title: Diversifying selection in human papillomavirus type 16 lineages based on complete genome analyses.
abstract: 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. 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.
authors.affiliation: Department of Microbiology & Immunology, Albert Einstein Comprehensive Cancer Center, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
authors.forename: Zigui
authors.initials: Z
authors.lastname: Chen
authors.forename: Masanori
authors.initials: M
authors.lastname: Terai
authors.forename: Leiping
authors.initials: L
authors.lastname: Fu
authors.forename: Rolando
authors.initials: R
authors.lastname: Herrero
authors.forename: Rob
authors.initials: R
authors.lastname: DeSalle
authors.forename: Robert D
authors.initials: RD
authors.lastname: Burk
mesh_terms: D000328:Adult; D001483:Base Sequence; D002584:Cervix Uteri / Q000821:virology; D003062:Codon / Q000235:genetics; D004279:DNA, Viral / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D016679:Genome, Viral; D006801:Humans; D008875:Middle Aged; D008969:Molecular Sequence Data; D016366:Open Reading Frames; D027383:Papillomaviridae / Q000145:classification* / Q000235:genetics* / Q000302:isolation & purification / Q000472:pathogenicity; D030361:Papillomavirus Infections / Q000821:virology; D010802:Phylogeny; D011110:Polymorphism, Genetic; D012641:Selection, Genetic; D012689:Sequence Homology, Nucleic Acid
chemical_list: D003062:Codon; D004279:DNA, Viral