Publications Search

Abstract

Title: Evolutionary dynamics of human papillomavirus types 18, 45 and 97 variant genomes.
Author: Chen Z,Desalle R,Schiffman M,Herrero R,Burk RD
Journal: J Virol
Year: 2008
Month: November

Abstract: 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 alpha7 species. Variant lineages of these HPV types were classified by sequence analysis of the URR/E6 region amongst 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%, and amino acid (aa) 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 (Af) 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 HPV18 diverged approximately 7.3 million years (Myr) ago, whereas HPV45 and HPV97 split off around 5.3 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 one million years (< 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 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%; with an 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 aa substitution rates within the E1 ORF (2.89% and 3.24%, respectively), while HPV45 E1 was highly conserved (aa 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-VLP based prophylactic vaccine.