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Comprehensive identification of somatic nucleotide variants in human brain tissue

Authors
  • Wang, Yifan1, 2
  • Bae, Taejeong3
  • Thorpe, Jeremy4
  • Sherman, Maxwell A.5, 6
  • Jones, Attila G.7, 7
  • Cho, Sean8, 4, 9
  • Daily, Kenneth10
  • Dou, Yanmei5
  • Ganz, Javier11, 12, 13
  • Galor, Alon5
  • Lobon, Irene14, 15
  • Pattni, Reenal16, 16
  • Rosenbluh, Chaggai7
  • Tomasi, Simone17
  • Tomasini, Livia17
  • Yang, Xiaoxu18, 19
  • Zhou, Bo16, 16
  • Akbarian, Schahram20, 20
  • Ball, Laurel L.18, 19
  • Bizzotto, Sara11, 12, 13
  • And 30 more
  • 1 University of Michigan Medical School, Ann Arbor, MI, 48109, USA , Ann Arbor (United States)
  • 2 University of Michigan Medical School, 100 Washtenaw Avenue, Ann Arbor, MI, 48109, USA , Ann Arbor (United States)
  • 3 Center for Individualized Medicine, Mayo Clinic, Rochester, MN, 55905, USA , Rochester (United States)
  • 4 Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA , Baltimore (United States)
  • 5 Harvard Medical School, Boston, MA, USA , Boston (United States)
  • 6 MIT Department of Electrical Engineering and Computer Science, Cambridge, MA, USA , Cambridge (United States)
  • 7 Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA , New York (United States)
  • 8 Kennedy Krieger Institute, Baltimore, MD, 21205, USA , Baltimore (United States)
  • 9 Present Address: Arcus Biosciences, Hayward, CA, 94545, USA , Hayward (United States)
  • 10 Sage Bionetworks, Seattle, WA, USA , Seattle (United States)
  • 11 Boston Children’s Hospital, Boston, MA, 02115, USA , Boston (United States)
  • 12 Harvard Medical School, Boston, MA, 02115, USA , Boston (United States)
  • 13 Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA , Cambridge (United States)
  • 14 PRBB, Barcelona, Catalonia, 08003, Spain , Barcelona (Spain)
  • 15 University of Barcelona, Barcelona, 08028, Spain , Barcelona (Spain)
  • 16 Stanford University School of Medicine, Stanford, CA, 94305, USA , Stanford (United States)
  • 17 Yale University, New Haven, CT, 06520, USA , New Haven (United States)
  • 18 University of California San Diego, La Jolla, CA, USA , La Jolla (United States)
  • 19 Rady Children’s Institute for Genomic Medicine, San Diego, CA, USA , San Diego (United States)
  • 20 Icahn School of Medicine at Mount Sinai, New York, NY, USA , New York (United States)
  • 21 Lieber Institute for Brain Development, Baltimore, MD, 21205, USA , Baltimore (United States)
  • 22 Johns Hopkins School of Medicine, Baltimore, MD, USA , Baltimore (United States)
  • 23 Vall d’Hebron Institut de Recerca, Barcelona, 08035, Spain , Barcelona (Spain)
  • 24 Centro de Investigación en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, 28031, Spain , Madrid (Spain)
  • 25 ICREA Academia, 08010 Barcelona, Spain , 08010 Barcelona (Spain)
  • 26 Catalan Institution of Research and Advanced Studies (ICREA), Barcelona, 08010, Spain , Barcelona (Spain)
  • 27 Barcelona Institute of Science and Technology (BIST), Barcelona, 08036, Spain , Barcelona (Spain)
  • 28 Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Barcelona, 08193, Spain , Cerdanyola del Vallès (Spain)
  • 29 Stanford Child Health Research Institute, Stanford, CA, 94305, USA , Stanford (United States)
Type
Published Article
Publication Date
Mar 29, 2021
Volume
22
Issue
1
Identifiers
DOI: 10.1186/s13059-021-02285-3
Source
Springer Nature
License
Green

Abstract

BackgroundPost-zygotic mutations incurred during DNA replication, DNA repair, and other cellular processes lead to somatic mosaicism. Somatic mosaicism is an established cause of various diseases, including cancers. However, detecting mosaic variants in DNA from non-cancerous somatic tissues poses significant challenges, particularly if the variants only are present in a small fraction of cells.ResultsHere, the Brain Somatic Mosaicism Network conducts a coordinated, multi-institutional study to examine the ability of existing methods to detect simulated somatic single-nucleotide variants (SNVs) in DNA mixing experiments, generate multiple replicates of whole-genome sequencing data from the dorsolateral prefrontal cortex, other brain regions, dura mater, and dural fibroblasts of a single neurotypical individual, devise strategies to discover somatic SNVs, and apply various approaches to validate somatic SNVs. These efforts lead to the identification of 43 bona fide somatic SNVs that range in variant allele fractions from ~ 0.005 to ~ 0.28. Guided by these results, we devise best practices for calling mosaic SNVs from 250× whole-genome sequencing data in the accessible portion of the human genome that achieve 90% specificity and sensitivity. Finally, we demonstrate that analysis of multiple bulk DNA samples from a single individual allows the reconstruction of early developmental cell lineage trees.ConclusionsThis study provides a unified set of best practices to detect somatic SNVs in non-cancerous tissues. The data and methods are freely available to the scientific community and should serve as a guide to assess the contributions of somatic SNVs to neuropsychiatric diseases.

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