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Journal of Virology, February 2009, p. 1443-1455, Vol. 83, No. 3
0022-538X/09/$08.00+0     doi:10.1128/JVI.02068-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Evolutionary Dynamics of Variant Genomes of Human Papillomavirus Types 18, 45, and 97{triangledown} ,{dagger}

Zigui Chen,1 Rob DeSalle,2 Mark Schiffman,3 Rolando Herrero,4 and Robert D. Burk1,5*

Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York,1 Sackler Institute of Comparative Genomics, American Museum of Natural History, New York, New York 10024,2 Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, Maryland,3 Proyecto Epidemiológico Guanacaste, Costa Rican Foundation for Health Sciences, San José, Costa Rica,4 Departments of Pediatrics, Epidemiology and Population Health, Obstetrics, Gynecology and Woman's Health, and Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, New York5

Received 1 October 2008/ Accepted 14 November 2008

Human papillomavirus type 18 (HPV18) and HPV45 account for approximately 20% of all cervix cancers. We show that HPV18, HPV45, and the recently discovered HPV97 comprise a clade sharing a most recent common ancestor within HPV {alpha}7 species. Variant lineages of these HPV types were classified by sequence analysis of the upstream regulatory region/E6 region among cervical samples from a population-based study in Costa Rica, and 27 representative genomes from each major variant lineage were sequenced. Nucleotide variation within HPV18 and HPV45 was 3.82% and 2.39%, respectively, and amino acid variation was 4.73% and 2.87%, respectively. Only 18 nucleotide variations, of which 10 were nonsynonymous, were identified among three HPV97 genomes. Full-genome comparisons revealed maximal diversity between HPV18 African and non-African variants (2.6% dissimilarity), whereas HPV18 Asian-American [E1 (AA)] and European (E2) variants were closely related (less than 0.5% dissimilarity); HPV45 genomes had a maximal difference of 1.6% nucleotides. Using a Bayesian Markov chain Monte Carlo (MCMC) method, the divergence times of HPV18, -45, and -97 from their most recent common ancestors indicated that HPV18 diverged approximately 7.7 million years (Myr) ago, whereas HPV45 and HPV97 split off around 5.7 Myr ago, in a period encompassing the divergence of the great ape species. Variants within the HPV18/45/97 lineages were estimated to have diverged from their common ancestors in the genus Homo within the last 1 Myr (<0.7 Myr). To investigate the molecular basis of HPV18, HPV45, and HPV97 evolution, regression models of codon substitution were used to identify lineages and amino acid sites under selective pressure. The E5 open reading frame (ORF) of HPV18 and the E4 ORFs of HPV18, HPV45, and HPV18/45/97 had nonsynonymous/synonymous substitution rate ratios (dN/dS) over 1 indicative of positive Darwinian selection. The L1 ORF of HPV18 genomes had an increased proportion of nonsynonymous substitutions (4.93%; average dN/dS ratio [M3] = 0.3356) compared to HPV45 (1.86%; M3 = 0.1268) and HPV16 (2.26%; M3 = 0.1330) L1 ORFs. In contrast, HPV18 and HPV16 genomes had similar amino acid substitution rates within the E1 ORF (2.89% and 3.24%, respectively), while HPV45 E1 was highly conserved (amino acid substitution rate was 0.77%). These data provide an evolutionary history of this medically important clade of HPVs and identify an unexpected divergence of the L1 gene of HPV18 that may have clinical implications for the long-term use of an L1-virus-like particle-based prophylactic vaccine.

* Corresponding author. Mailing address: 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

{triangledown} Published ahead of print on 26 November 2008.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org/.

Journal of Virology, February 2009, p. 1443-1455, Vol. 83, No. 3
0022-538X/09/$08.00+0     doi:10.1128/JVI.02068-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Leiner, S., Kahn, J. A. (2009). HPV Vaccination. NEJM 361: 1610-1611 [Full Text]  


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