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Cited by 117Single-cell and spatial transcriptomicsDevelopmental Biology and Gene RegulationCancer Genomics and Diagnostics

Landmarks of human embryonic development inscribed in somatic mutations

Open access
Bizzotto, Sara, Dou, Yanmei, Ganz, Javier, Doan, Ryan N., Kwon, Minseok, Bohrson, Craig L., Kim, Sonia N., Bae, Taejeong +4 more·2021·Science
DOI 10.1126/science.abe1544PMC PMC8170505
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Abstract

Mutations provide an enduring record: Somatic mutations pepper our cells with change, but because they are not in the germline, they do not propagate to the next generation. Bizzotto et al. leveraged data on the distribution of somatic mutations in adults to take a backward look at the earliest moments of human development. Calculation of cellular lineages on the basis of shared somatic mutations shows the number of cells from which the body will develop when the human embryo gastrulates. The lineage for forebrain cells is identifiable, as are the asymmetrical fates spun out of many of the gastrula cells. Science , this issue p. 1249

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  • Human brain tissues exhibit generation of clones with highly variable sizes both in vivo and in vitro.

    “It is important to note that the development of human brain tissues exhibits the generation of clones with highly variable sizes both in vivo and in vitro12,19.”

    From Single-cell brain organoid screening identifies developmental defects in autism (2023) · cites this paper as [19]

    The indexed passage (labeled Abstract; no page supplied) reports mosaic fractions ranging from 5% to 26% across cerebral cortex samples, supporting highly variable clonal amplification in human brain tissue in vivo. Our copy does not report variable clone sizes in brain tissue grown in vitro, so that part of the claim is not supported by this source. (LLM, conf=0.87)

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Research works printed but not linked: 31

  1. [1]Kalhor R, Developmental barcoding of whole mouse via homing CRISPR. Science 361, (2018). PMC6139672 30093604
  2. [3]Rodin RE, The landscape of somatic mutation in cerebral cortex of autistic and neurotypical individuals revealed by ultra-deep whole-genome sequencing. Nature Neuroscience, (2021). PMC7983596 33432195
  3. [4]Dou Y, Accurate detection of mosaic variants in sequencing data without matched controls. Nat Biotechnol 38, 314– 319 (2020). 31907404 PMC7065972
  4. [5]Ju YS, Somatic mutations reveal asymmetric cellular dynamics in the early human embryo. Nature 543, 714– 718 (2017). 28329761 PMC6169740
  5. [7]Lodato MA, Aging and neurodegeneration are associated with increased mutations in single human neurons. Science 359, 555– 559 (2018). 29217584 PMC5831169
  6. [9]Tate JG, COSMIC: the Catalogue Of Somatic Mutations In Cancer. Nucleic Acids Res 47, D941– D947 (2019). 30371878 PMC6323903
  7. [10]Zhang RR, Hepatic stem cells with self-renewal and liver repopulation potential are harbored in CDCP1-positive subpopulations of human fetal liver cells. Stem Cell Res Ther 9, 29 (2018). 29402311 PMC5800061
  8. [11]Rodin RE, The Landscape of Mutational Mosaicism in Autistic and Normal Human Cerebral Cortex. bioRxiv, 2020.2002.2011.944413 (2020).
  9. [12]Hupalowska A, CARM1 and Paraspeckles Regulate Pre-implantation Mouse Embryo Development. Cell 175, 1902– 1916 e1913 (2018). 30550788 PMC6292842
  10. [13]White MD, Long-Lived Binding of Sox2 to DNA Predicts Cell Fate in the Four-Cell Mouse Embryo. Cell 165, 75– 87 (2016). 27015308
  11. [14]Piotrowska K, Zernicka-Goetz M, Role for sperm in spatial patterning of the early mouse embryo. Nature 409, 517– 521 (2001). 11206548
  12. [15]Xiang L, A developmental landscape of 3D-cultured human pre-gastrulation embryos. Nature 577, 537– 542 (2020). 31830756
  13. [16]Evrony GD, Cell lineage analysis in human brain using endogenous retroelements. Neuron 85, 49– 59 (2015). 25569347 PMC4299461
  14. [17]Stuart T, Comprehensive Integration of Single-Cell Data. Cell 177, 1888– 1902 e1821 (2019). 31178118 PMC6687398
  15. [19]Huang AY, Parallel RNA and DNA analysis after deep sequencing (PRDD-seq) reveals cell type-specific lineage patterns in human brain. Proc Natl Acad Sci U S A, (2020). PMC7322034 32522880
  16. [20]Koh HY, Lee JH, Brain Somatic Mutations in Epileptic Disorders. Mol Cells 41, 881– 888 (2018). 30352490 PMC6199569
  17. [22]Genovese G, Mapping the human reference genome’s missing sequence by three-way admixture in Latino genomes. Am J Hum Genet 93, 411– 421 (2013). 23932108 PMC3971454
  18. [23]McKenna A, The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Research 20, 1297– 1303 (2010). 20644199 PMC2928508
  19. [24]Cibulskis K, Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples. Nat Biotechnol 31, 213– 219 (2013). 23396013 PMC3833702
  20. [25]Karczewski KJ, The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 581, 434– 443 (2020). 32461654 PMC7334197
  21. [26]Haeussler M, The UCSC Genome Browser database: 2019 update. Nucleic Acids Res 47, D853– D858 (2019). 30407534 PMC6323953
  22. [27]Karimzadeh M, Umap and Bismap: quantifying genome and methylome mappability. Nucleic Acids Res 46, e120 (2018). 30169659 PMC6237805
  23. [28]Larson DE, SomaticSniper: identification of somatic point mutations in whole genome sequencing data. Bioinformatics 28, 311– 317 (2012). 22155872 PMC3268238
  24. [29]Saunders CT, Strelka: accurate somatic small-variant calling from sequenced tumor-normal sample pairs. Bioinformatics 28, 1811– 1817 (2012). 22581179
  25. [30]Koboldt DC, VarScan 2: somatic mutation and copy number alteration discovery in cancer by exome sequencing. Genome Res 22, 568– 576 (2012). 22300766 PMC3290792
  26. [33]Chen M, Comparison of multiple displacement amplification (MDA) and multiple annealing and looping-based amplification cycles (MALBAC) in single-cell sequencing. PLoS One 9, e114520 (2014). 25485707 PMC4259343
  27. [34]Chen C, Single-cell whole-genome analyses by Linear Amplification via Transposon Insertion (LIANTI). Science 356, 189– 194 (2017). 28408603 PMC5538131
  28. [35]Zeileis A, Regression Models for Count Data in R. 2008 27, 25 (2008).
  29. [39]Rosenthal R, DeconstructSigs: delineating mutational processes in single tumors distinguishes DNA repair deficiencies and patterns of carcinoma evolution. Genome Biol 17, 31 (2016). 26899170 PMC4762164
  30. [40]Wang L, RSeQC: quality control of RNA-seq experiments. Bioinformatics 28, 2184– 2185 (2012). 22743226
  31. [41]Inoue F, A systematic comparison reveals substantial differences in chromosomal versus episomal encoding of enhancer activity. Genome Res 27, 38– 52 (2017). 27831498 PMC5204343

Cited by

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Authors
Bizzotto, S., Dou, Y., Ganz, J., Doan, R. N., Kwon, M., Bohrson, C. L., Kim, S. N., Bae, T., Abyzov, A., NIMH Brain Somatic Mosaicism Network, Park, P. J., & Walsh, C. A.
Affiliations
  • Broad Institute (US)
  • Harvard University (US)
  • Boston Children's Hospital (US)
  • Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA.
  • Mayo Clinic (US)
  • Brigham and Women's Hospital (US)
Corresponding author
  • Bizzotto, Sara
  • Dou, Yanmei
  • Ganz, Javier
  • Park, Peter J.
  • Walsh, Christopher A.
ORCID
Venue
Science
Publisher
American Association for the Advancement of Science (AAAS)
Published
2021-03-19
Volume
371
Issue
6535
Pages
1249-1253
ISSN
  • 0036-8075 (ISSN-L)
  • 1095-9203
DOI
10.1126/science.abe1544
PMC
PMC8170505
OpenAlex
W3137364735
Cited by
117
References
9
Citations by year
2026: 18 · 2025: 25 · 2024: 23 · 2023: 16 · 2022: 24 · 2021: 11
FWCI
5.81
Type
journal article
Language
en
Open access
Locations
  • Science (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
Funders
  • Howard Hughes Medical Institute
  • National Institute of Mental Health (U01MH106883, Brain Somatic Mosaicism Network)
  • National Institute of Neurological Disorders and Stroke (R01NS032457)
  • Paul G. Allen Family Foundation
  • American Brain Tumor Association (BRF1900016)
  • Brain SPORE (P50CA165952)
  • Manton Center for Orphan Disease Research, Boston Children’s Hospital
  • Harvard Medical School (Stuart H.Q. and Victoria Quan Fellowship in Neurobiology)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
Keywords
human embryonic development, somatic mutations, somatic single nucleotide variants, cell lineage reconstruction, asymmetric cell division, extraembryonic tissues, germ layers, gastrulation, cortical neurons, clonal mutations, mosaicism
MeSH terms
Whole Genome Sequencing, Adolescent, Adult, Cell Division, Clone Cells, Female, Gastrula, Germ Layers, Humans, Male, Mutation, Neurons, Genetic Variation, Prosencephalon, Cell Lineage, Polymorphism, Single Nucleotide, Organogenesis, Embryonic Development, Gastrulation, Neural Stem Cells, Single-Cell Analysis

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