uniparental disomy updated. J Med Genet;45:545–56.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  11. Strain L, Warner JP, Johnston T, Bonthron DT. (1995) A human parthenogenetic chimaera. Nat Genet;11:164–9.

    Article  PubMed  CAS  Google Scholar 

  12. Hall JG. (1996) Twinning: mechanisms and genetic implications. Curr Opin Genet Dev;6:343–7.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  15. Quaini F, Urbanek K, Beltrami AP, et al. (2002) Chimerism of the transplanted heart. N Engl J Med;346:5–15.

    Article  PubMed  Google Scholar 

  16. Malan V, Vekemans M, Turleau C. (2006) Chimera and other fertilization errors. Clin Genet;70:363–73.

    Article  PubMed  CAS  Google Scholar 

  17. Vogelstein B, Kinzler KW. (2002) The genetic basis of human cancer. Second Edition ed. New York: McGrawh-Hill.

    Google Scholar 

  18. Vogelstein B, Kinzler KW. (2004) Cancer genes and the pathways they control. Nature medicine;10:789–99.

    Article  PubMed  CAS  Google Scholar 

  19. Stratton MR, Campbell PJ, Futreal PA. (2009) The cancer genome. Nature;458:719–24.

    Article  PubMed  CAS  Google Scholar 

  20. Salk JJ, Fox EJ, Loeb LA. (2010) Mutational heterogeneity in human cancers: origin and consequences. Annu Rev Pathol;5:51–75.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  22. Rubin H. (2002) The disparity between human cell senescence in vitro and lifelong replication in vivo. Nat Biotechnol;20:675–81.

    Article  PubMed  CAS  Google Scholar 

  23. Takubo K, Izumiyama-Shimomura N, Honma N, et al. (2002) Telomere lengths are characteristic in each human individual. Exp Gerontol;37:523–31.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  25. Baird DM. (2008) Telomere dynamics in human cells. Biochimie;90:116–21.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  27. Strachan T, Read A. (2004) Human Molecular Genetics 3. Third edition ed. New York: Garland Publishing.

    Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  29. Terzioglu M, Larsson NG. (2007) Mitochondrial dysfunction in mammalian ageing. Novartis Found Symp;287:197–208; discussion 13.

    Google Scholar 

  30. Trifunovic A, Larsson NG. (2008) Mitochondrial dysfunction as a cause of ageing. J Intern Med;263:167–78.

    Article  PubMed  CAS  Google Scholar 

  31. Holt IJ, Harding AE, Morgan-Hughes JA. (1988) Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature;331:717–9.

    Article  PubMed  CAS  Google Scholar 

  32. Wallace DC, Singh G, Lott MT, et al. (1988) Mitochondrial DNA mutation associated with Leber’s hereditary optic neuropathy. Science;242:1427–30.

    Article  PubMed  CAS  Google Scholar 

  33. DiMauro S, Hirano M. (2005) Mitochondrial encephalomyopathies: an update. Neuromuscul Disord;15:276–86.

    Article  PubMed  Google Scholar 

  34. Larsson NG, Clayton DA. (1995) Molecular genetic aspects of human mitochondrial disorders. Annu Rev Genet;29:151–78.

    Article  PubMed  CAS  Google Scholar 

  35. Mohamed SA, Hanke T, Erasmi AW, et al. (2006) Mitochondrial DNA deletions and the aging heart. Exp Gerontol;41:508–17.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  37. van Ommen GJ. (2005) Frequency of new copy number variation in humans. Nat Genet;37:333–4.

    Article  PubMed  CAS  Google Scholar 

  38. Lupski JR. (2007) Genomic rearrangements and sporadic disease. Nat Genet;39:S43–7.

    Article  PubMed  CAS  Google Scholar 

  39. Hall JG. (2003) Twinning. Lancet;362:735–43.

    Article  PubMed  Google Scholar 

  40. Martin JA, Hamilton BE, Sutton PD, et al. (2007) Births: Final Data for 2005. National Vital Statistics Reports;56.

    Google Scholar 

  41. Gringras P, Chen W. (2001) Mechanisms for differences in monozygous twins. Early Hum Dev;64:105–17.

    Article  PubMed  CAS  Google Scholar 

  42. Busjahn A, Hur YM. (2006) Twin registries: an ongoing success story. Twin Res Hum Genet;9:705.

    Article  PubMed  Google Scholar 

  43. Merriman C. (1924) The intellectual resemblance of twins. Psycological Monographs;33:1–58.

    Google Scholar 

  44. Siemens H. (1924) Zwillingspathologie: Ihre Bedeutung; ihre Methodik; ihre bisherigen Ergebnisse. Berlin: Springer Verlag.

    Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  48. Faraone SV, Perlis RH, Doyle AE, et al. (2005) Molecular genetics of attention-deficit/hyperactivity disorder. Biological psychiatry;57:1313–23.

    Article  PubMed  CAS  Google Scholar 

  49. Folstein S, Rutter M. (1977) Genetic influences and infantile autism. Nature;265:726–8.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  54. Stunkard AJ, Foch TT, Hrubec Z. (1986) A twin study of human obesity. Jama;256:51–4.

    Article  PubMed  CAS  Google Scholar 

  55. Joseph J. (2002) Twin studies in psychiatry and psychology: science or pseudoscience? The Psychiatric quarterly;73:71–82.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  58. Machin GA. (1996) Some causes of genotypic and phenotypic discordance in monozygotic twin pairs. Am J Med Genet;61:216–28.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  60. Kaminsky ZA, Tang T, Wang SC, et al. (2009) DNA methylation profiles in monozygotic and dizygotic twins. Nat Genet;41:240–5.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  Google Scholar 

  62. Petronis A. (2006) Epigenetics and twins: three variations on the theme. Trends Genet;22:347–50.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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. Stumm M, Musebeck J, Tonnies H, et al. (2002) Partial trisomy 9p12p21.3 with a normal phenotype. J Med Genet; 39:141–4.

    Article  PubMed  CAS  Google Scholar 

  70. McAuliffe F, Winsor EJ, Chitayat D. (2005) Tetrasomy 9p mosaicism associated with a normal phenotype. Fetal Diagn Ther;20:219–22.

    Article  PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  76. Yurov YB, Iourov IY, Vorsanova SG, et al. (2007) Aneuploidy and confined chromosomal mosaicism in the developing human brain. PLoS ONE;2:e558.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  80. Garber M, Zody MC, Arachchi HM, et al. (2009) Closing gaps in the human genome using sequencing by synthesis. Genome Biol;10:R60.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  82. Coufal NG, Garcia-Perez JL, Peng GE, et al. (2009) L1 retrotransposition in human neural progenitor cells. Nature;460:1127–31.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  86. Hall JG. (1988) Review and hypotheses: somatic mosaicism: observations related to clinical genetics. Am J Hum Genet;43:355–63.

    PubMed  CAS  Google Scholar 

  87. Gottlieb B, Beitel LK, Trifiro MA. (2001) Somatic mosaicism and variable expressivity. Trends Genet;17:79–82.

    Article  PubMed  CAS  Google Scholar 

  88. Youssoufian H, Pyeritz RE. (2002) Mechanisms and consequences of somatic mosaicism in humans. Nat Rev Genet;3:748–58.

    Article  PubMed  CAS  Google Scholar 

  89. Erickson RP. (2003) Somatic gene mutation and human disease other than cancer. Mutat Res;543:125–36.

    Article  PubMed  CAS  Google Scholar 

  90. Hirschhorn R. (2003) In vivo reversion to normal of inherited mutations in humans. J Med Genet;40:721–8.

    Article  PubMed  CAS  Google Scholar 

  91. Notini AJ, Craig JM, White SJ. (2008) Copy number variation and mosaicism. Cytogenet Genome Res;123:270–7.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  93. Gottlieb B, Chalifour LE, Mitmaker B, et al. (2009) BAK1 gene variation and abdominal aortic aneurysms. Hum Mutat;30:1043–7.

    Article  PubMed  CAS  Google Scholar 

  94. Mandel JL. (1989) Dystrophin. The gene and its product. Nature;339:584–6.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  96. Roberts RG, Coffey AJ, Bobrow M, Bentley DR. (1993) Exon structure of the human dystrophin gene. Genomics;16:536–8.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  99. White SJ, Aartsma-Rus A, Flanigan KM, et al. (2006) Duplications in the DMD gene. Hum Mutat;27:938–45.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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. 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.

    Article  PubMed  Google Scholar 

  113. Delhanty JD. (2005) Mechanisms of aneuploidy induction in human oogenesis and early embryogenesis. Cytogenet Genome Res;111:237–44.

    Article  PubMed  CAS  Google Scholar 

  114. Munne S. (2006) Chromosome abnormalities and their relationship to morphology and development of human embryos. Reprod Biomed Online;12:234–53.

    Article  PubMed  Google Scholar 

  115. Kalousek DK. (2000) Pathogenesis of chromosomal mosaicism and its effect on early human development. Am J Med Genet;91:39–45.

    Article  PubMed  CAS  Google Scholar 

  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. Vanneste E, Voet T, Le Caignec C, et al. (2009) Chromosome instability is common in human cleavage-stage embryos. Nature medicine;15:577–83.

    Article  PubMed  CAS  Google Scholar 

  118. Hassold TJ, Jacobs PA. (1984) Trisomy in man. Annu Rev Genet;18:69–97.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  136. Nilsson K, Ponten J. (1975) Classification and biological nature of established human hematopoietic cell lines. Int J Cancer;15:321–41.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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. 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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  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. 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.

    Article  PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

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.

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Authors and Affiliations

  1. Department of Immunology Genetics and Pathology, Uppsala University, Uppsala, Sweden

    Jan P. Dumanski

  2. Department of Biology and Pharmaceutical Botany, Medical University of Gdansk, Gdansk, Poland

    Arkadiusz Piotrowski

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  1. Jan P. Dumanski
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Correspondence to Jan P. Dumanski .

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  1. Dept. Immunology, Genetics & Pathology, Uppsala University, Dag Hammarskjölds väg 20, Uppsala, 751 85, Sweden

    Lars Feuk

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Dumanski, J.P., Piotrowski, A. (2012). Structural Genetic Variation in the Context of Somatic Mosaicism. In: Feuk, L. (eds) Genomic Structural Variants. Methods in Molecular Biology, vol 838. Springer, New York, NY. https://doi.org/10.1007/978-1-61779-507-7_12

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  • DOI: https://doi.org/10.1007/978-1-61779-507-7_12

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