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

Abstract

Papillomaviruses are a heterogeneous group of DNA viruses with closed circular double-stranded DNA genomes of about 8 kb in size that contain three general regions. An upstream regulatory region (URR) contains sequences that control transcription and replication, an early region contains genes (e.g., E6, E7, E1, E2, E4, and E5) involved primarily in enzymatic activities, and a structural region produces the L1 capsid protein and L2, which facilitates packaging of the viral DNA. Human papillomaviruses (HPVs) are classified by the sequence similarity of their genomes. A cloned HPV genome whose L1 open reading frame (ORF) displays less than 90% similarity to previously designated types is defined as a novel type. To date, more than 90 different genotypes of the HPV have been fully characterized (21). Intratypic variants and subtypes are defined as HPVs that vary by less than 10% in their L1 DNA sequences (5, 21).HPVs are causally involved in the etiology of cervical cancer and its precursor lesions (16,17,43,49). Of the high-risk HPV types associated with cervical cancer, HPV16 is the most prevalent and is found in approximately half of all cancers (7, 49). Numerous variants of HPV16 have been identified in different geographic locations and ethnic groups (35,42,53,68). Although all HPV16 isolates are closely related, previous studies inferred five distinct phylogenetic branches among HPV16 variants: European (E), Asian (As), Asian-American (As-Am), African-1 (Af-1), and African-2 (Af-2), corresponding to the geographic locations from which the samples were obtained (12,34). Subsequent studies by sequence analyses of the HPV16 variants in other genomic regions (e.g., E6, L2, and L1) expanded and complemented this phylogenetic hypothesis (69).Although HPV16 variants are an important focus of phylogenetic studies and the molecular variants of E2, L2, L1, the URR, and especially the E6 region have been described in detail previously (28), covariation among different ORFs belonging to the same lineage or isolate have not been studied in great detail. HPV16 variants have demonstrable differences in biological properties in vitro which may be responsible, in part, for differences in pathogenicity, carcinogenic risk, and perhaps immunogenicity (28). Furthermore, HPV16 variants are associated with different cervical cancer risks (6,32,65,67). Although the diversifying selection in the HPV16 E6 and E7 oncogenes has been described recently (20), the evolutionary basis of the entire genome, coevolutionary mechanisms among different HPV16 genes, and their underlying biological significance remain unknown. Obtaining whole-genome sequences representative of the major HPV16 variants allowed us to determine with certainty nucleotide and amino acid sequence changes that are of potential evolutionary importance.Comparison of synonymous (silent; d S ) and nonsynonymous

Profile of physical status and gene variation of human papillomavirus 58 genome in cervical cancer

“…Three of the amino acid changes (SerAAla, ValALeu and LeuAPhe; S279A, V282L and L340F) were located in the C-terminal domain and one (SerAAla, S236A) was located in the hinged region. No amino acid changes were found in the transactivation domain of HPV 58 E2 protein, which could mean that the amino acids in the transactivation domain of HPV 58 E2 protein are quite conserved, compared with HPV 16 (Chen et al, 2005).…”

The immortalizing and transforming ability of two common human papillomavirus 16 E6 variants with different prevalences in cervical cancer

“…Compared with HPV16 prototype, AA differs by three amino acid changes within its E6 protein denoted Q14H/H78Y/L83V. Interestingly, amino acid changes at positions 14 and 83 were found to be under Darwinian selective pressure (Chen et al, 2005). On the basis of the predicted structural HPV16 E6 model, these residues are buried, there by effecting the stability and function of the E6 protein (Nomine et al, 2006).…”

Isolation and genomic characterization of the first Norway rat (Rattus norvegicus) papillomavirus and its phylogenetic position within Pipapillomavirus, primarily infecting rodents

“…(s/b/y) has been inferred from the correspondence of approximately 2 % difference in the L1 gene between major variants of mucosotropic types (Ong et al, 1993;Halpern, 2000;Chen et al, 2005) and an extended reduction of the human population ('bottleneck') that may have ended 100 000 years ago (Gibbons, 1995;Harpending et al, 1998). Most reliable evolutionary rates for PVs, ranging between 1.44610 28 and 2.69610 28 s/b/y, have been inferred from congruent phylogenies between members of the Carnivora and the genus Lambdapapillomavirus (l-PV; Rector et al, 2007).…”

“…Timing divergence events has become increasingly popular during the past years, including in PV evolutionary virology (Halpern, 2000;Chen et al, 2005). Under the most Rodent PV phylogeny Fig.…”