Abstract
Previous analyses have identified certain but limited evidence of recombination among HPV16 genomes, in accordance with a general perception that DNA viruses do not frequently recombine. In this evolutionary/bioinformatics study we have analyzed more than 3600 publicly available complete and partial HPV16 genomes. By studying the phylogenetic incongruence, similarity plots and the distribution patterns of lineage-specific SNPs, we identify several potential recombination events between the two major HPV16 evolutionary clades. These two clades comprise the (widely considered) phenotypically more benign (lower risk) lineage A and the (widely considered) phenotypically more aggressive (higher risk) non-European lineages B, C and D. We observe a frequency of potential recombinant sequences ranging between 0.3 and 1.2% which is low, but nevertheless considerable. Our findings have clinical implications and highlight that HPV16 genotyping and risk assessment based only on certain genomic regions and not the entire genome may provide a false genotype and, therefore, its associated risk estimate. Finally, based on this analysis, we have developed a bioinformatics tool that automates the entire process of HPV16 lineage genotyping, recombination detection and further identifies, within the submitted sequences, SNPs that have been reported in the literature to increase the risk of cancer.
Highlights
Human Papillomaviruses (HPVs) are members of the Papillomaviridae family that consist of a diversified group of small, non-enveloped, dsDNA viruses [1,2]
The software scans each HPV16 sequence for the presence of any of DNA viruses recombine with significantly lower frequency than RNA viruses [24]; there have been reports of homologous [25] and even non-homologous [27]
There have been reports of recombination events within alpha-HPVs, where recombination crossover sites were localized at the E6, E7, L2 and L1 genes, advocating that novel recombinant types could be formed upon a natural viral co-infection [29,30]
Summary
Human Papillomaviruses (HPVs) are members of the Papillomaviridae family that consist of a diversified group of small, non-enveloped, dsDNA viruses [1,2]. According to the Papillomavirus Nomenclature Committee, HPV genomes are further grouped into intratypic variants that have more than 98% sequence similarity with the reference sequence of the L1 gene [5]. Another method of classification, depending on the whole genome sequence, defines variant lineages and sub-lineages by a difference of 1%. The alpha-HPVs infect the mucosal epithelium and they are subdivided into high-risk (HR-HPV) and low-risk (LR-HPV) genotypes, considering their tumorigenic disposition [1,5,8,9]. HR-HPV infection is regarded as a major public health concern, since it is responsible for more than 99% of cervical cancer incidences while HPV16 DNA has been identified in more than 50% of cervical cancer cases worldwide [10,11]
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