Mosaicism in health and disease — clones picking up speed

  • Nature Reviews Genetics volume 18, pages 128142 (2017)
  • doi:10.1038/nrg.2016.145
  • Download Citation


Post-zygotic variation refers to genetic changes that arise in the soma of an individual and that are not usually inherited by the next generation. Although there is a paucity of research on such variation, emerging studies show that it is common: individuals are complex mosaics of genetically distinct cells, to such an extent that no two somatic cells are likely to have the exact same genome. Although most types of mutation can be involved in post-zygotic variation, structural genetic variants are likely to leave the largest genomic footprint. Somatic variation has diverse physiological roles and pathological consequences, particularly when acquired variants influence the clonal trajectories of the affected cells. Post-zygotic variation is an important confounder in medical genetic testing and a promising avenue for research: future studies could involve analyses of sorted and single cells from multiple tissue types to fully explore its potential.

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  1. 1.

    Clinical significance of chimerism. Am. J. Med. Genet. C Semin. Med. Genet. 151C, 148–151 (2009).

  2. 2.

    & De novo mutations in human genetic disease. Nat. Rev. Genet. 13, 565–575 (2012).

  3. 3.

    et al. Timing, rates and spectra of human germline mutation. Nat. Genet. 48, 126–133 (2016).

  4. 4.

    et al. Post-zygotic point mutations are an underrecognized source of de novo genomic variation. Am. J. Hum. Genet. 97, 67–74 (2015).

  5. 5.

    & in Genomic Structural Variants: Methods and Protocols (ed. Feuk, L.) 249–272 (Humana Press, 2012).

  6. 6.

    Somatic evolutionary genomics: mutations during development cause highly variable genetic mosaicism with risk of cancer and neurodegeneration. Proc. Natl Acad. Sci. USA 107 (Suppl. 1), 1725–1730 (2010). This is a pioneering theoretical paper predicting a high level of somatic mosaicism in humans and its consequences for cancer in the ageing population.

  7. 7.

    Rate, molecular spectrum, and consequences of human mutation. Proc. Natl Acad. Sci. USA 107, 961–968 (2010).

  8. 8.

    Evolution of the mutation rate. Trends Genet. 26, 345–352 (2010).

  9. 9.

    , & Non-heritable genetics of human disease: spotlight on post-zygotic genetic variation acquired during lifetime. J. Med. Genet. 50, 1–10 (2013).

  10. 10.

    et al. An estimation of the number of cells in the human body. Ann. Hum. Biol. 40, 463–471 (2013).

  11. 11.

    et al. Variation in genome-wide mutation rates within and between human families. Nat. Genet. 43, 712–714 (2011). This whole-genome sequencing study of two parent–offspring trios provides one of the first indications that somatic variation is far more common than germline variation at the fine-scale DNA sequence level.

  12. 12.

    et al. Rate of de novo mutations and the importance of father's age to disease risk. Nature 488, 471–475 (2012).

  13. 13.

    et al. De novo rates and selection of large copy number variation. Genome Res. 20, 1469–1481 (2010).

  14. 14.

    et al. Characteristics of de novo structural changes in the human genome. Genome Res. 25, 792–801 (2015).

  15. 15.

    & Human Molecular Genetics 3 (Garland Publishing, 2004).

  16. 16.

    et al. Telomere instability in the male germline. Hum. Mol. Genet. 15, 45–51 (2006).

  17. 17.

    & Fetal microchimerism in women with breast cancer. Cancer Res. 67, 9035–9038 (2007).

  18. 18.

    , , , & Case–control study of fetal microchimerism and breast cancer. PLoS ONE 3, e1706 (2008).

  19. 19.

    , , & Fetal microchimerism and maternal health: a review and evolutionary analysis of cooperation and conflict beyond the womb. Bioessays 37, 1106–1118 (2015).

  20. 20.

    et al. Microchimerism of male origin in a cohort of Danish girls. Chimerism (2016).

  21. 21.

    et al. Chromosome instability is common in human cleavage-stage embryos. Nat. Med. 15, 577–583 (2009). This study is the first to show that human embryos exhibit a surprisingly high frequency of structural genetic variation.

  22. 22.

    et al. Multiplicative mononuclear small hepatocytes in adult rat liver: their isolation as a homogeneous population and localization to periportal zone. Biochem. Biophys. Res. Commun. 342, 1160–1167 (2006).

  23. 23.

    et al. Hepatocyte ploidy in regenerating livers after partial hepatectomy, drug-induced necrosis, and cirrhosis. Eur. Surg. Res. 35, 148–160 (2003).

  24. 24.

    et al. The fetal thymus has a unique genomic copy number profile resulting from physiological T cell receptor gene rearrangement. Sci. Rep. 6, 23500 (2016).

  25. 25.

    Aneuploidy, polyploidy and ploidy reversal in the liver. Semin. Cell Dev. Biol. 24, 347–356 (2013).

  26. 26.

    , , & The repopulation potential of hepatocyte populations differing in size and prior mitotic expansion. Am. J. Pathol. 155, 2135–2143 (1999).

  27. 27.

    , & Hepatocyte transplantation into diseased mouse liver: kinetics of parenchymal repopulation and identification of the proliferative capacity of tetraploid and octaploid hepatocytes. Am. J. Pathol. 157, 1963–1974 (2000).

  28. 28.

    et al. Frequent aneuploidy among normal human hepatocytes. Gastroenterology 142, 25–28 (2012).

  29. 29.

    , , & Single cell sequencing reveals low levels of aneuploidy across mammalian tissues. Proc. Natl Acad. Sci. USA 111, 13409–13414 (2014). This paper estimates the rate of whole-chromosome-number variation in human tissues using single-cell sequencing.

  30. 30.

    et al. Somatic mutation in single human neurons tracks developmental and transcriptional history. Science 350, 94–98 (2015).

  31. 31.

    et al. Mosaic copy number variation in human neurons. Science 342, 632–637 (2013).

  32. 32.

    et al. Somatic retrotransposition alters the genetic landscape of the human brain. Nature 479, 534–537 (2011). The authors show that retrotransposons cause genetic mosaicism and affect gene expression in the brain.

  33. 33.

    et al. Single-neuron sequencing analysis of L1 retrotransposition and somatic mutation in the human brain. Cell 151, 483–496 (2012).

  34. 34.

    Genome mosaicism — one human, multiple genomes. Science 341, 358–359 (2013).

  35. 35.

    et al. Long neural genes harbor recurrent DNA break clusters in neural stem/progenitor cells. Cell 164, 644–655 (2016).

  36. 36.

    et al. The origin, mechanisms, incidence and clinical consequences of chromosomal mosaicism in humans. Hum. Reprod. Update 20, 571–581 (2014).

  37. 37.

    et al. Somatic mosaicism for copy-neutral loss of heterozygosity and DNA copy number variations in the human genome. BMC Genomics 16, 703 (2015).

  38. 38.

    , , , & Extensive genetic variation in somatic human tissues. Proc. Natl Acad. Sci. USA 109, 18018–18023 (2012).

  39. 39.

    et al. Somatic mosaicism for copy number variation in differentiated human tissues. Hum. Mutat. 29, 1118–1124 (2008). This is one of the first papers substantiating that human organs may differ substantially in their genetic composition by means of structural variation.

  40. 40.

    et al. Somatic mutations found in the healthy blood compartment of a 115-yr-old woman demonstrate oligoclonal hematopoiesis. Genome Res. 24, 733–742 (2014).

  41. 41.

    et al. Age-related somatic structural changes in the nuclear genome of human blood cells. Am. J. Hum. Genet. 90, 217–228 (2012).

  42. 42.

    et al. Detectable clonal mosaicism and its relationship to aging and cancer. Nat. Genet. 44, 651–658 (2012).

  43. 43.

    et al. Detectable clonal mosaicism from birth to old age and its relationship to cancer. Nat. Genet. 44, 642–650 (2012). References 41–43 together show how somatic mosaicism in the form of structural variation becomes more common with age and how it correlates with morbidity from cancer.

  44. 44.

    et al. Mosaic loss of chromosome Y in peripheral blood is associated with shorter survival and higher risk of cancer. Nat. Genet. 46, 624–628 (2014). This paper shows that the specific role of mosaic LOY is coupled to cancer risk and shortened lifespan in men.

  45. 45.

    et al. Smoking is associated with mosaic loss of chromosome Y. Science 347, 81–83 (2015). This paper shows evidence that mosaic LOY is associated with smoking.

  46. 46.

    et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N. Engl. J. Med. 371, 2477–2487 (2014).

  47. 47.

    et al. Age-related clonal hematopoiesis associated with adverse outcomes. N. Engl. J. Med. 371, 2488–2498 (2014). References 46 and 47 show that somatic variation at the DNA sequence level is linked to neoplasia.

  48. 48.

    et al. Detection of leukemia-associated mutations in peripheral blood DNA of hematologically normal elderly individuals. Leukemia 29, 1600–1602 (2015).

  49. 49.

    et al. Profound parental bias associated with chromosome 14 acquired uniparental disomy indicates targeting of an imprinted locus. Leukemia 29, 2069–2074 (2015).

  50. 50.

    et al. Characterization of large structural genetic mosaicism in human autosomes. Am. J. Hum. Genet. 96, 487–497 (2015).

  51. 51.

    & Extensive hidden genomic mosaicism revealed in normal tissue. Am. J. Hum. Genet. 98, 571–578 (2016).

  52. 52.

    et al. Female chromosome X mosaicism is age-related and preferentially affects the inactivated X chromosome. Nat. Commun. 7, 11843 (2016).

  53. 53.

    et al. Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat. Med. 20, 1472–1478 (2014).

  54. 54.

    , , & The role of mutations in epigenetic regulators in myeloid malignancies. Nat. Rev. Cancer 12, 599–612 (2012).

  55. 55.

    et al. Association between large detectable clonal mosaicism and type 2 diabetes with vascular complications. Nat. Genet. 45, 1040–1043 (2013).

  56. 56.

    et al. Mosaic loss of chromosome Y in blood is associated with Alzheimer disease. Am. J. Hum. Genet. 98, 1208–1219 (2016).

  57. 57.

    et al. High burden and pervasive positive selection of somatic mutations in normal human skin. Science 348, 880–886 (2015). In this paper, the staggering amount of somatic variation in human skin tissue is characterized in depth and is shown to involve pathways related to skin cancer.

  58. 58.

    et al. Analysis of the genetic phylogeny of multifocal prostate cancer identifies multiple independent clonal expansions in neoplastic and morphologically normal prostate tissue. Nat. Genet. 47, 367–372 (2015).

  59. 59.

    et al. Signatures of post-zygotic structural genetic aberrations in the cells of histologically normal breast tissue that can predispose to sporadic breast cancer. Genome Res. 25, 1521–1535 (2015).

  60. 60.

    et al. Concurrent DNA copy-number alterations and mutations in genes related to maintenance of genome stability in uninvolved mammary glandular tissue from breast cancer patients. Hum. Mutat. 36, 1088–1099 (2015).

  61. 61.

    et al. Chromosome translocations and covert leukemic clones are generated during normal fetal development. Proc. Natl Acad. Sci. USA 99, 8242–8247 (2002).

  62. 62.

    et al. Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis. Nat. Genet. 44, 1179–1181 (2012).

  63. 63.

    & Age-related changes in lymphocyte development and function. Nat. Immunol. 5, 133–139 (2004).

  64. 64.

    et al. The influence of age on T cell generation and TCR diversity. J. Immunol. 174, 7446–7452 (2005).

  65. 65.

    et al. B-cell diversity decreases in old age and is correlated with poor health status. Aging Cell 8, 18–25 (2009).

  66. 66.

    et al. Human bone marrow hematopoietic stem cells are increased in frequency and myeloid-biased with age. Proc. Natl Acad. Sci. USA 108, 20012–20017 (2011).

  67. 67.

    , , , & Change of human chromosome count distribution with age: evidence for a sex differences. Nature 197, 1080–1081 (1963).

  68. 68.

    & Age-associated aneuploidy: loss of Y chromosome from human bone marrow cells with aging. Cancer 30, 889–894 (1972).

  69. 69.

    et al. Mosaic loss of chromosome Y is associated with common variation near TCL1A. Nat. Genet. 48, 563–568 (2016).

  70. 70.

    , , & Molecular genetic evidence of Y chromosome loss in male patients with hematological disorders. Chin. Med. J. (Engl.) 120, 2002–2005 (2007).

  71. 71.

    Y chromosome structural and functional changes in human malignant diseases. Mutat. Res. 682, 21–27 (2009).

  72. 72.

    , , , & Loss of Y-chromosome does not correlate with age at onset of head and neck carcinoma: a case–control study. Braz. J. Med. Biol. Res. 45, 172–178 (2012).

  73. 73.

    , & Cancer cells preferentially lose small chromosomes. Int. J. Cancer 132, 2316–2326 (2013).

  74. 74.

    et al. The frequency of aneuploidy in cultured lymphocytes is correlated with age and gender but not with reproductive history. Am. J. Hum. Genet. 46, 1101–1111 (1990).

  75. 75.

    [No authors listed.] Loss of the Y chromosome from normal and neoplastic bone marrows. United Kingdom Cancer Cytogenetics Group (UKCCG). Genes Chromosomes Cancer 5, 83–88 (1992).

  76. 76.

    et al. Clinical significance of Y chromosome loss in hematologic disease. Genes Chromosomes Cancer 27, 11–16 (2000).

  77. 77.

    et al. Loss of the Y chromosome: an age-related or clonal phenomenon in acute myelogenous leukemia/myelodysplastic syndrome? Arch. Pathol. Lab. Med. 132, 1329–1332 (2008).

  78. 78.

    , , , & The significance of isolated Y chromosome loss in bone marrow metaphase cells from males over age 50 years. Leuk. Res. 35, 1297–1300 (2011).

  79. 79.

    et al. Male breast cancer, age and sex chromosome aneuploidy. Br. J. Cancer 108, 959–963 (2013).

  80. 80.

    et al. Loss of Y chromosome in peripheral blood of colorectal and prostate cancer patients. PLoS ONE 11, e0146264 (2016).

  81. 81.

    et al. New data shed light on Y-loss-related pathogenesis in myelodysplastic syndromes. Genes Chromosomes Cancer 54, 717–724 (2015).

  82. 82.

    et al. Increased loss of the Y chromosome in peripheral blood cells in male patients with autoimmune thyroiditis. J. Autoimmun. 38, J193–J196 (2012).

  83. 83.

    et al. Y chromosome loss in male patients with primary biliary cirrhosis. J. Autoimmun. 41, 87–91 (2013).

  84. 84.

    Why men die younger. N. Am. Actuar. J. 4, 83–111 (2000).

  85. 85.

    Central Intelligence Agency. The World Factbook 2013–2014 (Central Intelligence Agency, 2013).

  86. 86.

    et al. Single-cell, genome-wide sequencing identifies clonal somatic copy-number variation in the human brain. Cell Rep. 8, 1280–1289 (2014).

  87. 87.

    et al. Cell lineage analysis in human brain using endogenous retroelements. Neuron 85, 49–59 (2015).

  88. 88.

    et al. Somatic copy number mosaicism in human skin revealed by induced pluripotent stem cells. Nature 492, 438–442 (2012).

  89. 89.

    , & Single-cell genome sequencing: current state of the science. Nat. Rev. Genet. 17, 175–188 (2016).

  90. 90.

    et al. Genetic variants regulating immune cell levels in health and disease. Cell 155, 242–256 (2013).

  91. 91.

    , & Single-cell sequencing-based technologies will revolutionize whole-organism science. Nat. Rev. Genet. 14, 618–630 (2013).

  92. 92.

    et al. Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq. Science 352, 189–196 (2016).

  93. 93.

    et al. Mitotic recombination in patients with ichthyosis causes reversion of dominant mutations in KRT10. Science 330, 94–97 (2010).

  94. 94.

    , , & Revertant mosaicism in junctional epidermolysis bullosa due to multiple correcting second-site mutations in LAMB3. J. Clin. Invest. 117, 1240–1248 (2007).

  95. 95.

    et al. Spontaneous in vivo reversion to normal of an inherited mutation in a patient with adenosine deaminase deficiency. Nat. Genet. 13, 290–295 (1996).

  96. 96.

    , & Disappearing mosaicism. Suggested mechanism is growth advantage of normal over abnormal cell population. R. I. Med. J. 50, 184–189 (1967).

  97. 97.

    Cell selection in vivo in normal-G trisomic mosaics. Nature 219, 1028–1030 (1968).

  98. 98.

    Non-homologous pairing and crossing over in Drosophila melanogaster. Genetics 44, 1243–1256 (1959).

  99. 99.

    Revertant mosaicism in human genetic disorders. Am. J. Med. Genet. 85, 361–364 (1999).

  100. 100.

    et al. Revertant mutation releases confined lethal mutation, opening Pandora's box: a novel genetic pathogenesis. PLoS Genet. 10, e1004276 (2014).

  101. 101.

    et al. Chromothriptic cure of WHIM syndrome. Cell 160, 686–699 (2015).

  102. 102.

    et al. Unique features of the transcriptional response to model aneuploidy in human cells. BMC Genomics 15, 139 (2014).

  103. 103.

    et al. Aneuploidy affects proliferation and spontaneous immortalization in mammalian cells. Science 322, 703–709 (2008). This paper serves as a model of how aneuploid cells can be gradually removed from somatic tissues through lower fitness.

  104. 104.

    et al. FISH analysis on day 5 post-insemination of human arrested and blastocyst stage embryos. Prenat. Diagn. 20, 552–560 (2000).

  105. 105.

    et al. Chromosomal mosaicism in human preimplantation embryos: a systematic review. Hum. Reprod. Update 17, 620–627 (2011).

  106. 106.

    , , & Morphological and cytogenetic assessment of cleavage and blastocyst stage embryos. Mol. Hum. Reprod. 20, 117–126 (2014).

  107. 107.

    , , & Mosaic autosomal trisomy in cultures from spontaneous abortions. Am. J. Hum. Genet. 30, 609–617 (1978).

  108. 108.

    , & Spontaneous abortion and confined chromosomal mosaicism. Hum. Genet. 88, 642–646 (1992).

  109. 109.

    et al. Meiotic origin of trisomy in confined placental mosaicism is correlated with presence of fetal uniparental disomy, high levels of trisomy in trophoblast, and increased risk of fetal intrauterine growth restriction. Am. J. Hum. Genet. 60, 917–927 (1997).

  110. 110.

    et al. Confined placental mosaicism at chorionic villous sampling: risk factors and pregnancy outcome. Prenat. Diagn. 32, 1102–1108 (2012).

  111. 111.

    et al. Prenatal diagnosis of chromosomal mosaicism in over 1600 cases using array comparative genomic hybridization as a first line test. Prenat. Diagn. 34, 478–486 (2014).

  112. 112.

    & The distribution of chromosomal genotypes associated with Turner's syndrome: livebirth prevalence rates and evidence for diminished fetal mortality and severity in genotypes associated with structural X abnormalities or mosaicism. Hum. Genet. 64, 24–27 (1983).

  113. 113.

    et al. Parental origin of normal X chromosomes in Turner syndrome patients with various karyotypes: implications for the mechanism leading to generation of a 45,X karyotype. Am. J. Med. Genet. 111, 134–139 (2002).

  114. 114.

    & Turner syndrome revisited: review of new data supports the hypothesis that all viable 45,X cases are cryptic mosaics with a rescue cell line, implying an origin by mitotic loss. Hum. Genet. 133, 417–424 (2014). This paper summarizes data indicating that pure Turner syndrome 45,X is embryologically lethal.

  115. 115.

    et al. Cancer incidence in women with Turner syndrome in Great Britain: a national cohort study. Lancet Oncol. 9, 239–246 (2008).

  116. 116.

    et al. Buccal cell FISH and blood PCR-Y detect high rates of X chromosomal mosaicism and Y chromosomal derivatives in patients with Turner syndrome. Eur. J. Med. Genet. 56, 497–501 (2013).

  117. 117.

    et al. Y-chromosome markers in Turner syndrome: screening of 130 patients. J. Endocrinol. Invest. 33, 222–227 (2010).

  118. 118.

    , , , & The proportion of diploid 46,XX cells increases with time in women with Turner syndrome — a 10-year follow-up study. Genet. Test. Mol. Biomarkers 19, 82–87 (2015).

  119. 119.

    , , , & A sex-chromosome anomaly in a case of gonadal dysgenesis (Turner's syndrome). Lancet 1, 711–713 (1959).

  120. 120.

    & Classification and biological nature of established human hematopoietic cell lines. Int. J. Cancer 15, 321–341 (1975).

  121. 121.

    et al. Growth of diploid, Epstein–Barr virus-carrying human lymphoblastoid cell lines heterotransplanted into nude mice under immunologically privileged conditions. Int. J. Cancer 24, 103–113 (1979).

  122. 122.

    et al. Whole-exome sequencing of DNA from peripheral blood mononuclear cells (PBMC) and EBV-transformed lymphocytes from the same donor. BMC Genomics 12, 464 (2011).

  123. 123.

    , , , & Trisomy 7 in nonneoplastic cells. Genes Chromosomes Cancer 6, 199–205 (1993).

  124. 124.

    et al. Cross-generational reproductive fitness enforced by microchimeric maternal cells. Cell 162, 505–515 (2015).

  125. 125.

    & Multi-lineage potential of fetal cells in maternal tissue: a legacy in reverse. J. Cell Sci. 118, 1559–1563 (2005).

  126. 126.

    et al. Distant mesenchymal progenitors contribute to skin wound healing and produce collagen: evidence from a murine fetal microchimerism model. PLoS ONE 8, e62662 (2013).

  127. 127.

    , & Fetal microchimerism as an explanation of disease. Nat. Rev. Endocrinol. 7, 89–97 (2011).

  128. 128.

    , & Identification of fetal DNA and cells in skin lesions from women with systemic sclerosis. N. Engl. J. Med. 338, 1186–1191 (1998).

  129. 129.

    , , , & Chimerism in monochorionic dizygotic twins: case study and review. Am. J. Med. Genet. A 161A, 1817–1824 (2013).

  130. 130.

    et al. Transplanted bone marrow generates new neurons in human brains. Proc. Natl Acad. Sci. USA 100, 1364–1369 (2003).

  131. 131.

    et al. Phenotypically concordant and discordant monozygotic twins display different DNA copy-number-variation profiles. Am. J. Hum. Genet. 82, 763–771 (2008).

  132. 132.

    Mosaics and chimaeras. Br. Med. Bull. 25, 104–109 (1969).

  133. 133.

    et al. Mechanisms of mosaicism, chimerism and uniparental disomy identified by SNP array analysis. Hum. Mol. Genet. 19, 1263–1275 (2010).

  134. 134.

    et al. 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 (2010).

  135. 135.

    , , , & Screening newborn blood spots for 22q11.2 deletion syndrome using multiplex droplet digital PCR. Clin. Chem. 61, 182–190 (2015).

  136. 136.

    Somatic mosaicism in healthy human tissues. Trends Genet. 27, 217–223 (2011).

  137. 137.

    & Variation in cancer risk among tissues can be explained by the number of stem cell divisions. Science 347, 78–81 (2015).

  138. 138.

    et al. L1 retrotransposition can occur early in human embryonic development. Hum. Mol. Genet. 16, 1587–1592 (2007).

  139. 139.

    et al. L1 retrotransposition in human neural progenitor cells. Nature 460, 1127–1131 (2009).

  140. 140.

    et al. Epigenetic control of retrotransposon expression in human embryonic stem cells. Mol. Cell. Biol. 31, 300–316 (2011).

  141. 141.

    et al. The evidence for increased L1 activity in the site of human adult brain neurogenesis. PLoS ONE 10, e0117854 (2015).

  142. 142.

    et al. DNA instability in postmitotic neurons. Proc. Natl Acad. Sci. USA 105, 3467–3472 (2008).

  143. 143.

    et al. Post-zygotic and inter-individual structural genetic variation in a presumptive enhancer element of the locus between the IL10R β and IFNAR1 genes. PLoS ONE 8, e67752 (2013).

  144. 144.

    , , , & Nonhomologous DNA end joining (NHEJ) and chromosomal translocations in humans. Subcell. Biochem. 50, 279–296 (2010).

  145. 145.

    , , & Mechanisms of change in gene copy number. Nat. Rev. Genet. 10, 551–564 (2009).

  146. 146.

    et al. Generation of trisomies in cancer cells by multipolar mitosis and incomplete cytokinesis. Proc. Natl Acad. Sci. USA 107, 20489–20493 (2010).

  147. 147.

    et al. Twenty-four chromosome FISH in human IVF embryos reveals patterns of post-zygotic chromosome segregation and nuclear organisation. Chromosome Res. 20, 447–460 (2012).

  148. 148.

    et al. Telomere dysfunction triggers extensive DNA fragmentation and evolution of complex chromosome abnormalities in human malignant tumors. Proc. Natl Acad. Sci. USA 98, 12683–12688 (2001).

  149. 149.

    et al. Constitutional aneuploidy and cancer predisposition caused by biallelic mutations in BUB1B. Nat. Genet. 36, 1159–1161 (2004).

  150. 150.

    , , & Merotelic kinetochore orientation versus chromosome mono-orientation in the origin of lagging chromosomes in human primary cells. J. Cell Sci. 115, 507–515 (2002).

  151. 151.

    , , , & Human chromosomes with shorter telomeres and large heterochromatin regions have a higher frequency of acquired somatic cell aneuploidy. Mech. Ageing Dev. 125, 563–573 (2004).

  152. 152.

    et al. The origin and evolution of mutations in acute myeloid leukemia. Cell 150, 264–278 (2012).

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The authors thank L. Feuk and C. Rasi for critical evaluation of the manuscript. The study was sponsored by funding from the Olle Enqvist Byggmästare Foundation and Young Investigator Award from the European Research Council to L.A.F. and by the Swedish Cancer Society, the Swedish Research Council, the Swedish Heart-Lung Foundation, Torsten Söderberg's Foundation and Sci-Life-Lab-Uppsala and Uppsala University to J.P.D. D.G. is supported by grants from the Swedish Research Council, the Swedish Cancer Society, the Swedish Childhood Cancer Society, the Gunnar Nilsson Cancer Foundation, the Crafoord Foundation and the Strategic Cancer Research Program BioCARE.

Author information


  1. Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala SE-75108, Sweden.

    • Lars A. Forsberg
    •  & Jan P. Dumanski
  2. Science for Life Laboratory, Uppsala University, Uppsala SE-75108, Sweden.

    • Lars A. Forsberg
    •  & Jan P. Dumanski
  3. Departments of Clinical Genetics and Oncology-Pathology, Skåne Regional and University Laboratories, Lund University, Lund SE-22184, Sweden.

    • David Gisselsson


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Competing interests

Grants or support for research (J.P.D., D.G. and L.A.F.). Owning stock in or directorship of companies (J.P.D. and L.A.F.). Patents — holders and applicants (J.P.D. and L.A.F.). J.P.D. and L.A.F. are co-founders and shareholders in Cray Innovation AB.

Corresponding authors

Correspondence to Lars A. Forsberg or David Gisselsson or Jan P. Dumanski.



The community of cells outside the germ line that makes up a multicellular organism. Because monozygotic twins are derived from the same zygote, they can be regarded as a single soma from a genetic point of view.


A diploid cell resulting from the fusion of two haploid germ cells. Most multicellular organisms are derived from a single founder zygote. Organisms that are made of cells from more than one zygote are chimaeras. Distinct individuals derived from the same zygote are monozygotic twins.


The persistent presence in an individual of a small number of cells stemming from another person; for instance, cells originating from a mother in the soma of a child, and vice versa.

Bulk DNA

DNA isolated from a tissue sample that contains a mixture of different cell types and usually a very large number (many thousands or millions) of cells.

Post-zygotic variation

The presence of a genotypic variant in some but not all cells of an individual that are derived from the same zygote. It occurs through post-zygotic mutations (mosaicism) during or after the first mitotic division of the zygote. If mosaicism is confined to non-germ cells (somatic mosaicism), it represents variation that ceases to exist with the death of the host. If the variant is present in lineages that form germ cells (gonadal mosaicism), the variant can be inherited by the next generation.


This very rare phenomenon is synonymous with classical chimerism and refers to the blending of cellular lineages from different zygotes during early embryogenesis of a single individual.

De novo variation

A broad and sometimes not well-defined term, usually referring to a change in DNA that emerges in a family tree for the first time. In typical usage, it comprises germline-transmissible genetic variants caused by a mutation in gonadal cell lineages of the parent, or in the zygote before the first cell division.

Gonadal mosaicism

Genetic variation emerging in cells that develop into gonads (ovaries and testicles), leading to variation in a pool of different germ cells of an individual; it is one cause of de novo variation in the next generation. Gonadal mosaicism is closely related to gonosomal mosaicism, which refers to mosaic variants that are present in both somatic and germline lineages.

Mitochondrial heteroplasmy

The presence of more than one mitochondrial genome in a cell or individual.

Structural variants

Chromosomal changes affecting regions of at least 1 kb. Structural variation can include balanced alterations (in which copy number remains unchanged), such as translocations, inversions or copy-number-neutral loss-of-heterozygosity (CNNLOH; also called uniparental isodisomy). In addition, structural variation includes unbalanced changes, such as deletions and duplications, which are collectively referred to as copy-number variants (CNVs).


An increase in chromosome number in steps of one or several complete haploid sets. Normal human germ cells are haploid (23 chromosomes), whereas somatic cells are diploid (46 chromosomes). Examples of human polyploidy are triploidy (69 chromosomes) and tetraploidy (92 chromosomes).


Any change in chromosome number that does not occur in steps of one or several complete haploid sets.


The situation when one kinetochore of a chromosome is attached to microtubules emanating from two spindle poles.

Mitotic checkpoint slippage

When a cell exits mitosis even if its chromosomes are not properly oriented and the spindle assembly control machinery is still active.

Cryptic mosaicism

Mosaicism occurring at a level so low that it will not be detected by genetic screening of bulk DNA by current routine methods. Because the sensitivity of screening techniques is ever increasing, the level below which variation is considered cryptic versus detectable must remain flexible and depends on the methodological context.

Aberrant clonal expansions

(ACEs). Clones of non-cancerous cells (which can occur in any tissue) harbouring acquired post-zygotic mutations or chromosomal aberrations that provide the affected cells with a mild proliferative advantage, relative to unaffected cells. This phenomenon is also referred to as 'detectable clonal mosaicism' or 'clonal haematopoiesis'.


The part of the genome that is transcribed and retained in the mature RNA after splicing: that is, the exons. The exome constitutes about 1% of the human genome and includes all DNA sequences that are transcribed into mature RNA in all cells in the soma, in contrast to the transcriptome, which is the RNA transcribed in a specific cell type.


The first individual to be investigated in the genetic study of a family.

Uniparental disomy

When two copies of a chromosome or chromosomal region in a diploid genome come from the same parent, instead of one copy originating from the mother and the other from the father. When the disomy consists of two different homologues from the same parent, it is referred to as uniparental heterodisomy. When it consists of a duplicate of a single copy, it is called uniparental isodisomy.

Turner syndrome

A physical condition of a female lacking one sex chromosome or parts of a sex chromosome, most often having the blood karyotype 45,X.