Comprehensive identification of somatic nucleotide variants in human brain tissue

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• dc.contributor.author Wang, Yifan
• dc.contributor.author Lobon Garcia, Irene
• dc.contributor.author Juan, David
• dc.contributor.author Lizano González, Esther, 1974-
• dc.contributor.author Marquès i Bonet, Tomàs, 1975-
• dc.contributor.author Abyzov, Alexej
• dc.date.accessioned 2021-05-07T07:06:08Z
• dc.date.available 2021-05-07T07:06:08Z
• dc.date.issued 2021
• dc.description.abstract Background: Post-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. Results: Here, 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. Conclusions: This 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.
• dc.format.mimetype application/pdf
• dc.identifier.citation Wang Y, Bae T, Thorpe J, Sherman MA, Jones AG, Cho S et al. Comprehensive identification of somatic nucleotide variants in human brain tissue. Genome Biol. 2021;22(1):92. DOI: 10.1186/s13059-021-02285-3
• dc.identifier.doi http://dx.doi.org/10.1186/s13059-021-02285-3
• dc.identifier.issn 1474-7596
• dc.identifier.uri http://hdl.handle.net/10230/47345
• dc.language.iso eng
• dc.publisher BioMed Central
• dc.relation.ispartof Genome Biol. 2021;22(1):92
• dc.rights © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data ma
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.title Comprehensive identification of somatic nucleotide variants in human brain tissue
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion