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Journal of Virology, June 2005, p. 7014-7023, Vol. 79, No. 11
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.11.7014-7023.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Diversifying Selection in Human Papillomavirus Type 16 Lineages Based on Complete Genome Analyses

Zigui Chen,1 Masanori Terai,1,{dagger} Leiping Fu,1 Rolando Herrero,3 Rob DeSalle,4 and Robert D. Burk1,2*

Department of Microbiology & Immunology,1 Departments of Pediatrics, Epidemiology & Population Health, and Obstetrics, Gynecology and Women's Health, Albert Einstein Cancer Center, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461,2 Proyecto Epidemiológico Guanacaste, Costa Rican Foundation for Health Sciences, San José, Costa Rica,3 Division of Invertebrate Zoology, American Museum of Natural History, New York, New York 100244

Received 18 October 2004/ Accepted 27 January 2005

Human papillomavirus type 16 (HPV16) is the primary etiological agent of cervical cancer, the second most common cancer in women worldwide. Complete genomes of 12 isolates representing the major lineages of HPV16 were cloned and sequenced from cervicovaginal cells. The sequence variations within the open reading frames (ORFs) and noncoding regions were identified and compared with the HPV16R reference sequence (50). This whole-genome approach gives us unprecedented precision in detailing sequence-level changes that are under selection on a whole-viral-genome scale. Of 7,908 base pair nucleotide positions, 313 (4.0%) were variable. Within the 2,452 amino acids (aa) comprising 8 ORFs, 243 (9.9%) amino acid positions were variable. In order to investigate the molecular evolution of HPV16 variants, maximum likelihood models of codon substitution were used to identify lineages and amino acid sites under selective pressure. Five codon sites in the E5 (aa 48, 65) and E6 (aa 10, 14, 83) ORFs were demonstrated to be under diversifying selective pressure. The E5 ORF had the overall highest nonsynonymous/synonymous substitution rate ({omega}) ratio (M3 = 0.7965). The E2 gene had the next-highest {omega} ratio (M3 = 0.5611); however, no specific codons were under positive selection. These data indicate that the E6 and E5 ORFs are evolving under positive Darwinian selection and have done so in a relatively short time period. Whether response to selective pressure upon the E5 and E6 ORFs contributes to the biological success of HPV16, its specific biological niche, and/or its oncogenic potential remains to be established.

* Corresponding author. Mailing address: Albert Einstein Comprehensive Cancer Center, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461. Phone: (718) 430-3720. Fax: (718) 430-8975. E-mail: burk{at}aecom.yu.edu.

{dagger} Present address: National Research Institute for Child Health & Development, 3-35-31 Taishidoh, Setagaya, Tokyo 154-8567, Japan.

Journal of Virology, June 2005, p. 7014-7023, Vol. 79, No. 11
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.11.7014-7023.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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