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 mosai...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BioMed Central
2021
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| Online Access: | https://hdl.handle.net/1721.1/132104 |
| _version_ | 1826192998446137344 |
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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 |
| author2 | Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science |
| author_facet | Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science 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 |
| author_sort | Wang, Yifan |
| collection | MIT |
| 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. |
| first_indexed | 2024-09-23T09:32:25Z |
| format | Article |
| id | mit-1721.1/132104 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T09:32:25Z |
| publishDate | 2021 |
| publisher | BioMed Central |
| record_format | dspace |
| spelling | mit-1721.1/1321042024-01-02T15:57:55Z 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 Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science 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. 2021-09-20T17:41:59Z 2021-09-20T17:41:59Z 2021-03-29 2021-04-04T04:16:36Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/132104 Genome Biology. 2021 Mar 29;22(1):92 PUBLISHER_CC en https://doi.org/10.1186/s13059-021-02285-3 Creative Commons Attribution https://creativecommons.org/licenses/by/4.0/ The Author(s) application/pdf BioMed Central BioMed Central |
| spellingShingle | 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 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 |
| url | https://hdl.handle.net/1721.1/132104 |
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