{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T16:20:10Z","timestamp":1789057210471,"version":"build-2803163510"},"reference-count":56,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2018,10,27]],"date-time":"2018-10-27T00:00:00Z","timestamp":1540598400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Biotech &amp; Bioengineering"],"published-print":{"date-parts":[[2019,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Chinese hamster ovary cells, commonly used in the production of therapeutic proteins, are aneuploid. Their chromosomes bear structural abnormality and undergo changes in structure and number during cell proliferation. Some production cell lines are unstable and lose their productivity over time in the manufacturing process and during the product\u2019s life cycle. To better understand the link between genomic structural changes and productivity stability, an immunoglobulin G producing cell line was successively single\u2010cell cloned to obtain subclones that retained or lost productivity, and their genomic features were compared. Although each subclone started with a single karyotype, the progeny quickly diversified to a population with a distribution of chromosome numbers that is not distinctive from the parent and among subclones. The comparative genomic hybridization (CGH) analysis showed that the extent of copy variation of gene coding regions among different subclones stayed at levels of a few percent. Genome regions that were prone to loss of copies, including one with a product transgene integration site, were identified in CGH. The loss of the transgene copy was accompanied by loss of transgene transcript level. Sequence analysis of the host cell and parental producing cell showed prominent structural variations within the regions prone to loss of copies. Taken together, we demonstrated the transient nature of clonal homogeneity in cell line development and the retention of a population distribution of chromosome numbers; we further demonstrated that structural variation in the transgene integration region caused cell line instability. Future cell line development may target the transgene into structurally stable regions.<\/jats:p>","DOI":"10.1002\/bit.26823","type":"journal-article","created":{"date-parts":[[2018,8,25]],"date-time":"2018-08-25T09:06:24Z","timestamp":1535187984000},"page":"41-53","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":45,"title":["Recurring genomic structural variation leads to clonal instability and loss of productivity"],"prefix":"10.1002","volume":"116","author":[{"given":"Arpan A.","family":"Bandyopadhyay","sequence":"first","affiliation":[{"name":"Department of Chemical Engineering and Materials Science University of Minnesota Minneapolis Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofie A.","family":"O\u2019Brien","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering and Materials Science University of Minnesota Minneapolis Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8077-3617","authenticated-orcid":false,"given":"Liang","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering and Materials Science University of Minnesota Minneapolis Minnesota"},{"name":"Present address: East China University of Science and Technology Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsu\u2010Yuan","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering and Materials Science University of Minnesota Minneapolis Minnesota"},{"name":"Present address: MycoMagic Co. Ltd New Taipei City Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nandita","family":"Vishwanathan","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering and Materials Science University of Minnesota Minneapolis Minnesota"},{"name":"Present address: Merck Serono Corsier\u2010sur\u2010Vevey Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5964-2900","authenticated-orcid":false,"given":"Wei\u2010Shou","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering and Materials Science University of Minnesota Minneapolis Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,10,27]]},"reference":[{"key":"e_1_2_6_1_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/bit.26231"},{"key":"e_1_2_6_1_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/bit.24485"},{"issue":"11","key":"e_1_2_6_1_4_1","first-page":"45","article-title":"Genomics and systems biotechnology in biopharmaceutical processing","volume":"110","author":"Bandyopadhyay A.","year":"2014","journal-title":"Chemical Engineering Progress"},{"key":"e_1_2_6_1_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10295-017-1913-4"},{"key":"e_1_2_6_1_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/bit.10517"},{"key":"e_1_2_6_1_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/0014-4827(71)90149-2"},{"key":"e_1_2_6_1_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/bit.24347"},{"key":"e_1_2_6_1_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymeth.2011.11.002"},{"key":"e_1_2_6_1_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/bit.22158"},{"key":"e_1_2_6_1_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/bit.24733"},{"key":"e_1_2_6_1_12_1","doi-asserted-by":"publisher","DOI":"10.1042\/BA20000090"},{"key":"e_1_2_6_1_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00319690"},{"key":"e_1_2_6_1_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2005.12.111"},{"key":"e_1_2_6_1_15_1","doi-asserted-by":"publisher","DOI":"10.1263\/jbb.103.82"},{"key":"e_1_2_6_1_16_1","unstructured":"European Medicines Agency.\u00a0ICH Harmonized Tripartite Guideline Q5D Quality of biotechnological products: derivation and characterisation of cell substrates used for production of biotechnological\/biological products 1998."},{"key":"e_1_2_6_1_17_1","doi-asserted-by":"publisher","DOI":"10.1097\/00002371-199705000-00007"},{"key":"e_1_2_6_1_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/bit.25990"},{"key":"e_1_2_6_1_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biologicals.2016.01.001"},{"key":"e_1_2_6_1_20_1","doi-asserted-by":"publisher","DOI":"10.3181\/00379727-122-31293"},{"key":"e_1_2_6_1_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/bit.26268"},{"key":"e_1_2_6_1_22_1","doi-asserted-by":"publisher","DOI":"10.1021\/bp0501524"},{"key":"e_1_2_6_1_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbiotec.2009.09.008"},{"key":"e_1_2_6_1_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/bit.23189"},{"key":"e_1_2_6_1_25_1","doi-asserted-by":"publisher","DOI":"10.1021\/bp000144h"},{"key":"e_1_2_6_1_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0290(19980405)58:1<73::AID-BIT8>3.0.CO;2-R"},{"key":"e_1_2_6_1_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0290(19990920)64:6<741::AID-BIT14>3.0.CO;2-X"},{"key":"e_1_2_6_1_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/btpr.2594"},{"key":"e_1_2_6_1_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/bit.26002"},{"key":"e_1_2_6_1_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep08572"},{"key":"e_1_2_6_1_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.2624"},{"key":"e_1_2_6_1_32_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp324"},{"key":"e_1_2_6_1_33_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp352"},{"key":"e_1_2_6_1_34_1","unstructured":"Martinet D. Derouazi M. Besuchet N. Wicht M. Beckmann J. &Wurm F. M.(2007).Karyotype of CHO DG44 cells. Paper presented at the Cell Technology for Cell Products Dordrecht."},{"key":"e_1_2_6_1_35_1","doi-asserted-by":"publisher","DOI":"10.1002\/btpr.2572"},{"key":"e_1_2_6_1_36_1","unstructured":"Biotechnology Journal 2018"},{"key":"e_1_2_6_1_37_1","doi-asserted-by":"publisher","DOI":"10.1093\/biostatistics\/kxh008"},{"key":"e_1_2_6_1_38_1","doi-asserted-by":"publisher","DOI":"10.1093\/dnares\/dsu029"},{"key":"e_1_2_6_1_39_1","doi-asserted-by":"publisher","DOI":"10.1002\/bit.23216"},{"key":"e_1_2_6_1_40_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.10.1.401"},{"key":"e_1_2_6_1_41_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts378"},{"key":"e_1_2_6_1_42_1","doi-asserted-by":"publisher","DOI":"10.3181\/00379727-132-34285"},{"issue":"4","key":"e_1_2_6_1_43_1","first-page":"540","article-title":"Reciprocal translocation observed in end\u2010of\u2010production cells of a commercial CHO\u2010based process","volume":"69","author":"Rouiller Y.","year":"2015","journal-title":"PDA Journal of Pharmaceutical Science and Technology"},{"key":"e_1_2_6_1_44_1","first-page":"56","article-title":"Step\u2010wise and punctuated genome evolution drive phenotype changes of tumor cells","volume":"771","author":"Stepanenko A.","year":"2015","journal-title":"Mutation Research\/DNA Repair"},{"key":"e_1_2_6_1_45_1","doi-asserted-by":"publisher","DOI":"10.1002\/bit.26453"},{"key":"e_1_2_6_1_46_1","doi-asserted-by":"publisher","DOI":"10.1002\/biot.201700495"},{"key":"e_1_2_6_1_47_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12896-016-0238-0"},{"key":"e_1_2_6_1_48_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btl646"},{"key":"e_1_2_6_1_49_1","doi-asserted-by":"publisher","DOI":"10.1002\/bit.26311"},{"key":"e_1_2_6_1_50_1","doi-asserted-by":"publisher","DOI":"10.1002\/biot.201500455"},{"key":"e_1_2_6_1_51_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF01550985"},{"key":"e_1_2_6_1_52_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.1041640121"},{"key":"e_1_2_6_1_53_1","doi-asserted-by":"publisher","DOI":"10.3390\/pr1030296"},{"key":"e_1_2_6_1_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbiotec.2010.04.004"},{"key":"e_1_2_6_1_55_1","doi-asserted-by":"publisher","DOI":"10.1002\/bit.21665"},{"key":"e_1_2_6_1_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cels.2017.04.009"},{"key":"e_1_2_6_1_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbiotec.2010.03.020"}],"container-title":["Biotechnology and Bioengineering"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fbit.26823","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/bit.26823","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T12:39:13Z","timestamp":1759927153000},"score":1,"resource":{"primary":{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/10.1002\/bit.26823"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,10,27]]},"references-count":56,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2019,1]]}},"alternative-id":["10.1002\/bit.26823"],"URL":"https:\/\/doi.org\/10.1002\/bit.26823","archive":["Portico"],"relation":{},"ISSN":["0006-3592","1097-0290"],"issn-type":[{"value":"0006-3592","type":"print"},{"value":"1097-0290","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,10,27]]},"assertion":[{"value":"2018-03-29","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-08-23","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-10-27","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}