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Gene editing of NCF1 loci is associated with homologous recombination and chromosomal rearrangements
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Gene editing of NCF1 loci is associated with homologous recombination and chromosomal rearrangements
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Journal Article
Gene editing of NCF1 loci is associated with homologous recombination and chromosomal rearrangements
2024
Overview
CRISPR-based genome editing of pseudogene-associated disorders, such as p47
phox
-deficient chronic granulomatous disease (p47 CGD), is challenged by chromosomal rearrangements due to presence of multiple targets. We report that interactions between highly homologous sequences that are localized on the same chromosome contribute substantially to post-editing chromosomal rearrangements. We successfully employed editing approaches at the
NCF1
gene and its pseudogenes,
NCF1B
and
NCF1C
, in a human cell line model of p47 CGD and in patient-derived human hematopoietic stem and progenitor cells. Upon genetic engineering, a droplet digital PCR-based method identified cells with altered copy numbers, spanning megabases from the edited loci. We attributed the high aberration frequency to the interaction between repetitive sequences and their predisposition to recombination events. Our findings emphasize the need for careful evaluation of the target-specific genomic context, such as the presence of homologous regions, whose instability can constitute a risk factor for chromosomal rearrangements upon genome editing.
Simultaneous editing of the
NCF1
and its pseudogenes in p47
phox
-deficient chronic granulomatous disease is associated with homologous recombination and chromosomal rearrangements due to presence of multiple targets of high sequence similarity.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
