High Mutation Rates in Non-human Primates Edited by Cytosine Base Editors.

Area of Science:

• Genomics
• Gene Editing Technologies
• Animal Models

Background:

• Gene-edited animals are increasingly utilized in research and development.
• Genome-wide mutation rates in these animals are not well-characterized.
• Understanding mutation rates is crucial for assessing the safety and efficacy of gene editing.

Purpose of the Study:

• To analyze and compare genome-wide mutation rates in animals edited by different gene editing technologies.
• To specifically investigate the mutation rates associated with cytosine base editors (CBEs).
• To establish the necessity of evaluating de novo mutations in gene-edited animals.

Main Methods:

• Analysis of publicly available genome sequencing datasets from parent-offspring trios.
• Comparative analysis of mutation rates between gene-edited and unedited control animals.
• Utilizing a streamlined bioinformatics pipeline for de novo mutation detection.

Main Results:

• Cytosine base editors (CBEs) induced a remarkably high mutation rate in non-human primates, approximately 158-fold higher than controls.
• CBE-edited mice exhibited a 4-fold increase in mutation rate compared to unedited mice.
• Significant genome-wide de novo mutations were detected in CBE-edited animals.

Conclusions:

• Cytosine base editors (CBEs) are associated with substantially elevated genome-wide mutation rates in animals.
• Thorough evaluation of de novo mutations is essential when employing CBEs in animal models.
• These findings underscore the importance of rigorous safety assessments for gene-edited animals in translational medicine.