Sistema de Salut de Catalunya
Institut Català de la Salut
[Wang Y] Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, 100 Washtenaw Avenue, Ann Arbor, MI 48109, USA. [Bae T] Department of Health Sciences Research, Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, USA. [Thorpe J] Program in Biochemistry, Cellular and Molecular Biology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA. [Sherman MA] Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. MIT Department of Electrical Engineering and Computer Science, Cambridge, MA, USA. [Jones AG] Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. [Cho S] Department of Neurology, Kennedy Krieger Institute, Baltimore, MD 21205, USA. Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA. Arcus Biosciences, Hayward, CA 94545, USA 2142, USA. [Soriano E] Department of Cell Biology, Physiology and Immunology, and Institute of Neurosciences, University of Barcelona, 08028 Barcelona, Spain. Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Centro de Investigación en Red sobre Enfermedades Neurodegenerativas (CIBERNED), 28031 Madrid, Spain. ICREA Academia, 08010 Barcelona, Spain
Vall d'Hebron Barcelona Hospital Campus
2021-12-01T07:28:58Z
2021-12-01T07:28:58Z
2021-03-29
Nucleòtid somàtic; Teixit cerebral
Nucleótido somático; Tejido cerebral
Somatic nucleotide; Brain tissue
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.
This work was supported by National Institute of Mental Health by the following awards: U01MH106874, U01MH106876, U01MH106883, U01MH106882, U01MH106884, U01MH106891, U01MH106892, U01MH106893, U01MH108898.
Article
Published version
English
ADN - Anàlisi; Seqüència de nucleòtids; Anomalies cromosòmiques; PHENOMENA AND PROCESSES::Genetic Phenomena::Genetic Variation::Mutation::Chromosome Aberrations::Mosaicism; PHENOMENA AND PROCESSES::Genetic Phenomena::Genetic Variation; ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT::Investigative Techniques::Genetic Techniques::Sequence Analysis::Sequence Analysis, DNA::DNA Mutational Analysis; FENÓMENOS Y PROCESOS::fenómenos genéticos::variación genética::mutación::aberraciones cromosómicas::mosaicismo; FENÓMENOS Y PROCESOS::fenómenos genéticos::variación genética; TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS::técnicas de investigación::técnicas genéticas::análisis de secuencias::análisis de secuencias de ADN::análisis de mutaciones del ADN
BMC
Genome Biology;22
https://doi.org/10.1186/s13059-021-02285-3
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
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