BEable-GPS: Database of disease mutations that can be caused by a base editor Genome Biology。

Title: Comparison of cytosine base editors and development of the BEable-GPS database for targeting Pathogenic SNVs
Journal:
Ying Wang, Runze Gaoze, et al.
published on 10/23/2019
DOI:
WeChat Link:
CRISPR/Cas-based cytosine base editor(CBE) is a new generation of genome editing tools developed in recent years, integrated by Cas editing enzymes and cytosine deaminase, to achieve efficient C-to-T mono-base editing at targeted locations. Because it does not depend on the characteristics of bichain fractures in genomic DNA, it has great potential for clinical applications, such as the correction of single-base mutations associated with human diseases. C-to-T and T-to-C account for about 60% of the single base mutations associated with all human diseases, and in theory these C-to-T and T-to-C mutations can be produced or corrected using the cytosine base editor (Figure 1).。 The David Liu team at Harvard University and the Akihiko Kondo team at Kobe University in Japan first reported this base editing technique in The Nature and Science magazines in 2016, causing worldwide sensations and being named one of science magazine's top 10 scientific breakthroughs of the year in 2017. Currently, using the combination of different types of gene editing enzymes
and different types of cytosine deaminase
, dozens of optimized versions of base editors have been reported worldwide, including by Yang Li, a researcher at the Institute of Computational Biology Partners of the
-German Mag institute in China, in collaboration with Professors Chen Jia and Huang Li xu of the School of Life at Shanghai University of Science and Technology. The team first began the development of base editors and related basic innovation theory research in China, revealed the complex interactions and molecular mechanisms of different base editing and modification in the body, discovered the new mechanism for the interaction of external Cas editing enzymes with endogenetic cytosine deaminase to produce genomic mutations, and constructed an enhanced base base that can reduce genomic mutations. The base editor system eBE, through screening and systematic research, further created an efficient genomic base editor hA3A-eBEs that can be used in methylated regions and an efficient genomic base editor dCpf1-eBEs (Figure 2) that lowers genomic loss and insertion mutations. However, due to the differences in substrate sequence preferences between different base editors, there is no systematic comparative study of the efficacy of these base editors. At the same time, there is no systematic integration and summary of the single base mutation points associated with human diseases that can be used by different base editors in the field of gene editing.。 Recently, Yang Li's team and Professor Chen Jia's team worked closely together again, publishing a research paper entitled "
" on Gene Biology, which for the first time systematically compared the editing efficiency and purity of the editing products of five representative base editors
at common targeting points. The study found that, on the one hand, BE4max and hA3A-eBE-Y130F achieved the highest editing efficiency, and because the hA3A-eBE-Y130F base editor integrated highly catalytic activity of hA3A cytosine deaminase, its editing ability in human disease-related mutation points is most prominent. On the other hand, the dCpf1-eBE base editor has the highest editing product purity because it integrates dCpf1
gene editing enzymes that completely lose the activity of the DNA inchease, which produces the fewest editing by-products during the base editing process.In order to better promote basic theory and potential clinical application of base editors in human disease-related mutation site, researchers collected and integrated information on all known human disease-related mutation site, predicted the potential of up to 20 base editors for these mutation site by computational biology, and further integrated the building of the BEable-GPS
database (
). The database contains editable information from 20 base editor systems for 17,077 C-to-T and 5,032 T-to-C mutation points. Statistics show that 20 base editors can jointly simulate the production of 94.34% of C-to-T single base mutation points, while correcting 94.28% of T-to-C base mutation
. On the database knowledge website, by searching for gene names corresponding to human disease-related mutation sites and selecting up to 20 base editor systems, researchers can obtain base editors and their corresponding gRNA sequences
that can be used for different mutation sites. It is worth noting that the database also integrates the service function of base editing and prediction of any sequence, which provides theoretical support for the wider application of base editor.。 A variety of base editors have been developed to achieve C-to-T editing in different genomic contexts. Here, we compare a panel of five base editors on their C-to-T editing efficiencies and product purity at commonly editable sites, including some human pathogenic C-to-T mutations. We further profile the accessibilities of 20 base editors to all possible pathogenic mutations in silico. Finally, we build the BEable-GPS (Base Editable prediction of Global Pathogenic SNVs) database for users to select proper base editors to model or correct disease-related mutations. The in vivo comparison and in silico profiling catalog the availability of base editors and their broad applications in biomedical studies.
(Source: Science.com)