@article{da898c8fd345441fb78438d918a53d23,
title = "Comprehensive identification of somatic nucleotide variants in human brain tissue",
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.",
author = "{Brain Somatic Mosaicism Network} and Yifan Wang and Taejeong Bae and Jeremy Thorpe and Sherman, {Maxwell A.} and Jones, {Attila G.} and Sean Cho and Kenneth Daily and Yanmei Dou and Javier Ganz and Alon Galor and Irene Lobon and Reenal Pattni and Chaggai Rosenbluh and Simone Tomasi and Livia Tomasini and Xiaoxu Yang and Bo Zhou and Schahram Akbarian and Ball, {Laurel L.} and Sara Bizzotto and Emery, {Sarah B.} and Ryan Doan and Liana Fasching and Yeongjun Jang and David Juan and Esther Lizano and Luquette, {Lovelace J.} and Moldovan, {John B.} and Rujuta Narurkar and Oetjens, {Matthew T.} and Rodin, {Rachel E.} and Shobana Sekar and Shin, {Joo Heon} and Eduardo Soriano and Straub, {Richard E.} and Weichen Zhou and Andrew Chess and Gleeson, {Joseph G.} and Tomas Marqu{\`e}s-Bonet and Park, {Peter J.} and Peters, {Mette A.} and Jonathan Pevsner and Walsh, {Christopher A.} and Weinberger, {Daniel R.} and Vaccarino, {Flora M.} and Moran, {John V.} and Urban, {Alexander E.} and Kidd, {Jeffrey M.} and Mills, {Ryan E.} and Alexej Abyzov",
note = "Funding Information: Members of the BSMN consortiums are listed in the supplementary file. We thank Geetha Senthil and Thomas Lehner for organizing the BSMN consortium. We express our gratitude to the NDA team for providing collaborative data storage space and support for data transfer needed for the successful completion of this study. This study was supported by NIMH grants U01MH106892, U01MH106876, U01MH106883, U01MH106874, U01MH106893, U01MH106882, U01MH108898, U01MH106891, and U01MH106884. Funding Information: This work was supported by National Institute of Mental Health by the following awards: U01MH106874, U01MH106876, U01MH106883, U01MH106882, U01MH106884, U01MH106891, U01MH106892, U01MH106893, U01MH108898. Publisher Copyright: {\textcopyright} 2021, The Author(s).",
year = "2021",
month = dec,
doi = "10.1186/s13059-021-02285-3",
language = "English (US)",
volume = "22",
journal = "Genome Biology",
issn = "1474-7596",
publisher = "BioMed Central",
number = "1",
}