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James Chodosh, Gurdeep Singh, Christopher Robinson, Jeong Yoon Lee, Jaya Rajaiya, Morris Jones, David Dyer, Donald Seto; Proteotyping as a tool to study the evolution of human adenoviruses associated with epidemic keratoconjunctivitis. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):4843.
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© ARVO (1962-2015); The Authors (2016-present)
Human adenoviruses of species D (HAdV-D) cause infections of mucosal epithelia, including the ocular surface. HAdV-D types 8, 37, 53, 54, 56, and 64 are the known etiologic agents of epidemic keratoconjunctivitis, a severe and highly contagious ocular surface infection associated with prolonged corneal inflammation. HAdV-D is also the largest and fastest growing HAdV species, populated by 45 of 70 typed HAdVs in GenBank, and 13 of the 18 HAdVs most recently typed. Because the viruses within HAdV-D appear to evolve by multiple rounds of homologous recombination, the degree of relatedness across numerous types at specific genetic loci can be difficult to discern by traditional bioinformatics tools. Proteotyping is a novel bioinformatics approach that provides a unique overview of homologous recombination events in genome evolution.
In proteotyping, maximum likelihood trees are used to align amino acid sequences of hypervariable, frequently recombined proteins. The clade-guided consensus sequence is determined, and each amino acid is assigned a unique, arbitrary color. Consensus residues are colored white, and gaps in the alignment are colored black. A threshold of <10% sequence divergence is used to distinguish unique proteotypes. Proteotyping analysis was applied to open reading frames across 38 whole genome sequenced HAdV-Ds, including those associated with epidemic keratoconjunctivitis.
Among hypervariable regions, the hexon protein was found to be the most variable (least recombined) with 28 proteotypes, while the putative E3 CR1α protein had only 6 proteotypes for 38 viruses, suggesting significant prior recombination. The E3 CR1β and CR1γ, and fiber proteins had 14, 15, and 22 proteotypes, respectively. The fiber proteotype most closely predicted corneal tropism. Highly conserved genes such as DNA polymerase had only one proteotype. HAdV-D proteotyping results correlated well with the results of traditional recombination analyses, including Bootscan and SimPlot.
Proteotyping identifies unique amino acid signatures across a virus species, providing both an overview of recombination patterns as well as detailed information about conserved and variant amino acid positions that phylogenetic trees cannot offer. Proteotyping represents a valuable tool to discern the evolution of viruses within HAdV-D associated with epidemic keratoconjunctivitis.
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