Automated design of CRISPR prime editors for 56,000 human pathogenic variants

Summary: Prime editors (PEs) are clustered regularly interspaced short palindromic repeats (CRISPR)-based genome engineering tools that can introduce precise base-pair edits. We developed an automated pipeline to correct (therapeutic editing) or introduce (disease modeling) human pathogenic variants...

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Autores principales:	John A. Morris, Jahan A. Rahman, Xinyi Guo, Neville E. Sanjana
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Biotechnology Computational bioinformatics Science Q
Acceso en línea:	https://doaj.org/article/aa7b5526d2e142efb6b75729e67ecc1b
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spelling	oai:doaj.org-article:aa7b5526d2e142efb6b75729e67ecc1b2021-11-20T05:10:54ZAutomated design of CRISPR prime editors for 56,000 human pathogenic variants2589-004210.1016/j.isci.2021.103380https://doaj.org/article/aa7b5526d2e142efb6b75729e67ecc1b2021-11-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2589004221013511https://doaj.org/toc/2589-0042Summary: Prime editors (PEs) are clustered regularly interspaced short palindromic repeats (CRISPR)-based genome engineering tools that can introduce precise base-pair edits. We developed an automated pipeline to correct (therapeutic editing) or introduce (disease modeling) human pathogenic variants from ClinVar that optimizes the design of several RNA constructs required for prime editing and avoids predicted off-targets in the human genome. However, using optimal PE design criteria, we find that only a small fraction of these pathogenic variants can be targeted. Through the use of alternative Cas9 enzymes and extended templates, we increase the number of targetable pathogenic variants from 32,000 to 56,000 variants and make these pre-designed PE constructs accessible through a web-based portal (http://primeedit.nygenome.org). Given the tremendous potential for therapeutic gene editing, we also assessed the possibility of developing universal PE constructs, finding that common genetic variants impact only a small minority of designed PEs.John A. MorrisJahan A. RahmanXinyi GuoNeville E. SanjanaElsevierarticleBiotechnologyComputational bioinformaticsScienceQENiScience, Vol 24, Iss 11, Pp 103380- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biotechnology Computational bioinformatics Science Q
spellingShingle	Biotechnology Computational bioinformatics Science Q John A. Morris Jahan A. Rahman Xinyi Guo Neville E. Sanjana Automated design of CRISPR prime editors for 56,000 human pathogenic variants
description	Summary: Prime editors (PEs) are clustered regularly interspaced short palindromic repeats (CRISPR)-based genome engineering tools that can introduce precise base-pair edits. We developed an automated pipeline to correct (therapeutic editing) or introduce (disease modeling) human pathogenic variants from ClinVar that optimizes the design of several RNA constructs required for prime editing and avoids predicted off-targets in the human genome. However, using optimal PE design criteria, we find that only a small fraction of these pathogenic variants can be targeted. Through the use of alternative Cas9 enzymes and extended templates, we increase the number of targetable pathogenic variants from 32,000 to 56,000 variants and make these pre-designed PE constructs accessible through a web-based portal (http://primeedit.nygenome.org). Given the tremendous potential for therapeutic gene editing, we also assessed the possibility of developing universal PE constructs, finding that common genetic variants impact only a small minority of designed PEs.
format	article
author	John A. Morris Jahan A. Rahman Xinyi Guo Neville E. Sanjana
author_facet	John A. Morris Jahan A. Rahman Xinyi Guo Neville E. Sanjana
author_sort	John A. Morris
title	Automated design of CRISPR prime editors for 56,000 human pathogenic variants
title_short	Automated design of CRISPR prime editors for 56,000 human pathogenic variants
title_full	Automated design of CRISPR prime editors for 56,000 human pathogenic variants
title_fullStr	Automated design of CRISPR prime editors for 56,000 human pathogenic variants
title_full_unstemmed	Automated design of CRISPR prime editors for 56,000 human pathogenic variants
title_sort	automated design of crispr prime editors for 56,000 human pathogenic variants
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/aa7b5526d2e142efb6b75729e67ecc1b
work_keys_str_mv	AT johnamorris automateddesignofcrisprprimeeditorsfor56000humanpathogenicvariants AT jahanarahman automateddesignofcrisprprimeeditorsfor56000humanpathogenicvariants AT xinyiguo automateddesignofcrisprprimeeditorsfor56000humanpathogenicvariants AT nevilleesanjana automateddesignofcrisprprimeeditorsfor56000humanpathogenicvariants
_version_	1718419560344846336

Automated design of CRISPR prime editors for 56,000 human pathogenic variants

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