Genome scale analysis of pathogenic variants targetable for single base editing

Area of Science:

• Genetics
• Molecular Biology
• Biotechnology

Background:

• Single nucleotide variants (SNVs) are responsible for approximately 90% of human genetic diseases.
• CRISPR/Cas9 base editors offer precise nucleotide correction without inducing double-stranded DNA breaks.

Purpose of the Study:

• To identify all pathogenic variants efficiently targetable by current base editing systems.
• To provide a foundation for developing targeted gene therapies.

Main Methods:

• Utilized the ClinVar database (GRCh37_clinvar_20171203) to identify pathogenic and likely pathogenic variants.
• Analyzed variants for the presence of Protospacer Adjacent Motif (PAM) sequences.
• Assessed the feasibility of single nucleotide editing without altering adjacent bases using R scripts.

Main Results:

• Analyzed 21 base editing systems from 9 publications.
• Cytosine (C) to Thymine (T) base editors can target 3196 mutations (46% of pathogenic T>C variants).
• Adenine (A) to Guanine (G) base editors can target 6900 mutations (34% of pathogenic G>A variants).

Conclusions:

• Current base editing systems can target a substantial number of pathogenic mutations.
• Ongoing protein engineering and development of novel Cas9 enzymes will expand targeting capabilities.
• The identified targetable mutations provide a significant resource for developing novel genetic therapies.