Abstract
Papillomaviruses (PVs) are a heterogeneous group of DNA viruses that can infect fish, birds, reptiles, and mammals. PVs infecting humans (HPVs) phylogenetically cluster into five genera (Alpha-, Beta-, Gamma-, Mu- and Nu-PV), with differences in tissue tropism and carcinogenicity. The evolutionary features associated with the divergence of Papillomaviridae are not well understood. Using a combination of k-mer distributions, genetic metrics, and phylogenetic algorithms, we sought to evaluate the characteristics and differences of Alpha-, Beta- and Gamma-PVs constituting the majority of HPV genomes. A total of 640 PVs including 442 HPV types, 27 non-human primate PV types, and 171 non-primate animal PV types were evaluated. Our analyses revealed the highest genetic diversity amongst Gamma-PVs compared to the Alpha and Beta PVs, suggesting reduced selective pressures on Gamma-PVs. Using a sequence alignment-free trimer (k = 3) phylogeny algorithm, we reconstructed a phylogeny that grouped most HPV types into a monophyletic clade that was further split into three branches similar to alignment-based classifications. Interestingly, a subset of low-risk Alpha HPVs (the species Alpha-2, 3, 4, and 14) split from other HPVs and were clustered with non-human primate PVs. Surprisingly, the trimer-constructed phylogeny grouped the Gamma-6 species types originally isolated from the cervicovaginal region with the main Alpha-HPV clade. These data indicate that characterization of papillomavirus heterogeneity via orthogonal approaches reveals novel insights into the biological understanding of HPV genomes.
Highlights
Evolutionary incongruence of PV genera inferred from different genes has been reported [2,36], we found that the majority of genomes maintained a consistent clustering using either early (E1-E2) or later genes (L2-L1) when based on the trimer distribution (Figure S3A)
Using the sequences of a large number of viral genomes, we provide evidence of differential evolutionary constraints associated with the heterogeneity of human papillomavirus (HPV) genomes
The separation of a low-risk Alpha-HPV clade (i.e., Alpha-HPV-LR2) from the main clustering of HPV genomes was consistently supported by trimer phylogeny, codon usage and dinucleotide suppression
Summary
Persistent infection of high-risk human papillomaviruses (such as HPV types 16 and 18) is associated with cervical cancer as well as cancers of the lower genital tract and head and neck regions [3]. PV genomes typically contain eight open reading frames (ORFs) that encode core and accessory viral proteins [4]. Core proteins include two early products (E1 and E2) and two late products (L1 and L2), are highly conserved among all papillomaviruses and are involved in viral genome replication and viral assembly, respectively. The accessory proteins (E5, E6 and E7) show greater variability in gene expression and function and are not present in all PV types. After establishing infection by accessing the epithelial basal layer, PV genes are regulated by multiple promoters and a complex patterns of mRNA splicing that coordinates viral gene expression with different stages of the viral life cycle [5]
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