Abstract
Pervasive purifying selection on non-synonymous substitutions is a hallmark of papillomavirus genome history, but the role of selection on and the drift of non-coding DNA motifs on HPV diversification is poorly understood. In this study, more than a thousand complete genomes representing Alphapapillomavirus types, lineages, and SNP variants were examined phylogenetically and interrogated for the number and position of non-coding DNA sequence motifs using Principal Components Analyses, Ancestral State Reconstructions, and Phylogenetic Independent Contrasts. For anciently diverged Alphapapillomavirus types, composition of the four nucleotides (A, C, G, T), codon usage, trimer usage, and 13 established non-coding DNA sequence motifs revealed phylogenetic clusters consistent with genetic drift. Ancestral state reconstruction and Phylogenetic Independent Contrasts revealed ancient genome alterations, particularly for the CpG and APOBEC3 motifs. Each evolutionary analytical method we performed supports the unanticipated conclusion that genetic drift and different evolutionary drivers have structured Alphapapillomavirus genomes in distinct ways during successive epochs, even extending to differences in more recently formed variant lineages.