Abstract
BackgroundIn the coevolution of viruses and their hosts, viruses often capture host genes, gaining advantageous functions (e.g. immune system control). Identifying functional similarities shared by viruses and their hosts can help decipher mechanisms of pathogenesis and accelerate virus-targeted drug and vaccine development. Cellular homologs in viruses are usually documented using pairwise-sequence comparison methods. Yet, pairwise-sequence searches have limited sensitivity resulting in poor identification of divergent homologies.ResultsMethods based on profiles from multiple sequences provide a more sensitive alternative to identify similarities in host-pathogen systems. The present work describes a profile-based bioinformatics pipeline that we call the Domain Analysis of Symbionts and Hosts (DASH). DASH provides a web platform for the functional analysis of viral and host genomes. This study uses Human Herpesvirus 8 (HHV-8) as a model to validate the methodology. Our results indicate that HHV-8 shares at least 29% of its genes with humans (fourteen immunomodulatory and ten metabolic genes). DASH also suggests functions for fifty-one additional HHV-8 structural and metabolic proteins. We also perform two other comparative genomics studies of human viruses: (1) a broad survey of eleven viruses of disparate sizes and transcription strategies; and (2) a closer examination of forty-one viruses of the order Mononegavirales. In the survey, DASH detects human homologs in 4/5 DNA viruses. None of the non-retro-transcribing RNA viruses in the survey showed evidence of homology to humans. The order Mononegavirales are also non-retro-transcribing RNA viruses, however, and DASH found homology in 39/41 of them. Mononegaviruses display larger fractions of human similarities (up to 75%) than any of the other RNA or DNA viruses (up to 55% and 29% respectively).ConclusionsWe conclude that gene sharing probably occurs between humans and both DNA and RNA viruses, in viral genomes of differing sizes, regardless of transcription strategies. Our method (DASH) simultaneously analyzes the genomes of two interacting species thereby mining functional information to identify shared as well as exclusive domains to each organism. Our results validate our approach, showing that DASH has potential as a pipeline for making therapeutic discoveries in other host-symbiont systems. DASH results are available at http://tinyurl.com/spouge-dash.
Highlights
In the coevolution of viruses and their hosts, viruses often capture host genes, gaining advantageous functions
Domain Analysis of Symbionts and Hosts (DASH): An automated system for the whole-genome detection of functional similarity in host-symbiont systems DASH automates the functional characterization of host and symbiont genomes through genome-wide profilebased similarity searches
DASH allows the analysis of fifty-two reference viral genomes
Summary
In the coevolution of viruses and their hosts, viruses often capture host genes, gaining advantageous functions (e.g. immune system control). Cellular homologs in viruses are usually documented using pairwise-sequence comparison methods. Many species interact persistently in symbiosis through mutualistic, commensalistic, or parasitic relationships Such symbiotic associations can lead to long histories of coevolution, promoting horizontal transfer of genes between the corresponding species. In the case of parasitic symbionts like viruses, most of the documented cases of gene transfer involve proteins with functions related to host immune system control or evasion. Homologs in host-virus systems have been traditionally identified [3,4,5] using pairwise sequence comparison methods like BLAST [6] and FASTA [7]. Pairwise sequence comparison has limited sensitivity, in detecting distant homologies. Profile sequence searches, which combine information from multiple sequences (e.g. PSSMs (Position Specific Scoring Matrices) [8,9], HMMs (Hidden Markov Models) [10,11,12,13]), have greater sensitivity than pair-wise sequence comparison in detecting distant homologs [9,14]
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