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Despite their industrial relevance, comprehensive data on their genomic background and stability remains limited. Here, we systematically analyze the genetic landscape of various HEK293 cell lines in response to cultivation conditions, clonal selection, genetic manipulation and over time in culture. Adherent HEK293 were adapted to suspension growth using different serum\u2010free media. Whole genome sequences from these cell lines were analyzed together with previously published data from additional variants in common use. All data sets were aligned against the human reference genome, enabling the assessment of genome stability by evaluation of variants and revealing a conserved genetic core across all lines, regardless of cultivation history or phenotypic divergence. Evaluation of the functional implications of conserved core mutations identified an enrichment in genes related to cellular structure, morphology and cellular connectivity. The distribution of structural variants and single nucleotide polymorphisms indicated a gradual accumulation of mutations over time in culture rather than abrupt shifts in response to environmental changes. Notably, the integrated adenoviral genes remained highly conserved with respect to copy number, integration site and sequence integrity. These findings provide insight into the genomic evolution of HEK293 cells and offer a foundation for further multi\u2010omics studies aimed at optimizing HEK293 cells for applications in biopharmaceutical production.<\/jats:p>","DOI":"10.1002\/bit.70105","type":"journal-article","created":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T13:48:43Z","timestamp":1762782523000},"page":"436-448","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Comparative Analysis of HEK293 Genomic Variability"],"prefix":"10.1002","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-6486-4390","authenticated-orcid":false,"given":"Georg","family":"Smesnik","sequence":"first","affiliation":[{"name":"Institute of Bioprocess Science and Engineering, Department of Biotechnology and Food Science CD Laboratory of Knowledge\u2010Based Production of Gene Therapy Vectors, BOKU University Vienna Austria"},{"name":"Institute of Bioprocess Science and Engineering, Department of Biotechnology and Food Science BOKU University Vienna Austria"},{"name":"Institute of Animal Cell Technology and Systems Biology, Department of Biotechnology and Food Science BOKU University Vienna Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikolaus","family":"Virgolini","sequence":"additional","affiliation":[{"name":"Institute of Bioprocess Science and Engineering, Department of Biotechnology and Food Science CD Laboratory of Knowledge\u2010Based Production of Gene Therapy Vectors, BOKU University Vienna Austria"},{"name":"Institute of Bioprocess Science and Engineering, Department of Biotechnology and Food Science BOKU University Vienna Austria"},{"name":"Institute of Animal Cell Technology and Systems Biology, Department of Biotechnology and Food Science BOKU University Vienna Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Toth","sequence":"additional","affiliation":[{"name":"Institute of Bioprocess Science and Engineering, Department of Biotechnology and Food Science CD Laboratory of Knowledge\u2010Based Production of Gene Therapy Vectors, BOKU University Vienna Austria"},{"name":"Institute of Bioprocess Science and Engineering, Department of Biotechnology and Food Science BOKU University Vienna Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6007-7697","authenticated-orcid":false,"given":"Astrid","family":"D\u00fcrauer","sequence":"additional","affiliation":[{"name":"Institute of Bioprocess Science and Engineering, Department of Biotechnology and Food Science CD Laboratory of Knowledge\u2010Based Production of Gene Therapy Vectors, BOKU University Vienna Austria"},{"name":"Institute of Bioprocess Science and Engineering, Department of Biotechnology and Food Science BOKU University Vienna Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6324-9338","authenticated-orcid":false,"given":"Nicole","family":"Borth","sequence":"additional","affiliation":[{"name":"Institute of Bioprocess Science and Engineering, Department of Biotechnology and Food Science CD Laboratory of Knowledge\u2010Based Production of Gene Therapy Vectors, BOKU University Vienna Austria"},{"name":"Institute of Animal Cell Technology and Systems Biology, Department of Biotechnology and Food Science BOKU University Vienna Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,11,10]]},"reference":[{"key":"e_1_2_9_2_1","unstructured":"Andrews S. 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