Our aim was to study the phylogenetic relationships of all known papillomaviruses (PVs) and the possibility of establishing a supratype taxonomic classification based on this information. Of the many detectably homologous segments present in PV genomes, a 291-bp segment of the L1 gene is notable because it is flanked by the MY09 and MY11 consensus primers and contains highly conserved amino acid residues which simplify sequence alignment. We determined the MY09-MY11 sequences of human PV type 20 (HPV-20), HPV-21, HPV-22, HPV-23, HPV-24, HPV-36, HPV-37, HPV-38, HPV-48, HPV-50, HPV-60, HPV-70, HPV-72, HPV-73, ovine (sheep) PV, bovine PV type 3 (BPV-3), BPV-5, and BPV-6 and created a database which now encompasses HPV-1 to HPV-70, HPV-72, HPV-73, seven yet untyped HPV genomes, and 15 animal PV types. Three additional animal PVs were analyzed on the basis of other sequence data. We constructed phylogenies based on partial L1 and E6 gene sequences and distinguished five major clades that we call supergroups. One of them unites 54 genital PV types, which can be further divided into eleven groups. The second supergroup has 24 types and unites most PVs that are typically found in epidermodysplasia verruciformis patients but also includes several types typical of other cutaneous lesions, like HPV-4. The third supergroup unites the six known ungulate fibropapillomaviruses, the fourth includes the cutaneous ungulate PVs BPV-3, BPV-4, and BPV-6, and the fifth includes HPV-1, HPV-41, HPV-63, the canine oral PV, and the cottontail rabbit PV. The chaffinch PV and two rodent PVs, Micromys minutus PV and Mastomys natalensis PV, are left ungrouped because of the relative isolation of each of their lineages. Within most supergroups, groups formed on the basis of cladistic principles unite phenotypically similar PV types. We discuss the basis of our classification, the concept of the PV type, speciation, PV-host evolution, and estimates of their rates of evolution. During the last decade, papillomaviruses (PVs) have at-tracted increasing scientific attention, as they are quantitatively the most important group of viruses associated with benign and malignant neoplasia in humans (40, 73). Currently, more than 70 different human PV (HPV) types are known (15), and additional evidence from partial sequences indicates the exis-tence of a further 13 which would qualify as novel HPV types (2, 5). Other PV types have also been identified in mammals and birds (61). The large number of PV types and poorly defined lower-(e.g., subtypes) and higher-order classifications (e.g., mucosal HPVs) have become a potential source of con-fusion, and it seems desirable to investigate the possibility of giving them some internal taxonomic organization. Before this is done, it is necessary to have a clear definition of the objects one is classifying and reliable hypotheses about their phylog-eny. PV types are the objects to be classified, and they are defined by genomic properties rather than serology; thus, the term serotype is not used. The original definition was by DNA hy-bridization criteria (9), but this method had a serious limitation in that the values determined for genomic similarities were frequently very different from and inconsistently related to nucleotide sequence similarities. In fact, PVs which show little or no relatedness by hybridization could still have a greater than 50% nucleotide similarity. This is due to the scattered distribution of short sequence homologies. To overcome this inconsistency, an HPV genome is now defined as a new HPV type when it shows a more than 10% dissimilarity in the com-bined nucleotide sequences of the E6, E7, and L1 genes when compared with those of any previously known type (15). This requires the sequencing of about 2.4 kb, or roughly one-third, of the genome of all new isolates and then sequence alignment and the calculation of dissimilarity according to certain oper-ational criteria. Phylogenetic research uses homologous features such as nu-cleotide sequences to reconstruct evolutionary relationships which are graphically represented as trees. As a result of large systematic sequencing efforts (for a review, see reference 13), the PVs have become the best-known DNA virus family and an important resource for the study of virus evolution (4, 7, 31, 50, 65). Since the first extensive phylogenetic studies of PVs were done (7, 65), there has been a doubling of the number of PV types for which complete or partial sequence information is known. There are indications that the rate at which new genital HPV types are detected is slowing down (5, 66), while only small efforts to detect novel PVs in animals are presently made. However, many new HPV genomes related to the epider-modysplasia verruciformis (EV) HPVs have recently been found in skin cancers from renal transplant patients (2, 57). Because of this increase in the number of known sequences, the advent of fresh analytical approaches, and the need for taxonomic investigation, we felt it would be helpful to under-take a revision of PV phylogeny. Given the objects to be classified and their phylogeny, there are broadly three main taxonomic approaches one can take.
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