Skip to main content

Advertisement

SpringerLink
Log in

Investigating somatic aneuploidy in the brain: why we need a new model

  • Review
  • Published:
Chromosoma Aims and scope Submit manuscript

Abstract

The steady occurrence of DNA mutations is a key source for evolution, generating the genomic variation in the population upon which natural selection acts. Mutations driving evolution have to occur in the oocytes and sperm in order to be transmitted to the next generation. Through similar mechanisms, mutations also accumulate in somatic cells (e.g., skin cells, neurons, lymphocytes) during development and adult life. The concept that somatic cells can collect new mutations with time suggests that we are a mosaic of cells with different genomic compositions. Particular attention has been recently paid to somatic mutations in the brain, with a focus on the relationship between this phenomenon and the origin of human diseases. Given this progressive accumulation of mutations, it is likely that an increased load of somatic mutations is present later in life and that this could be associated with late-life diseases and aging. In this review, we focus on a particular type of mutation: the loss and/or gain of whole chromosomes (i.e., aneuploidy) caused by errors in chromosomes segregation in neurons and glia. Currently, it is hard to grasp the functional impact of somatic mutation in the brain because we lack reliable estimates of the proportion of aneuploid cells in the normal brain across different ages. Here, we revisit the key studies that attempted to quantify the proportion of aneuploid cells in both normal and diseased brains and highlight the deep inconsistencies among the different studies done in the last 15 years. Finally, our review highlights several limitations of studies performed in human and rodent models and explores a possible translational role for non-human primates.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Andriani GA, Vijg J, Montagna C (2016) Mechanisms and consequences of aneuploidy and chromosome instability in the aging brain. Mech Ageing Dev doi: 10.1016/j.mad.2016.03.007

  • Alikani M, Cohen J, Tomkin G, Garrisi GJ, Mack C, Scott RT (1999) Human embryo fragmentation in vitro and its implications for pregnancy and implantation. Fertil Steril 71:836–842

    Article  CAS  PubMed  Google Scholar 

  • Arendt T, Brückner MK, Mosch B, Lösche A (2010) Selective cell death of hyperploid neurons in Alzheimer’s disease. Am J Pathol 177

  • Bakken, T.E., Miller, J.A., Ding, S.L., Sunkin, S.M., Smith, K.A., Ng, L., Szafer, A., Dalley, R.A., Royall, J.J., Lemon, T., et al. (2016). A comprehensive transcriptional map of primate brain development. Nature 535(7612), pp.367–375

  • Baslan T, Kendall J, Rodgers L, Cox H, Riggs M, Stepansky A, Troge J, Ravi K, Esposito D, Lakshmi B, et al. (2012) Genome-wide copy number analysis of single cells. Nat Protoc 7:1024–1041

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bushman DM, Chun J (2013) The genomically mosaic brain: aneuploidy and more in neural diversity and disease. Semin Cell Dev Biol 24:357–369

    Article  PubMed  PubMed Central  Google Scholar 

  • Cai, X., Evrony, G.D., Lehmann, H.S., Elhosary, P.C., Mehta, B.K., Poduri, A., and Walsh, C.A. (2014). Single-cell, genome-wide sequencing identifies clonal somatic copy-number variation in the human brain. Cell Rep 8(5), pp.1280–1289

  • Carbone L, Chavez SL (2015) Mammalian pre-implantation chromosomal instability: species comparison, evolutionary considerations, and pathological correlations. Systems biology in reproductive medicine 61:321–335

    Article  PubMed  Google Scholar 

  • Chan AW (2013) Progress and prospects for genetic modification of nonhuman primate models in biomedical research. ILAR J 54:211–223

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chavez SL, Loewke KE, Han J, Moussavi F, Colls P, Munne S, Behr B, Reijo Pera RA (2012) Dynamic blastomere behaviour reflects human embryo ploidy by the four-cell stage. Nat Commun 3:1251

    Article  PubMed  PubMed Central  Google Scholar 

  • Cimini D (2008) Merotelic kinetochore orientation, aneuploidy, and cancer. Biochim Biophys Acta 1786:32–40

    CAS  PubMed  Google Scholar 

  • Crasta K, Ganem NJ, Dagher R, Lantermann AB, Ivanova EV, Pan Y, Nezi L, Protopopov A, Chowdhury D, Pellman D (2012) DNA breaks and chromosome pulverization from errors in mitosis. Nature 482:53–58

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Daley T, Smith AD (2014) Modeling genome coverage in single-cell sequencing. Bioinformatics 30:3159–3165

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Evrony GD, Cai X, Lee E, Hills LB, Elhosary PC, Lehmann HS, Parker JJ, Atabay KD, Gilmore EC, Poduri A, et al. (2012) Single-neuron sequencing analysis of L1 retrotransposition and somatic mutation in the human brain. Cell 151:483–496

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Faggioli F, Wang T, Vijg J, Montagna C (2012) Chromosome-specific accumulation of aneuploidy in the aging mouse brain. Hum Mol Genet 21:5246–5253

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fenech M, Kirsch-Volders M, Natarajan AT, Surralles J, Crott JW, Parry J, Norppa H, Eastmond DA, Tucker JD, Thomas P (2011) Molecular mechanisms of micronucleus, nucleoplasmic bridge and nuclear bud formation in mammalian and human cells. Mutagenesis 26:125–132

    Article  CAS  PubMed  Google Scholar 

  • Fischer, H.-G., Morawski, M., Brückner, M.K., Mittag, A., Tarnok, A., and Arendt, T. (2012). Changes in neuronal DNA content variation in the human brain during aging. Aging Cell 11(4), pp.628–633

  • Ford CE, Jones KW, Polani PE, De Almeida JC, Briggs JH (1959) A sex-chromosome anomaly in a case of gonadal dysgenesis (Turner’s syndrome). Lancet 1:711–713

    Article  CAS  PubMed  Google Scholar 

  • Garvin T, Aboukhalil R, Kendall J, Baslan T, Atwal GS, Hicks J, Wigler M, Schatz MC (2015) Interactive analysis and assessment of single-cell copy-number variations. Nat Methods 12:1058–1060

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gawad C, Koh W, Quake SR (2016) Single-cell genome sequencing: current state of the science. Nat Rev Genet 17:175–188

    Article  CAS  PubMed  Google Scholar 

  • Gladyshev, V.N. (2016). Aging: progressive decline in fitness due to the rising deleteriome adjusted by genetic, environmental, and stochastic processes. Aging Cell 15(4), pp.594–602

  • Gole J, Gore A, Richards A, Chiu YJ, Fung HL, Bushman D, Chiang HI, Chun J, Lo YH, Zhang K (2013) Massively parallel polymerase cloning and genome sequencing of single cells using nanoliter microwells. Nat Biotechnol 31(12), pp.1126–1132

  • 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 34:212–220

    Article  CAS  PubMed  Google Scholar 

  • Jacobs PA, Strong JA (1959) A case of human intersexuality having a possible XXY sex-determining mechanism. Nature 183:302–303

    Article  CAS  PubMed  Google Scholar 

  • Jacobs PA, Court Brown WM, Doll R (1961) Distribution of human chromosome counts in relation to age. Nature 191:1178–80

  • Janssen A, van der Burg M, Szuhai K, Kops GJ, Medema RH (2011) Chromosome segregation errors as a cause of DNA damage and structural chromosome aberrations. Science 333:1895–1898

    Article  CAS  PubMed  Google Scholar 

  • Kaushal D, Contos JJA, Treuner K, Yang AH, Kingsbury MA, Rehen SK, McConnell MJ, Okabe M, Barlow C, Chun J (2003) Alteration of gene expression by chromosome loss in the postnatal mouse brain. J Neurosci Off J Soc Neurosci 23(13), pp. 5599–5606

  • Kingsbury MA, Friedman B, McConnell MJ, Rehen SK, Yang AH, Kaushal D, Chun J (2005) Aneuploid neurons are functionally active and integrated into brain circuitry. Proc Natl Acad Sci U S A 102:6143–6147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Knouse K, Wu J, Whittaker C, Amon A (2014) Single cell sequencing reveals low levels of aneuploidy across mammalian tissues. Proc Natl Acad Sci 111

  • Kolano A, Brunet S, Silk AD, Cleveland DW, Verlhac MH (2012) Error-prone mammalian female meiosis from silencing the spindle assembly checkpoint without normal interkinetochore tension. Proc Natl Acad Sci U S A 109:E1858–E1867

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lejeune, J., Gautier, M., and Turpin, R. (1959). The chromosomes of man. The Lancet, 273(7078), pp.885–886

  • Leung ML, Wang Y, Waters J, Navin NE (2015) SNES: single nucleus exome sequencing. Genome Biol 16:55

    Article  PubMed  PubMed Central  Google Scholar 

  • Macosko EZ, Basu A, Satija R, Nemesh J, Shekhar K, Goldman M, Tirosh I, Bialas AR, Kamitaki N, Martersteck EM, et al. (2015) Highly parallel genome-wide expression profiling of individual cells using nanoliter droplets. Cell 161:1202–1214

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mali P, Yang L, Esvelt KM, Aach J, Guell M, DiCarlo JE, Norville JE, Church GM (2013) RNA-guided human genome engineering via Cas9. Science 339:823–826

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McConnell MJ, Lindberg MR, Brennand KJ, Piper JC, Voet T, Cowing-Zitron C, Shumilina S, Lasken RS, Vermeesch JR, Hall IM, et al. (2013) Mosaic copy number variation in human neurons. Science 342:632–637

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mosch B, Morawski M, Mittag A, Lenz D, Tarnok A, Arendt T (2007) Aneuploidy and DNA replication in the normal human brain and Alzheimer’s disease. J Neurosci 27:6859–6867

    Article  CAS  PubMed  Google Scholar 

  • Müller, H.A. (1962). Cytophotometrische DNS-Messungen an ganglienzellkernen des nucleus dentatus beim menschen. Naturwissenschaften

  • Muotri AR, Gage FH (2006) Generation of neuronal variability and complexity. Nature 441:1087–1093

    Article  CAS  PubMed  Google Scholar 

  • Navin N, Kendall J, Troge J, Andrews P, Rodgers L, McIndoo J, Cook K, Stepansky A, Levy D, Esposito D, et al. (2011) Tumour evolution inferred by single-cell sequencing. Nature 472:90–94

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ning L, Li Z, Wang G, Hu W, Hou Q, Tong Y, Zhang M, Chen Y, Qin L, Chen X, et al. (2015) Quantitative assessment of single-cell whole genome amplification methods for detecting copy number variation using hippocampal neurons. Sci Rep 5:11415

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Osada T, Kusakabe H, Akutsu H, Yagi T, Yanagimachi R (2002) Adult murine neurons: their chromatin and chromosome changes and failure to support embryonic development as revealed by nuclear transfer. Cytogenetic and genome research, 97(1-2), pp.7–12

  • Osada T, Kakazu N, Watanabe M, Yamane H, Yagi T (2009) The chromosomal constitution of postmitotic neurons, assessed by neuronal nuclear transfer into oocytes and in ES cell lines derived from them. Cytogenet. Genome Res 125(3), pp. 201–212

  • Pack, S.D., Weil, R.J., Vortmeyer, A.O., Zeng, W., Li, J., Okamoto, H., Furuta, M., Pak, E., Lubensky, I.A., Oldfield, E.H., et al. (2005). Individual adult human neurons display aneuploidy: detection by fluorescence in situ hybridization and single neuron PCR. Cell cycle (Georgetown, Tex) 4(12), pp.1758–1760

  • Pamphlett R, Morahan, JM Luquin, N Yu B (2011) Looking for differences in copy number between blood and brain in sporadic amyotrophic lateral sclerosis. Muscle Nerve, 44(4), pp.492–498

  • Peterson SE, Yang AH, Bushman DM, Westra JW, Yung YC, Barral S, Mutoh T, Rehen SK, Chun J (2012) Aneuploid cells are differentially susceptible to caspase-mediated death during embryonic cerebral cortical development. J Neurosci Off J Soc Neurosci 32:16213–16222

    Article  CAS  Google Scholar 

  • Poduri A, Evrony GD, Cai X, Walsh CA (2013) Somatic mutation, genomic variation, and neurological disease. Science 341:1237758

    Article  PubMed  PubMed Central  Google Scholar 

  • Pouladi MA, Morton AJ, Hayden MR (2013) Choosing an animal model for the study of Huntington’s disease. Nat Rev Neurosci 14:708–721

    Article  CAS  PubMed  Google Scholar 

  • Rakic P (2009) Evolution of the neocortex: a perspective from developmental biology. Nat Rev Neurosci 10:724–735

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 U S A 98:13361–13366

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rehen SK, Yung YC, McCreight MP, Kaushal D, Yang AH, Almeida BS, Kingsbury MA, Cabral KM, McConnell MJ, Anliker B, et al. (2005) Constitutional aneuploidy in the normal human brain. J Neurosci Off J Soc Neurosci 25:2176–2180

    Article  CAS  Google Scholar 

  • Roelfsema PR, Treue S (2014) Basic neuroscience research with nonhuman primates: a small but indispensable component of biomedical research. Neuron 82:1200–1204

    Article  CAS  PubMed  Google Scholar 

  • Samora CP, Mogessie B, Conway L, Ross JL, Straube A, McAinsh AD (2011) MAP4 and CLASP1 operate as a safety mechanism to maintain a stable spindle position in mitosis. Nat Cell Biol 13:1040–1050

    Article  CAS  PubMed  Google Scholar 

  • Schrock E, du Manoir S, Veldman T, Schoell B, Wienberg J, Ferguson-Smith MA, Ning Y, Ledbetter DH, Bar-Am I, Soenksen D, et al. (1996) Multicolor spectral karyotyping of human chromosomes. Science 273:494–497

    Article  CAS  PubMed  Google Scholar 

  • Singer T, McConnell MJ, Marchetto MC, Coufal NG, Gage FH (2010) LINE-1 retrotransposons: mediators of somatic variation in neuronal genomes? Trends Neurosci 33:345–354

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Thomas P, Fenech M (2008) Chromosome 17 and 21 aneuploidy in buccal cells is increased with ageing and in Alzheimer’s disease. Mutagenesis 23

  • Thompson SL, Bakhoum SF, Compton DA (2010) Mechanisms of chromosomal instability. Current biology: CB 20:R285–R295

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tijo JH, Levan A (1956) The chromosome number of man. Hereditas 42

  • van den Bos H, Spierings DC, Taudt AS, Bakker B, Porubsky D, Falconer E, Novoa C, Halsema N, Kazemier HG, Hoekstra-Wakker K, et al. (2016a) Single-cell whole genome sequencing reveals no evidence for common aneuploidy in normal and Alzheimer’s disease neurons. Genome Biol 17:116

    Article  PubMed  PubMed Central  Google Scholar 

  • van den Bos H, Spierings DCJ, Taudt AS, Bakker B, Porubský D, Falconer E, Novoa C, Halsema N, Kazemier HG, Hoekstra-Wakker K, et al. (2016b) Single-cell whole genome sequencing reveals no evidence for common aneuploidy in normal and Alzheimer’s disease neurons. Genome Biol 17:1–9

    Article  Google Scholar 

  • Westra JW, Peterson SE, Yung YC, Mutoh T, Barral S, Chun J (2008) Aneuploid mosaicism in the developing and adult cerebellar cortex. J Comp Neurol 507:1944–1951

    Article  PubMed  Google Scholar 

  • Westra JW, Rivera RR, Bushman DM, Yung YC, Peterson SE, Barral S, Chun J (2010) Neuronal DNA content variation (DCV) with regional and individual differences in the human brain. J Comp Neurol 518:3981–4000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • White AK, VanInsberghe M, Petriv OI, Hamidi M, Sikorski D, Marra MA, Piret J, Aparicio S, Hansen CL (2011) High-throughput microfluidic single-cell RT-qPCR. Proc Natl Acad Sci U S A 108:13999–14004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang Y, Geldmacher DS, Herrup K (2001) DNA replication precedes neuronal cell death in Alzheimer’s disease. J Neurosci Off J Soc Neurosci 21:2661–2668

    CAS  Google Scholar 

  • Yang AH, Kaushal D, Rehen SK, Kriedt K, Kingsbury MA, McConnell MJ, Chun J (2003) Chromosome segregation defects contribute to aneuploidy in normal neural progenitor cells. J Neurosci Off J Soc Neurosci 23(32), pp.10454–10462

  • Yurov, Y.B., Vostrikov, V.M., Vorsanova, S.G., Monakhov, V.V., and Iourov, I.Y. (2001). Multicolor fluorescent in situ hybridization on post-mortem brain in schizophrenia as an approach for identification of low-level chromosomal aneuploidy in neuropsychiatric diseases. Brain Dev 23, pp.S186–S190

  • Yurov YB, Iourov IY, Vorsanova SG, Liehr T, Kolotii AD, Kutsev SI, Pellestor F, Beresheva AK, Demidova I, Kravets VS, et al. (2007) Aneuploidy and confined chromosomal mosaicism in the developing human brain. PLoS One 2

  • Zhang CZ, Spektor A, Cornils H, Francis JM, Jackson EK, Liu S, Meyerson M, Pellman D (2015) Chromothripsis from DNA damage in micronuclei. Nature 522:179–184

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 338:1622–1626

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

The authors are grateful to Dr. Steven Kohama for reviewing and providing comments on this manuscript. They also thank members of the Carbone and Chavez lab for helpful discussions and apologize to the authors whose work they were unable to describe.

Author information

Authors and Affiliations

  1. Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA

    Jimi L. Rosenkrantz & Lucia Carbone

  2. Department of Medicine, Oregon Health and Science University, Portland, OR, USA

    Lucia Carbone

  3. Knight Cardiovascular Institute, Oregon Health and Science University, Portland, OR, USA

    Lucia Carbone

  4. Division of Neuroscience, Primate Genetics Section, Oregon National Primate Research Center, Beaverton, OR, USA

    Lucia Carbone

Authors
  1. Jimi L. Rosenkrantz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lucia Carbone
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lucia Carbone.

Ethics declarations

Funding

Jimi Rosenkrantz is supported by the Collins Medical Trust Foundation and Glenn/AFAR Scholarship for Research in the Biology of Aging. Lucia Carbone is supported by the Office of the Director/Office of Research Infrastructure Programs (OD/ORIP) of the NIH (grant no. OD011092).

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Additional information

This article is related to the 21st International Chromosome Conference (Foz do Iguaçu, Brazil, July 10–13, 2016).

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rosenkrantz, J.L., Carbone, L. Investigating somatic aneuploidy in the brain: why we need a new model. Chromosoma 126, 337–350 (2017). https://doi.org/10.1007/s00412-016-0615-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00412-016-0615-4

Keywords

Search

Navigation