Genome scale analysis of pathogenic variants targetable for single base editing
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RESEARCH
Open Access
Genome scale analysis of pathogenic variants targetable for single base editing Alexander V. Lavrov1* , Georgi G. Varenikov2 and Mikhail Yu Skoblov1,2,3 From 11th International Young Scientists School “Systems Biology and Bioinformatics” – SBB-2019 Novosibirsk, Russia. 24-28 June 2019
Abstract Background: Single nucleotide variants account for approximately 90% of all known pathogenic variants responsible for human diseases. Recently discovered CRISPR/Cas9 base editors can correct individual nucleotides without cutting DNA and inducing double-stranded breaks. We aimed to find all possible pathogenic variants which can be efficiently targeted by any of the currently described base editors and to present them for further selection and development of targeted therapies. Methods: ClinVar database (GRCh37_clinvar_20171203) was used to search and select mutations available for current single-base editing systems. We included only pathogenic and likely pathogenic variants for further analysis. For every potentially editable mutation we checked the presence of PAM. If a PAM was found, we analyzed the sequence to find possibility to edit only one nucleotide without changing neighboring nucleotides. The code of the script to search Clinvar database and to analyze the sequences was written in R and is available in the appendix. Results: We analyzed 21 editing system currently reported in 9 publications. Every system has different working characteristics such as the editing window and PAM sequence. C > T base editors can precisely target 3196 mutations (46% of all pathogenic T > C variants), and A > G editors – 6900 mutations (34% of all pathogenic G > A variants). Conclusions: Protein engineering helps to develop new enzymes with a narrower window of base editors as well as using new Cas9 enzymes with different PAM sequences. But, even now the list of mutations which can be targeted with currently available systems is huge enough to choose and develop new targeted therapies. Keywords: Base editor CRISPR/Cas9, ABE, APOBEC, PmCDA1, Pathogenic variants, Hereditary diseases
Background There are currently over 6000 monogenic diseases according to OMIM [1]. Different DNA alterations may cause a disease, however the main reason of monogenic diseases is a pathogenic single nucleotide variant (SNV). SNVs account for approximately 90% of all records in * Correspondence: [email protected] 1 Research Center for Medical Genetics, Moscow, Russia Full list of author information is available at the end of the article
ClinVar [2] database (Fig. 1a), 23% of which are pathogenic or likely pathogenic (Fig. 1b). Modern molecular genetic techniques, early diagnostics and advanced symptomatic and pathogenic treatment for many hereditary diseases are now available. Despite significant advancement in treating orphan diseases true cure is possible only by direct correction of mutated genes. Genome editing is thought to be the main breakthrough in treating monogenic diseases. The CRISPR/Cas9 system is one of the most
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