Chromothripsis as an on-target consequence of CRISPR–Cas9 genome editing
Apr 1, 2021·,,
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0 min read
Mitchell L. Leibowitz
Stamatis Papathanasiou
Phillip A. Doerfler
Logan Blaine
Lili Sun
Yu Yao
Cheng-Zhong Zhang
Mitchell J. Weiss
David Pellman
Abstract
Genome editing has therapeutic potential for treating genetic diseases and cancer. However, the currently most practicable approaches rely on the generation of DNA double-strand breaks (DSBs), which can give rise to a poorly characterized spectrum of chromosome structural abnormalities. Here, using model cells and single-cell whole-genome sequencing, as well as by editing at a clinically relevant locus in clinically relevant cells, we show that CRISPR–Cas9 editing generates structural defects of the nucleus, micronuclei and chromosome bridges, which initiate a mutational process called chromothripsis. Chromothripsis is extensive chromosome rearrangement restricted to one or a few chromosomes that can cause human congenital disease and cancer. These results demonstrate that chromothripsis is a previously unappreciated on-target consequence of CRISPR–Cas9-generated DSBs.
Type
Publication
Nature Genetics, 53(895)
Status
Peer-reviewed
Authors
Logan Blaine
(he/him)
PhD Candidate in Bioinformatics and Integrative Genomics
Logan is a Ph.D. candidate in Biomedical Informatics at Harvard Medical School building probabilistic machine learning systems that reason over large-scale biological data. His work in the Pinello Lab develops Bayesian & deep learning models — spanning representation learning, generative modeling, and causal inference — to turn high-throughput single-cell experiments into testable hypotheses about biological mechanism, with the broader goal of building computational systems that can reason under uncertainty and close the loop with experimental biology.
Outside of lab, he enjoys training for marathons (and the occasional IRONMAN triathlon) and bikepacking around Vermont.