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Analysis of Integration Sites of Jaagsiekte Sheep Retrovirus in Ovine Pulmonary Adenocarcinoma

Christina Cousens,^1,* Jeanette V. Bishop,^2, Adrian W. Philbey,^1, Clare A. Gill,³ Massimo Palmarini,⁴ Jonathan O. Carlson,² James C. DeMartini,² and J. Michael Sharp^1,

Moredun Research Institute, Edinburgh EH26 0PZ, United Kingdom,¹ Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, Colorado 80523,² Department of Animal Science, Texas A&M University, College Station, Texas 77843-2471,³ Department of Medical Microbiology, College of Veterinary Medicine, University of Georgia, Athens, Georgia⁴

Received 27 January 2004/ Accepted 9 April 2004

Ovine pulmonary adenocarcinoma (OPA) is an infectious lung tumor of sheep caused by Jaagsiekte sheep retrovirus (JSRV). To test the hypothesis that JSRV insertional mutagenesis is involved in the oncogenesis of OPA, we cloned and characterized 70 independent integration sites from 23 cases of OPA. Multiple integration sites were identified in most tumors. BLAST analysis of the sequences did not disclose any potential oncogenic motifs or any identical integration sites in different tumors. Thirty-seven of the integration sites were mapped to individual chromosomes by PCR with a panel of sheep-hamster hybrid cell lines. Integration sites were found on 20 of the 28 sheep chromosomes, suggesting a random distribution. However, four integration sites from four different tumors mapped to chromosome 16. By Southern blot hybridization, probes derived from two of these sites mapped to within 5 kb of each other on normal sheep DNA. These sites were found within a single sheep bacterial artificial chromosome clone and were further mapped to only 2.5 kb apart, within an uncharacterized predicted gene and less than 200 kb from a mitogen-activated protein kinase-encoding gene. These findings suggest that there is at least one common integration site for JSRV in OPA and add weight to the hypothesis that insertional mutagenesis is involved in the development of this tumor.

C. Cousens and J. V. Bishop contributed equally to this work.

Present address: Department of Veterinary Pathology, University of Glasgow, Glasgow G61 1QH, United Kingdom.

Present address: Veterinary Laboratories Agency, Edinburgh EH26 0PZ, United Kingdom.

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