1932

Abstract

Somatic mutations arise postzygotically, producing genetic differences between cells in an organism. Well established as a driver of cancer, somatic mutations also exist in nonneoplastic cells, including in the brain. Technological advances in nucleic acid sequencing have enabled recent breakthroughs that illuminate the roles of somatic mutations in aging and degenerative diseases of the brain. Somatic mutations accumulate during aging in human neurons, a process termed genosenium. A number of recent studies have examined somatic mutations in Alzheimer's disease (AD), primarily from the perspective of genes causing familial AD. We have also gained new information on genome-wide mutations, providing insights into the cellular events driving somatic mutation and cellular dysfunction. This review highlights recent concepts, methods, and findings in the progress to understand the role of brain somatic mutation in aging and AD.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-genom-121520-081242
2021-08-31
2024-03-28
Loading full text...

Full text loading...

/deliver/fulltext/genom/22/1/annurev-genom-121520-081242.html?itemId=/content/journals/10.1146/annurev-genom-121520-081242&mimeType=html&fmt=ahah

Literature Cited

  1. 1. 
    Alavi Naini SM, Soussi-Yanicostas N 2015. Tau hyperphosphorylation and oxidative stress, a critical vicious circle in neurodegenerative tauopathies?. Oxid. Med. Cell Longev. 2015.151979
    [Google Scholar]
  2. 2. 
    Alexandrov LB, Jones PH, Wedge DC, Sale JE, Campbell PJ et al. 2015. Clock-like mutational processes in human somatic cells. Nat. Genet. 47:1402–7
    [Google Scholar]
  3. 3. 
    Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S et al. 2013. Signatures of mutational processes in human cancer. Nature 500:415–21
    [Google Scholar]
  4. 4. 
    Alexandrov LB, Stratton MR. 2014. Mutational signatures: the patterns of somatic mutations hidden in cancer genomes. Curr. Opin. Genet. Dev. 24:52–60
    [Google Scholar]
  5. 5. 
    Arendt T, Brückner MK, Lösche A. 2015. Regional mosaic genomic heterogeneity in the elderly and in Alzheimer's disease as a correlate of neuronal vulnerability. Acta Neuropathol 130:501–10
    [Google Scholar]
  6. 6. 
    Arendt T, Brückner MK, Mosch B, Lösche A. 2010. Selective cell death of hyperploid neurons in Alzheimer's disease. Am. J. Pathol. 177:15–20
    [Google Scholar]
  7. 7. 
    Axelman K, Basun H, Winblad B, Lannfelt L. 1994. A large Swedish family with Alzheimer's disease with a codon 670/671 amyloid precursor protein mutation: a clinical and genealogical investigation. Arch. Neurol. 51:1193–97
    [Google Scholar]
  8. 8. 
    Bae T, Tomasini L, Mariani J, Zhou B, Roychowdhury T et al. 2018. Different mutational rates and mechanisms in human cells at pregastrulation and neurogenesis. Science 359:550–55
    [Google Scholar]
  9. 9. 
    Baldassari S, Ribierre T, Marsan E, Adle-Biassette H, Ferrand-Sorbets S et al. 2019. Dissecting the genetic basis of focal cortical dysplasia: a large cohort study. Acta Neuropathol 138:885–900
    [Google Scholar]
  10. 10. 
    Baulac S, Ishida S, Marsan E, Miquel C, Biraben A et al. 2015. Familial focal epilepsy with focal cortical dysplasia due to DEPDC5 mutations. Ann. Neurol. 77:675–83
    [Google Scholar]
  11. 11. 
    Beck JA, Poulter M, Campbell TA, Uphill JB, Adamson G et al. 2004. Somatic and germline mosaicism in sporadic early-onset Alzheimer's disease. Hum. Mol. Genet. 13:1219–24
    [Google Scholar]
  12. 12. 
    Blokzijl F, de Ligt J, Jager M, Sasselli V, Roerink S et al. 2016. Tissue-specific mutation accumulation in human adult stem cells during life. Nature 538:260–64
    [Google Scholar]
  13. 13. 
    Brandner S, Raeber A, Sailer A, Blättler T, Fischer M et al. 1996. Normal host prion protein (PrPC) is required for scrapie spread within the central nervous system. PNAS 93:13148–51
    [Google Scholar]
  14. 14. 
    Brettschneider J, Del Tredici K, Lee VM, Trojanowski JQ. 2015. Spreading of pathology in neurodegenerative diseases: a focus on human studies. Nat. Rev. Neurosci. 16:109–20
    [Google Scholar]
  15. 15. 
    Burns KH. 2020. Our conflict with transposable elements and its implications for human disease. Annu. Rev. Pathol. Mech. Dis. 15:51–70
    [Google Scholar]
  16. 16. 
    Bushman DM, Kaeser GE, Siddoway B, Westra JW, Rivera RR et al. 2015. Genomic mosaicism with increased amyloid precursor protein (APP) gene copy number in single neurons from sporadic Alzheimer's disease brains. eLife 4:e05116
    [Google Scholar]
  17. 17. 
    Butterfield DA, Castegna A, Lauderback CM, Drake J. 2002. Evidence that amyloid beta-peptide-induced lipid peroxidation and its sequelae in Alzheimer's disease brain contribute to neuronal death. Neurobiol. Aging 23:655–64
    [Google Scholar]
  18. 18. 
    Cai X, Evrony GD, Lehmann HS, Elhosary PC, Mehta BK et al. 2014. Single-cell, genome-wide sequencing identifies clonal somatic copy-number variation in the human brain. Cell Rep 8:1280–89
    [Google Scholar]
  19. 19. 
    Chappell L, Russell AJC, Voet T. 2018. Single-cell (multi)omics technologies. Annu. Rev. Genom. Hum. Genet. 19:15–41
    [Google Scholar]
  20. 20. 
    Chen C, Xing D, Tan L, Li H, Zhou G et al. 2017. Single-cell whole-genome analyses by Linear Amplification via Transposon Insertion (LIANTI). Science 356:189–94
    [Google Scholar]
  21. 21. 
    Chun H, Im H, Kang YJ, Kim Y, Shin JH et al. 2020. Severe reactive astrocytes precipitate pathological hallmarks of Alzheimer's disease via H2O2 production. Nat. Neurosci. 23:1555–66
    [Google Scholar]
  22. 22. 
    Collin M, Bigley V, McClain KL, Allen CE. 2015. Cell(s) of origin of Langerhans cell histiocytosis. Hematol. Oncol. Clin. N. Am. 29:825–38
    [Google Scholar]
  23. 23. 
    Cuyvers E, Sleegers K. 2016. Genetic variations underlying Alzheimer's disease: evidence from genome-wide association studies and beyond. Lancet Neurol 15:857–68
    [Google Scholar]
  24. 24. 
    David DC, Hauptmann S, Scherping I, Schuessel K, Keil U et al. 2005. Proteomic and functional analyses reveal a mitochondrial dysfunction in P301L tau transgenic mice. J. Biol. Chem. 280:23802–14
    [Google Scholar]
  25. 25. 
    de Calignon A, Polydoro M, Suárez-Calvet M, William C, Adamowicz DH et al. 2012. Propagation of tau pathology in a model of early Alzheimer's disease. Neuron 73:685–97
    [Google Scholar]
  26. 26. 
    D'Gama AM, Geng Y, Couto JA, Martin B, Boyle EA et al. 2015. Mammalian target of rapamycin pathway mutations cause hemimegalencephaly and focal cortical dysplasia. Ann. Neurol. 77:720–25
    [Google Scholar]
  27. 27. 
    D'Gama AM, Woodworth MB, Hossain AA, Bizzotto S, Hatem NE et al. 2017. Somatic mutations activating the mTOR pathway in dorsal telencephalic progenitors cause a continuum of cortical dysplasias. Cell Rep 21:3754–66
    [Google Scholar]
  28. 28. 
    Diamond EL, Durham BH, Haroche J, Yao Z, Ma J et al. 2016. Diverse and targetable kinase alterations drive histiocytic neoplasms. Cancer Discov. 6:154–65
    [Google Scholar]
  29. 29. 
    Dias-Santagata D, Fulga TA, Duttaroy A, Feany MB. 2007. Oxidative stress mediates tau-induced neurodegeneration in Drosophila. J. Clin. Investig. 117:236–45
    [Google Scholar]
  30. 30. 
    Doan RN, Miller MB, Kim SN, Rodin RE, Ganz J et al. 2021. MIPP-Seq: ultra-sensitive rapid detection and validation of low-frequency mosaic mutations. BMC Med. Genom. 14:47
    [Google Scholar]
  31. 31. 
    Dong X, Zhang L, Milholland B, Lee M, Maslov AY et al. 2017. Accurate identification of single-nucleotide variants in whole-genome-amplified single cells. Nat. Methods 14:491–93
    [Google Scholar]
  32. 32. 
    Dumanski JP, Lambert JC, Rasi C, Giedraitis V, Davies H et al. 2016. Mosaic loss of chromosome Y in blood is associated with Alzheimer disease. Am. J. Hum. Genet. 98:1208–19
    [Google Scholar]
  33. 33. 
    Enge M, Arda HE, Mignardi M, Beausang J, Bottino R et al. 2017. Single-cell analysis of human pancreas reveals transcriptional signatures of aging and somatic mutation patterns. Cell 171:321–30.e14
    [Google Scholar]
  34. 34. 
    Erwin JA, Paquola AC, Singer T, Gallina I, Novotny M et al. 2016. L1-associated genomic regions are deleted in somatic cells of the healthy human brain. Nat. Neurosci. 19:1583–91
    [Google Scholar]
  35. 35. 
    Evrony GD, Cai X, Lee E, Hills LB, Elhosary PC et al. 2012. Single-neuron sequencing analysis of L1 retrotransposition and somatic mutation in the human brain. Cell 151:483–96
    [Google Scholar]
  36. 36. 
    Franco I, Helgadottir HT, Moggio A, Larsson M, Vrtacnik P et al. 2019. Whole genome DNA sequencing provides an atlas of somatic mutagenesis in healthy human cells and identifies a tumor-prone cell type. Genome Biol. 20:285
    [Google Scholar]
  37. 37. 
    Franco I, Johansson A, Olsson K, Vrtacnik P, Lundin P et al. 2018. Somatic mutagenesis in satellite cells associates with human skeletal muscle aging. Nat. Commun. 9:800
    [Google Scholar]
  38. 38. 
    Frost B, Hemberg M, Lewis J, Feany MB. 2014. Tau promotes neurodegeneration through global chromatin relaxation. Nat. Neurosci. 17:357–66
    [Google Scholar]
  39. 39. 
    Gabbita SP, Lovell MA, Markesbery WR. 1998. Increased nuclear DNA oxidation in the brain in Alzheimer's disease. J. Neurochem. 71:2034–40
    [Google Scholar]
  40. 40. 
    García-Nieto PE, Morrison AJ, Fraser HB. 2019. The somatic mutation landscape of the human body. Genome Biol. 20:298
    [Google Scholar]
  41. 41. 
    Garraway LA, Lander ES. 2013. Lessons from the cancer genome. Cell 153:17–37
    [Google Scholar]
  42. 42. 
    Gate D, Saligrama N, Leventhal O, Yang AC, Unger MS et al. 2020. Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer's disease. Nature 577:399–404
    [Google Scholar]
  43. 43. 
    Geller LN, Potter H. 1999. Chromosome missegregation and trisomy 21 mosaicism in Alzheimer's disease. Neurobiol. Dis. 6:167–79
    [Google Scholar]
  44. 44. 
    Genovese G, Kahler AK, Handsaker RE, Lindberg J, Rose SA et al. 2014. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N. Engl. J. Med. 371:2477–87
    [Google Scholar]
  45. 45. 
    Gleeson JG, Minnerath S, Kuzniecky RI, Dobyns WB, Young ID et al. 2000. Somatic and germline mosaic mutations in the doublecortin gene are associated with variable phenotypes. Am. J. Hum. Genet. 67:574–81
    [Google Scholar]
  46. 46. 
    Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F et al. 1991. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature 349:704–6
    [Google Scholar]
  47. 47. 
    Guo C, Jeong HH, Hsieh YC, Klein HU, Bennett DA et al. 2018. Tau activates transposable elements in Alzheimer's disease. Cell Rep. 23:2874–80
    [Google Scholar]
  48. 48. 
    Hazen JL, Faust GG, Rodriguez AR, Ferguson WC, Shumilina S et al. 2016. The complete genome sequences, unique mutational spectra, and developmental potency of adult neurons revealed by cloning. Neuron 89:1223–36
    [Google Scholar]
  49. 49. 
    Head E, Lott IT, Wilcock DM, Lemere CA. 2016. Aging in Down syndrome and the development of Alzheimer's disease neuropathology. Curr. Alzheimer Res. 13:18–29
    [Google Scholar]
  50. 50. 
    Helgadottir HT, Lundin P, Wallén Arzt E, Lindström AK, Graff C, Eriksson M 2019. Somatic mutation that affects transcription factor binding upstream of CD55 in the temporal cortex of a late-onset Alzheimer disease patient. Hum. Mol. Genet. 28:2675–85
    [Google Scholar]
  51. 51. 
    Hoang ML, Kinde I, Tomasetti C, McMahon KW, Rosenquist TA et al. 2016. Genome-wide quantification of rare somatic mutations in normal human tissues using massively parallel sequencing. PNAS 113:9846–51
    [Google Scholar]
  52. 52. 
    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. Neurobiol. Dis. 34:212–20
    [Google Scholar]
  53. 53. 
    Ivashko-Pachima Y, Hadar A, Grigg I, Korenková V, Kapitansky O et al. 2021. Discovery of autism/intellectual disability somatic mutations in Alzheimer's brains: mutated ADNP cytoskeletal impairments and repair as a case study. Mol. Psychiatry 26:161933
    [Google Scholar]
  54. 54. 
    Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman PV et al. 2014. Age-related clonal hematopoiesis associated with adverse outcomes. N. Engl. J. Med. 371:2488–98
    [Google Scholar]
  55. 55. 
    Jamuar SS, Lam A-TN, Kircher M, D'Gama AM, Wang J et al. 2014. Somatic mutations in cerebral cortical malformations. N. Engl. J. Med. 371:733–43
    [Google Scholar]
  56. 56. 
    Jin M, Shepardson N, Yang T, Chen G, Walsh D, Selkoe DJ 2011. Soluble amyloid β-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration. PNAS 108:5819–24
    [Google Scholar]
  57. 57. 
    Karch CM, Goate AM. 2015. Alzheimer's disease risk genes and mechanisms of disease pathogenesis. Biol. Psychiatry 77:43–51
    [Google Scholar]
  58. 58. 
    Keogh MJ, Wei W, Aryaman J, Walker L, van den Ameele J et al. 2018. High prevalence of focal and multi-focal somatic genetic variants in the human brain. Nat. Commun. 9:4257
    [Google Scholar]
  59. 59. 
    Keogh MJ, Wei W, Wilson I, Coxhead J, Ryan S et al. 2017. Genetic compendium of 1511 human brains available through the UK Medical Research Council Brain Banks Network Resource. Genome Res. 27:165–73
    [Google Scholar]
  60. 60. 
    Kfoury N, Holmes BB, Jiang H, Holtzman DM, Diamond MI. 2012. Trans-cellular propagation of Tau aggregation by fibrillar species. J. Biol. Chem. 287:19440–51
    [Google Scholar]
  61. 61. 
    Khurana V, Merlo P, DuBoff B, Fulga TA, Sharp KA et al. 2012. A neuroprotective role for the DNA damage checkpoint in tauopathy. Aging Cell 11:360–62
    [Google Scholar]
  62. 62. 
    Kim J, Zhao B, Huang AY, Miller MB, Lodato MA et al. 2020. APP gene copy number changes reflect exogenous contamination. Nature 584:E20–28
    [Google Scholar]
  63. 63. 
    Knouse KA, Wu J, Whittaker CA, Amon A 2014. Single cell sequencing reveals low levels of aneuploidy across mammalian tissues. PNAS 111:13409–14
    [Google Scholar]
  64. 64. 
    Koh HY, Kim SH, Jang J, Kim H, Han S et al. 2018. BRAF somatic mutation contributes to intrinsic epileptogenicity in pediatric brain tumors. Nat. Med. 24:1662–68
    [Google Scholar]
  65. 65. 
    Kucab JE, Zou X, Morganella S, Joel M, Nanda AS et al. 2019. A compendium of mutational signatures of environmental agents. Cell 177:821–36.e16
    [Google Scholar]
  66. 66. 
    Lee JH, Huynh M, Silhavy JL, Kim S, Dixon-Salazar T et al. 2012. De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause hemimegalencephaly. Nat. Genet. 44:941–45
    [Google Scholar]
  67. 67. 
    Lee JH, Lee JE, Kahng JY, Kim SH, Park JS et al. 2018. Human glioblastoma arises from subventricular zone cells with low-level driver mutations. Nature 560:243–47
    [Google Scholar]
  68. 68. 
    Lee MH, Liu CS, Zhu Y, Kaeser GE, Rivera R et al. 2020. Reply to: APP gene copy number changes reflect exogenous contamination. Nature 584:E29–33
    [Google Scholar]
  69. 69. 
    Lee MH, Siddoway B, Kaeser GE, Segota I, Rivera R et al. 2018. Somatic APP gene recombination in Alzheimer's disease and normal neurons. Nature 563:639–45
    [Google Scholar]
  70. 70. 
    Lee-Six H, Olafsson S, Ellis P, Osborne RJ, Sanders MA et al. 2019. The landscape of somatic mutation in normal colorectal epithelial cells. Nature 574:532–37
    [Google Scholar]
  71. 71. 
    Leija-Salazar M, Pittman A, Mokretar K, Morris H, Schapira AH, Proukakis C. 2020. Investigation of somatic mutations in human brains targeting genes associated with Parkinson's disease. Front. Neurol 11:57042
    [Google Scholar]
  72. 72. 
    Levy-Lahad E, Wijsman EM, Nemens E, Anderson L, Goddard KA et al. 1995. A familial Alzheimer's disease locus on chromosome 1. Science 269:970–73
    [Google Scholar]
  73. 73. 
    Lodato MA, Rodin RE, Bohrson CL, Coulter ME, Barton AR et al. 2018. Aging and neurodegeneration are associated with increased mutations in single human neurons. Science 359:555–59
    [Google Scholar]
  74. 74. 
    Lodato MA, Walsh CA. 2019. Genome aging: somatic mutation in the brain links age-related decline with disease and nominates pathogenic mechanisms. Hum. Mol. Genet. 28:R197–206
    [Google Scholar]
  75. 75. 
    Lodato MA, Woodworth MB, Lee S, Evrony GD, Mehta BK et al. 2015. Somatic mutation in single human neurons tracks developmental and transcriptional history. Science 350:94–98
    [Google Scholar]
  76. 76. 
    Lyras L, Cairns NJ, Jenner A, Jenner P, Halliwell B. 1997. An assessment of oxidative damage to proteins, lipids, and DNA in brain from patients with Alzheimer's disease. J. Neurochem. 68:2061–69
    [Google Scholar]
  77. 77. 
    Martincorena I, Fowler JC, Wabik A, Lawson ARJ, Abascal F et al. 2018. Somatic mutant clones colonize the human esophagus with age. Science 362:911–17
    [Google Scholar]
  78. 78. 
    Martincorena I, Roshan A, Gerstung M, Ellis P, Van Loo P et al. 2015. Tumor evolution. High burden and pervasive positive selection of somatic mutations in normal human skin. Science 348:880–86
    [Google Scholar]
  79. 79. 
    Mass E, Jacome-Galarza CE, Blank T, Lazarov T, Durham BH et al. 2017. A somatic mutation in erythro-myeloid progenitors causes neurodegenerative disease. Nature 549:389–93
    [Google Scholar]
  80. 80. 
    Maynard S, Fang EF, Scheibye-Knudsen M, Croteau DL, Bohr VA. 2015. DNA damage, DNA repair, aging, and neurodegeneration. Cold Spring Harb. . Perspect. Med. 5:a025130
    [Google Scholar]
  81. 81. 
    McConnell MJ, Lindberg MR, Brennand KJ, Piper JC, Voet T et al. 2013. Mosaic copy number variation in human neurons. Science 342:632–37
    [Google Scholar]
  82. 82. 
    Mecocci P, MacGarvey U, Beal MF. 1994. Oxidative damage to mitochondrial DNA is increased in Alzheimer's disease. Ann. Neurol. 36:747–51
    [Google Scholar]
  83. 83. 
    Miller MB, Geoghegan JC, Supattapone S. 2011. Dissociation of infectivity from seeding ability in prions with alternate docking mechanism. PLOS Pathog 7:e1002128
    [Google Scholar]
  84. 84. 
    Miller MB, Wang DW, Wang F, Noble GP, Ma J et al. 2013. Cofactor molecules induce structural transformation during infectious prion formation. Structure 21:2061–68
    [Google Scholar]
  85. 85. 
    Muyas F, Zapata L, Guigó R, Ossowski S. 2020. The rate and spectrum of mosaic mutations during embryogenesis revealed by RNA sequencing of 49 tissues. Genome Med 12:49
    [Google Scholar]
  86. 86. 
    Nath S, Agholme L, Kurudenkandy FR, Granseth B, Marcusson J, Hallbeck M. 2012. Spreading of neurodegenerative pathology via neuron-to-neuron transmission of β-amyloid. J. Neurosci. 32:8767–77
    [Google Scholar]
  87. 87. 
    Nicolas G, Acuna-Hidalgo R, Keogh MJ, Quenez O, Steehouwer M et al. 2018. Somatic variants in autosomal dominant genes are a rare cause of sporadic Alzheimer's disease. Alzheimer's Dement. 14:1632–39
    [Google Scholar]
  88. 88. 
    Oakley H, Cole SL, Logan S, Maus E, Shao P et al. 2006. Intraneuronal β-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer's disease mutations: potential factors in amyloid plaque formation. J. Neurosci. 26:10129–40
    [Google Scholar]
  89. 89. 
    Ochoa Thomas E, Zuniga G, Sun W, Frost B 2020. Awakening the dark side: retrotransposon activation in neurodegenerative disorders. Curr. Opin. Neurobiol. 61:65–72
    [Google Scholar]
  90. 90. 
    Osorio FG, Rosendahl Huber A, Oka R, Verheul M, Patel SH et al. 2018. Somatic mutations reveal lineage relationships and age-related mutagenesis in human hematopoiesis. Cell Rep 25:2308–16.e4
    [Google Scholar]
  91. 91. 
    Pao PC, Patnaik D, Watson LA, Gao F, Pan L et al. 2020. HDAC1 modulates OGG1-initiated oxidative DNA damage repair in the aging brain and Alzheimer's disease. Nat. Commun. 11:2484
    [Google Scholar]
  92. 92. 
    Parcerisas A, Rubio SE, Muhaisen A, Gomez-Ramos A, Pujadas L et al. 2014. Somatic signature of brain-specific single nucleotide variations in sporadic Alzheimer's disease. J. Alzheimer's Dis. 42:1357–82
    [Google Scholar]
  93. 93. 
    Park JS, Lee J, Jung ES, Kim MH, Kim IB et al. 2019. Brain somatic mutations observed in Alzheimer's disease associated with aging and dysregulation of tau phosphorylation. Nat. Commun. 10:3090
    [Google Scholar]
  94. 94. 
    Pericak-Vance MA, Bebout JL, Gaskell PC Jr., Yamaoka LH, Hung WY et al. 1991. Linkage studies in familial Alzheimer disease: evidence for chromosome 19 linkage. Am. J. Hum. Genet. 48:1034–50
    [Google Scholar]
  95. 95. 
    Petti AA, Williams SR, Miller CA, Fiddes IT, Srivatsan SN et al. 2019. A general approach for detecting expressed mutations in AML cells using single cell RNA-sequencing. Nat. Commun. 10:3660
    [Google Scholar]
  96. 96. 
    Poduri A, Evrony GD, Cai X, Elhosary PC, Beroukhim R et al. 2012. Somatic activation of AKT3 causes hemispheric developmental brain malformations. Neuron 74:41–48
    [Google Scholar]
  97. 97. 
    Poduri A, Evrony GD, Cai X, Walsh CA. 2013. Somatic mutation, genomic variation, and neurological disease. Science 341:1237758
    [Google Scholar]
  98. 98. 
    Potter H. 1991. Review and hypothesis: Alzheimer disease and Down syndrome—chromosome 21 nondisjunction may underlie both disorders. Am. J. Hum. Genet. 48:1192–200
    [Google Scholar]
  99. 99. 
    Protasova MS, Gusev FE, Grigorenko AP, Kuznetsova IL, Rogaev EI, Andreeva TV. 2017. Quantitative analysis of L1-retrotransposons in Alzheimer's disease and aging. Biochemistry 82:962–71
    [Google Scholar]
  100. 100. 
    Proukakis C. 2020. Somatic mutations in neurodegeneration: an update. Neurobiol. Dis. 144:105021
    [Google Scholar]
  101. 101. 
    Proukakis C, Houlden H, Schapira AH. 2013. Somatic alpha-synuclein mutations in Parkinson's disease: hypothesis and preliminary data. Mov. Disord. 28:705–12
    [Google Scholar]
  102. 102. 
    Proukakis C, Shoaee M, Morris J, Brier T, Kara E et al. 2014. Analysis of Parkinson's disease brain-derived DNA for alpha-synuclein coding somatic mutations. Mov. Disord. 29:1060–64
    [Google Scholar]
  103. 103. 
    Rehen SK, Yung YC, McCreight MP, Kaushal D, Yang AH et al. 2005. Constitutional aneuploidy in the normal human brain. J. Neurosci. 25:2176–80
    [Google Scholar]
  104. 104. 
    Reznik-Wolf H, Machado J, Haroutunian V, DeMarco L, Walter GF et al. 1998. Somatic mutation analysis of the APP and Presenilin 1 and 2 genes in Alzheimer's disease brains. J. Neurogenet. 12:55–65
    [Google Scholar]
  105. 105. 
    Rivière JB, Mirzaa GM, O'Roak BJ, Beddaoui M, Alcantara D et al. 2012. De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes. Nat. Genet. 44:934–40
    [Google Scholar]
  106. 106. 
    Rogaev EI, Sherrington R, Rogaeva EA, Levesque G, Ikeda M et al. 1995. Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene. Nature 376:775–78
    [Google Scholar]
  107. 107. 
    Rowe IF, Ridler MAC, Gibberd FB. 1989. Presenile dementia associated with mosaic trisomy 21 in a patient with a Down syndrome child. Lancet 334:229
    [Google Scholar]
  108. 108. 
    Sala Frigerio C, Lau P, Troakes C, Deramecourt V, Gele P et al. 2015. On the identification of low allele frequency mosaic mutations in the brains of Alzheimer's disease patients. Alzheimer's Dement 11:1265–76
    [Google Scholar]
  109. 109. 
    Schellenberg GD, Bird TD, Wijsman EM, Orr HT, Anderson L et al. 1992. Genetic linkage evidence for a familial Alzheimer's disease locus on chromosome 14. Science 258:668–71
    [Google Scholar]
  110. 110. 
    Selkoe DJ, Hardy J. 2016. The amyloid hypothesis of Alzheimer's disease at 25 years. EMBO Mol. Med. 8:595–608
    [Google Scholar]
  111. 111. 
    Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G et al. 1995. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature 375:754–60
    [Google Scholar]
  112. 112. 
    St. George-Hyslop P, Haines J, Rogaev E, Mortilla M, Vaula G et al. 1992. Genetic evidence for a novel familial Alzheimer's disease locus on chromosome 14. Nat. Genet. 2:330–34
    [Google Scholar]
  113. 113. 
    Stratton MR, Campbell PJ, Futreal PA. 2009. The cancer genome. Nature 458:719–24
    [Google Scholar]
  114. 114. 
    Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J et al. 1993. Apolipoprotein E: high-avidity binding to β-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. PNAS 90:1977–81
    [Google Scholar]
  115. 115. 
    Su B, Wang X, Lee HG, Tabaton M, Perry G et al. 2010. Chronic oxidative stress causes increased tau phosphorylation in M17 neuroblastoma cells. Neurosci. Lett. 468:267–71
    [Google Scholar]
  116. 116. 
    Sun W, Samimi H, Gamez M, Zare H, Frost B. 2018. Pathogenic tau-induced piRNA depletion promotes neuronal death through transposable element dysregulation in neurodegenerative tauopathies. Nat. Neurosci. 21:1038–48
    [Google Scholar]
  117. 117. 
    Swaminathan S, Huentelman MJ, Corneveaux JJ, Myers AJ, Faber KM et al. 2012. Analysis of copy number variation in Alzheimer's disease in a cohort of clinically characterized and neuropathologically verified individuals. PLOS ONE 7:e50640
    [Google Scholar]
  118. 118. 
    Tanzi RE, Gusella JF, Watkins PC, Bruns GA, St. George-Hyslop P 1987. Amyloid beta protein gene: cDNA, mRNA distribution, and genetic linkage near the Alzheimer locus. Science 235:880–84
    [Google Scholar]
  119. 119. 
    Thomas P, Fenech M. 2008. Chromosome 17 and 21 aneuploidy in buccal cells is increased with ageing and in Alzheimer's disease. Mutagenesis 23:57–65
    [Google Scholar]
  120. 120. 
    Uchiyama Y, Nakashima M, Watanabe S, Miyajima M, Taguri M et al. 2016. Ultra-sensitive droplet digital PCR for detecting a low-prevalence somatic GNAQ mutation in Sturge-Weber syndrome. Sci. Rep. 6:22985
    [Google Scholar]
  121. 121. 
    Upton KR, Gerhardt DJ, Jesuadian JS, Richardson SR, Sánchez-Luque FJ et al. 2015. Ubiquitous L1 mosaicism in hippocampal neurons. Cell 161:228–39
    [Google Scholar]
  122. 122. 
    van den Bos H, Spierings DC, Taudt AS, Bakker B, Porubsky D et al. 2016. Single-cell whole genome sequencing reveals no evidence for common aneuploidy in normal and Alzheimer's disease neurons. Genome Biol 17:116
    [Google Scholar]
  123. 123. 
    Vijg J, Dong X. 2020. Pathogenic mechanisms of somatic mutation and genome mosaicism in aging. Cell 182:12–23
    [Google Scholar]
  124. 124. 
    Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA Jr., Kinzler KW. 2013. Cancer genome landscapes. Science 339:1546–58
    [Google Scholar]
  125. 125. 
    Wei W, Keogh MJ, Aryaman J, Golder Z, Kullar PJ et al. 2019. Frequency and signature of somatic variants in 1461 human brain exomes. Genet. Med. 21:904–12
    [Google Scholar]
  126. 126. 
    Wellcome Sanger Inst 2020. Mutational signatures (v3.1 - June 2020) Catalogue of Somatic Mutations in Cancer (COSMIC) https://cancer.sanger.ac.uk/cosmic/signatures
  127. 127. 
    Westra JW, Barral S, Chun J 2009. A reevaluation of tetraploidy in the Alzheimer's disease brain. Neurodegener. Dis. 6:221–29
    [Google Scholar]
  128. 128. 
    Wnorowski M, Prosch H, Prayer D, Janssen G, Gadner H, Grois N. 2008. Pattern and course of neurodegeneration in Langerhans cell histiocytosis. J. Pediatr. 153:127–32
    [Google Scholar]
  129. 129. 
    Yin Y, Jiang Y, Lam KG, Berletch JB, Disteche CM et al. 2019. High-throughput single-cell sequencing with linear amplification. Mol. Cell 76:676–90.e10
    [Google Scholar]
  130. 130. 
    Yurov YB, Iourov IY, Monakhov VV, Soloviev IV, Vostrikov VM, Vorsanova SG. 2005. The variation of aneuploidy frequency in the developing and adult human brain revealed by an interphase FISH study. J. Histochem. Cytochem. 53:385–90
    [Google Scholar]
  131. 131. 
    Yurov YB, Vorsanova SG, Liehr T, Kolotii AD, Iourov IY. 2014. X chromosome aneuploidy in the Alzheimer's disease brain. Mol. Cytogenet. 7:20
    [Google Scholar]
  132. 132. 
    Zhang L, Dong X, Lee M, Maslov AY, Wang T, Vijg J 2019. Single-cell whole-genome sequencing reveals the functional landscape of somatic mutations in B lymphocytes across the human lifespan. PNAS 116:9014–19
    [Google Scholar]
  133. 133. 
    Zhou B, Haney MS, Zhu X, Pattni R, Abyzov A, Urban AE. 2018. Detection and quantification of mosaic genomic DNA variation in primary somatic tissues using ddPCR: analysis of mosaic transposable-element insertions, copy-number variants, and single-nucleotide variants. Methods Mol. Biol. 1768:173–90
    [Google Scholar]
  134. 134. 
    Zong C, Lu S, Chapman AR, Xie XS. 2012. Genome-wide detection of single-nucleotide and copy-number variations of a single human cell. Science 338:1622–26
    [Google Scholar]
/content/journals/10.1146/annurev-genom-121520-081242
Loading
/content/journals/10.1146/annurev-genom-121520-081242
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error