A large CRISPR-induced bystander mutation causes immune dysregulation

A persistent concern with CRISPR-Cas9 gene editing has been the potential to generate mutations at off-target genomic sites. While CRISPR-engineering mice to delete a ~360 bp intronic enhancer, here we discovered a founder line that had marked immune dysregulation caused by a 24 kb tandem duplicatio...

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Autores principales: Simeonov, Dimitre R., Brandt, Alexander J., Chan, Alice Y., Cortez, Jessica T., Li, Zhongmei, Woo, Jonathan M., Lee, Youjin, Carvalho, Claudia M. B., Indart, Alyssa C., Roth, Theodore L., Zou, James, May, Andrew P., Lupski, James R., Anderson, Mark S., Buaas, F. William, Rokhsar, Daniel S., Marson, Alexander
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6379443/
https://www.ncbi.nlm.nih.gov/pubmed/30793048
http://dx.doi.org/10.1038/s42003-019-0321-x
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author Simeonov, Dimitre R.
Brandt, Alexander J.
Chan, Alice Y.
Cortez, Jessica T.
Li, Zhongmei
Woo, Jonathan M.
Lee, Youjin
Carvalho, Claudia M. B.
Indart, Alyssa C.
Roth, Theodore L.
Zou, James
May, Andrew P.
Lupski, James R.
Anderson, Mark S.
Buaas, F. William
Rokhsar, Daniel S.
Marson, Alexander
author_facet Simeonov, Dimitre R.
Brandt, Alexander J.
Chan, Alice Y.
Cortez, Jessica T.
Li, Zhongmei
Woo, Jonathan M.
Lee, Youjin
Carvalho, Claudia M. B.
Indart, Alyssa C.
Roth, Theodore L.
Zou, James
May, Andrew P.
Lupski, James R.
Anderson, Mark S.
Buaas, F. William
Rokhsar, Daniel S.
Marson, Alexander
author_sort Simeonov, Dimitre R.
collection PubMed
description A persistent concern with CRISPR-Cas9 gene editing has been the potential to generate mutations at off-target genomic sites. While CRISPR-engineering mice to delete a ~360 bp intronic enhancer, here we discovered a founder line that had marked immune dysregulation caused by a 24 kb tandem duplication of the sequence adjacent to the on-target deletion. Our results suggest unintended repair of on-target genomic cuts can cause pathogenic “bystander” mutations that escape detection by routine targeted genotyping assays.
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spelling pubmed-63794432019-02-21 A large CRISPR-induced bystander mutation causes immune dysregulation Simeonov, Dimitre R. Brandt, Alexander J. Chan, Alice Y. Cortez, Jessica T. Li, Zhongmei Woo, Jonathan M. Lee, Youjin Carvalho, Claudia M. B. Indart, Alyssa C. Roth, Theodore L. Zou, James May, Andrew P. Lupski, James R. Anderson, Mark S. Buaas, F. William Rokhsar, Daniel S. Marson, Alexander Commun Biol Article A persistent concern with CRISPR-Cas9 gene editing has been the potential to generate mutations at off-target genomic sites. While CRISPR-engineering mice to delete a ~360 bp intronic enhancer, here we discovered a founder line that had marked immune dysregulation caused by a 24 kb tandem duplication of the sequence adjacent to the on-target deletion. Our results suggest unintended repair of on-target genomic cuts can cause pathogenic “bystander” mutations that escape detection by routine targeted genotyping assays. Nature Publishing Group UK 2019-02-18 /pmc/articles/PMC6379443/ /pubmed/30793048 http://dx.doi.org/10.1038/s42003-019-0321-x Text en © The Author(s) 2019 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Simeonov, Dimitre R.
Brandt, Alexander J.
Chan, Alice Y.
Cortez, Jessica T.
Li, Zhongmei
Woo, Jonathan M.
Lee, Youjin
Carvalho, Claudia M. B.
Indart, Alyssa C.
Roth, Theodore L.
Zou, James
May, Andrew P.
Lupski, James R.
Anderson, Mark S.
Buaas, F. William
Rokhsar, Daniel S.
Marson, Alexander
A large CRISPR-induced bystander mutation causes immune dysregulation
title A large CRISPR-induced bystander mutation causes immune dysregulation
title_full A large CRISPR-induced bystander mutation causes immune dysregulation
title_fullStr A large CRISPR-induced bystander mutation causes immune dysregulation
title_full_unstemmed A large CRISPR-induced bystander mutation causes immune dysregulation
title_short A large CRISPR-induced bystander mutation causes immune dysregulation
title_sort large crispr-induced bystander mutation causes immune dysregulation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6379443/
https://www.ncbi.nlm.nih.gov/pubmed/30793048
http://dx.doi.org/10.1038/s42003-019-0321-x
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