Evidence of Diversifying Selection in Human Papillomavirus Type 16 E6 But Not E7 Oncogenes

Human papillomavirus type 16 is a common sexually transmitted pathogen capable of giving rise to cervical intraepithelial neoplasia and invasive carcinoma through the expression and activity of two adjacent oncogenes: E6 and E7. Naturally occurring amino acid variation is commonly observed in the E6 protein but to a much lesser extent in E7. In order to investigate the evolutionary mechanisms involved in the generation and maintenance of this variation, we examine 42 distinct E6-E7 haplotypes using codon-based genealogical techniques. These techniques involve estimation of the ratio of nonsynonymous to synonymous substitutions (dn/ds) and allow testing for directional (positive) natural selection. Positive selection was detected for four codon sites within the E6 oncogene but not in any E7 codons. The amino acid compositions and locations of selected sites are described. Possible sources of natural selection including antiviral immune pressure and polymorphism of host cellular proteins are discussed.