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Comprehensive identification of somatic nucleotide variants in human 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...

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Autores principales: Wang, Yifan, Bae, Taejeong, Thorpe, Jeremy, Sherman, Maxwell A., Jones, Attila G., Cho, Sean, Daily, Kenneth, Dou, Yanmei, Ganz, Javier, Galor, Alon, Lobon, Irene, Pattni, Reenal, Rosenbluh, Chaggai, Tomasi, Simone, Tomasini, Livia, Yang, Xiaoxu, Zhou, Bo, Akbarian, Schahram, Ball, Laurel L., Bizzotto, Sara, Emery, Sarah B., Doan, Ryan, Fasching, Liana, Jang, Yeongjun, Juan, David, Lizano, Esther, Luquette, Lovelace J., Moldovan, John B., Narurkar, Rujuta, Oetjens, Matthew T., Rodin, Rachel E., Sekar, Shobana, Shin, Joo Heon, Soriano, Eduardo, Straub, Richard E., Zhou, Weichen, Chess, Andrew, Gleeson, Joseph G., Marquès-Bonet, Tomas, Park, Peter J., Peters, Mette A., Pevsner, Jonathan, Walsh, Christopher A., Weinberger, Daniel R., Vaccarino, Flora M., Moran, John V., Urban, Alexander E., Kidd, Jeffrey M., Mills, Ryan E., Abyzov, Alexej
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006362/
https://www.ncbi.nlm.nih.gov/pubmed/33781308
http://dx.doi.org/10.1186/s13059-021-02285-3
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author Wang, Yifan
Bae, Taejeong
Thorpe, Jeremy
Sherman, Maxwell A.
Jones, Attila G.
Cho, Sean
Daily, Kenneth
Dou, Yanmei
Ganz, Javier
Galor, Alon
Lobon, Irene
Pattni, Reenal
Rosenbluh, Chaggai
Tomasi, Simone
Tomasini, Livia
Yang, Xiaoxu
Zhou, Bo
Akbarian, Schahram
Ball, Laurel L.
Bizzotto, Sara
Emery, Sarah B.
Doan, Ryan
Fasching, Liana
Jang, Yeongjun
Juan, David
Lizano, Esther
Luquette, Lovelace J.
Moldovan, John B.
Narurkar, Rujuta
Oetjens, Matthew T.
Rodin, Rachel E.
Sekar, Shobana
Shin, Joo Heon
Soriano, Eduardo
Straub, Richard E.
Zhou, Weichen
Chess, Andrew
Gleeson, Joseph G.
Marquès-Bonet, Tomas
Park, Peter J.
Peters, Mette A.
Pevsner, Jonathan
Walsh, Christopher A.
Weinberger, Daniel R.
Vaccarino, Flora M.
Moran, John V.
Urban, Alexander E.
Kidd, Jeffrey M.
Mills, Ryan E.
Abyzov, Alexej
author_facet Wang, Yifan
Bae, Taejeong
Thorpe, Jeremy
Sherman, Maxwell A.
Jones, Attila G.
Cho, Sean
Daily, Kenneth
Dou, Yanmei
Ganz, Javier
Galor, Alon
Lobon, Irene
Pattni, Reenal
Rosenbluh, Chaggai
Tomasi, Simone
Tomasini, Livia
Yang, Xiaoxu
Zhou, Bo
Akbarian, Schahram
Ball, Laurel L.
Bizzotto, Sara
Emery, Sarah B.
Doan, Ryan
Fasching, Liana
Jang, Yeongjun
Juan, David
Lizano, Esther
Luquette, Lovelace J.
Moldovan, John B.
Narurkar, Rujuta
Oetjens, Matthew T.
Rodin, Rachel E.
Sekar, Shobana
Shin, Joo Heon
Soriano, Eduardo
Straub, Richard E.
Zhou, Weichen
Chess, Andrew
Gleeson, Joseph G.
Marquès-Bonet, Tomas
Park, Peter J.
Peters, Mette A.
Pevsner, Jonathan
Walsh, Christopher A.
Weinberger, Daniel R.
Vaccarino, Flora M.
Moran, John V.
Urban, Alexander E.
Kidd, Jeffrey M.
Mills, Ryan E.
Abyzov, Alexej
author_sort Wang, Yifan
collection PubMed
description 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13059-021-02285-3.
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spelling pubmed-80063622021-03-30 Comprehensive identification of somatic nucleotide variants in human brain tissue Wang, Yifan Bae, Taejeong Thorpe, Jeremy Sherman, Maxwell A. Jones, Attila G. Cho, Sean Daily, Kenneth Dou, Yanmei Ganz, Javier Galor, Alon Lobon, Irene Pattni, Reenal Rosenbluh, Chaggai Tomasi, Simone Tomasini, Livia Yang, Xiaoxu Zhou, Bo Akbarian, Schahram Ball, Laurel L. Bizzotto, Sara Emery, Sarah B. Doan, Ryan Fasching, Liana Jang, Yeongjun Juan, David Lizano, Esther Luquette, Lovelace J. Moldovan, John B. Narurkar, Rujuta Oetjens, Matthew T. Rodin, Rachel E. Sekar, Shobana Shin, Joo Heon Soriano, Eduardo Straub, Richard E. Zhou, Weichen Chess, Andrew Gleeson, Joseph G. Marquès-Bonet, Tomas Park, Peter J. Peters, Mette A. Pevsner, Jonathan Walsh, Christopher A. Weinberger, Daniel R. Vaccarino, Flora M. Moran, John V. Urban, Alexander E. Kidd, Jeffrey M. Mills, Ryan E. Abyzov, Alexej Genome Biol Research 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13059-021-02285-3. BioMed Central 2021-03-29 /pmc/articles/PMC8006362/ /pubmed/33781308 http://dx.doi.org/10.1186/s13059-021-02285-3 Text en © The Author(s) 2021 Open AccessThis 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 made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Wang, Yifan
Bae, Taejeong
Thorpe, Jeremy
Sherman, Maxwell A.
Jones, Attila G.
Cho, Sean
Daily, Kenneth
Dou, Yanmei
Ganz, Javier
Galor, Alon
Lobon, Irene
Pattni, Reenal
Rosenbluh, Chaggai
Tomasi, Simone
Tomasini, Livia
Yang, Xiaoxu
Zhou, Bo
Akbarian, Schahram
Ball, Laurel L.
Bizzotto, Sara
Emery, Sarah B.
Doan, Ryan
Fasching, Liana
Jang, Yeongjun
Juan, David
Lizano, Esther
Luquette, Lovelace J.
Moldovan, John B.
Narurkar, Rujuta
Oetjens, Matthew T.
Rodin, Rachel E.
Sekar, Shobana
Shin, Joo Heon
Soriano, Eduardo
Straub, Richard E.
Zhou, Weichen
Chess, Andrew
Gleeson, Joseph G.
Marquès-Bonet, Tomas
Park, Peter J.
Peters, Mette A.
Pevsner, Jonathan
Walsh, Christopher A.
Weinberger, Daniel R.
Vaccarino, Flora M.
Moran, John V.
Urban, Alexander E.
Kidd, Jeffrey M.
Mills, Ryan E.
Abyzov, Alexej
Comprehensive identification of somatic nucleotide variants in human brain tissue
title Comprehensive identification of somatic nucleotide variants in human brain tissue
title_full Comprehensive identification of somatic nucleotide variants in human brain tissue
title_fullStr Comprehensive identification of somatic nucleotide variants in human brain tissue
title_full_unstemmed Comprehensive identification of somatic nucleotide variants in human brain tissue
title_short Comprehensive identification of somatic nucleotide variants in human brain tissue
title_sort comprehensive identification of somatic nucleotide variants in human brain tissue
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006362/
https://www.ncbi.nlm.nih.gov/pubmed/33781308
http://dx.doi.org/10.1186/s13059-021-02285-3
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