Frequent Gene Conversion In Human Embryos Induced By Double Strand Breaks
Mitalipov, S.
Show abstract
Applications of genome editing ultimately depend on DNA repair triggered by targeted double-strand breaks (DSBs). However, repair mechanisms in human cells remain poorly understood and vary across different cell types. Here we report that DSBs selectively induced on a mutant allele in heterozygous human embryos are repaired by gene conversion using an intact wildtype homolog as a template in up to 40% of targeted embryos. We also show that targeting of homozygous loci facilitates an interplay of non-homologous end joining (NHEJ) and gene conversion and results in embryos which carry identical indel mutations on both loci. Additionally, conversion tracks may expand bidirectionally well beyond the target region leading to an extensive loss of heterozygosity (LOH). Our study demonstrates that gene conversion and NHEJ are two major DNA DSB repair mechanisms in preimplantation human embryos. While gene conversion could be applicable for gene correction, extensive LOH presents a serious safety concern.
Matching journals
The top 5 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Mitochondrial DNA variants segregate during human preimplantation development into genetically different cell lineages that are maintained postnatally 94%
- Novel truncating mutations in CTNND1 cause a dominant craniofacial and cardiac syndrome 92%
- Differential expression of a disease-associated MRE11 variant reveals distinct phenotypic outcomes 92%
Similar papers in this journal
- The DNA helicase FANCJ (BRIP1) functions in Double Strand Break repair processing, but not crossover formation during Prophase I of meiosis in male mice 93%
- Pathways and signatures of mutagenesis at targeted DNA nicks 92%
- Mutation Of MLH3 Endonuclease Motif Reveals Integration Between Crossover Pathways In Mammalian Meiosis 92%
Similar papers in this journal
- Biallelic pathogenic variants in TRMT1 disrupt tRNA modification and induce a syndromic neurodevelopmental disorder 92%
- Mutations in MYLPF cause a novel segmental amyoplasia that manifests as distal arthrogryposis 92%
- Missense variants affecting the actin-binding domains of PLS3 cause X-linked congenital diaphragmatic hernia and body wall defects 91%
Similar papers in this journal
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.