{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE255nnn/GSE255084/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Other"],"species":["Homo sapiens"],"gds_type":["Other"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE255084"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"Base editors provoke non-predictable chromosomal translocations and off-target editing [CAST-Seq]","description":"Base editing has emerged as a promising alternative to CRISPR-Cas nuclease-based genome editing, in part because of its promise of reduced genotoxicity. Here, we performed a comprehensive genome-wide analysis of base editing-induced off-target effects. Primary human T cells were edited at three genomic loci (CCR5, EMX1, FANCF) using either CRISPR-Cas9 nuclease, an adenine base editor (ABE8e), one of three cytosine base editors (CBEs), or Cas9 nickase. We used CAST-Seq to identify gross chromosomal aberrations and off-target sites (OTs), followed by rhAmp-Seq to evaluate on-target activity (44-84% modified alleles) and mutagenic effects at >100 putative OTs. On-target CAST-Seq reads showed large (>200 bp) aberrations ranging from 45% for Cas9 to 5% for ABE, 2-7% for CBEs, and 0% for nickase-edited cells. While ABE8e editing induced few translocations, more than 10% of the alleles were modified in 17 of the 40 identified OTs. In contrast, chromosomal translocation events in some CBE-treated cells exceeded that found in Cas9-edited T cells by 3-fold. Furthermore, extensive C-to-T conversion (≤99% of alleles) and mutagenesis (≤7% of alleles) were detected in T cells edited with a hyperactive CBE, whereas recently developed CBE variants (TadCBEd or CBE-T1.52) showed only marginal OT activity. In conclusion, our study revealed the genotoxic potential of ABE8e and the hyperactive evoCDA1-BE4max. These base editors induced mutagenic OT editing at sites that were not altered by CRISPR-Cas9 nucleases complexed with the same gRNA, suggesting that the mechanism of gRNA-dependent OT activity of base editors is different from that of CRISPR-Cas nucleases.","dates":{"publication":"2026/09/28"},"accession":"GSE255084","cross_references":{"GSM":["GSM8063786","GSM8063785","GSM8063784","GSM8063783","GSM8063782","GSM8063781","GSM8063780","GSM8063779","GSM8063778","GSM8063777","GSM8063776","GSM8063789","GSM8063788","GSM8063787","GSM8873386","GSM8063720","GSM8873387","GSM8873388","GSM8873389","GSM8873382","GSM8873383","GSM8873384","GSM8873385","GSM8063719","GSM8063718","GSM8063717","GSM8063716","GSM8873380","GSM8873381","GSM8873397","GSM8063731","GSM8063730","GSM8873398","GSM8873399","GSM8873393","GSM8873394","GSM8873395","GSM8873396","GSM8063729","GSM8063728","GSM8063727","GSM8873390","GSM8873391","GSM8063726","GSM8063725","GSM8873392","GSM8063724","GSM8063723","GSM8063722","GSM8063721","GSM8873364","GSM8063742","GSM8063741","GSM8873365","GSM8873366","GSM8063740","GSM8873400","GSM8873367","GSM8873362","GSM8873363","GSM8873368","GSM8873401","GSM8873369","GSM8873402","GSM8063739","GSM8063738","GSM8063737","GSM8063736","GSM8063735","GSM8063734","GSM8063733","GSM8063732","GSM8063753","GSM8873375","GSM8063752","GSM8873376","GSM8873377","GSM8063751","GSM8063750","GSM8873378","GSM8873371","GSM8873372","GSM8873373","GSM8873374","GSM8873379","GSM8063749","GSM8063748","GSM8063747","GSM8873370","GSM8063746","GSM8063745","GSM8063744","GSM8063743","GSM8063764","GSM8063763","GSM8063762","GSM8063761","GSM8063760","GSM8063759","GSM8063758","GSM8063757","GSM8063756","GSM8063755","GSM8063754","GSM8063775","GSM8063774","GSM8063773","GSM8063772","GSM8063771","GSM8063770","GSM8063769","GSM8063768","GSM8063767","GSM8063766","GSM8063765"],"GPL":["24676"],"GSE":["255084"],"taxon":["Homo sapiens"]}}