Dataset Information

Comparative Functional Analysis of 12 Mammalian IFN-?4 Orthologs.

ABSTRACT: IFN-?4 is a novel type-III interferon with strong clinical significance in humans. Only a subset of individuals--up to 10% of Asians, 50% of Europeans, and 90% of Africans--carry the ?G allele of a genetic variant rs368234815-TT/?G and are genetically able to produce IFN-?4 protein. Carriers of the ?G allele have impaired ability to clear infection with hepatitis C virus (HCV). IFN-?4 is also predicted to exist and be functionally important in several nonhuman mammals. In this study, we present the first comparative analysis of 12 mammalian IFN-?4 orthologs in a human hepatic cell line, HepG2, which supports signaling of the human IFN-?4. We show that despite differences in protein sequences, functional properties of the recombinant human and nonhuman IFN-?4 proteins are comparable-they are all expressed as predominantly cytoplasmic proteins that are biologically active for induction of interferon signaling. We show that several IFN-?4 orthologs can be detected by Western blotting, flow cytometry, and confocal imaging using a monoclonal antibody developed for the human IFN-?4. Studies of IFN-?4 in animals should help improve our understanding of the biology of this novel clinically important interferon in normal and disease conditions.

SUBMITTER: Paquin A

PROVIDER: S-EPMC4722605 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Comparative Functional Analysis of 12 Mammalian IFN-λ4 Orthologs.

Paquin Ashley A Onabajo Olusegun O OO Tang Wei W Prokunina-Olsson Ludmila L

Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 20150826 1

IFN-λ4 is a novel type-III interferon with strong clinical significance in humans. Only a subset of individuals--up to 10% of Asians, 50% of Europeans, and 90% of Africans--carry the ΔG allele of a genetic variant rs368234815-TT/ΔG and are genetically able to produce IFN-λ4 protein. Carriers of the ΔG allele have impaired ability to clear infection with hepatitis C virus (HCV). IFN-λ4 is also predicted to exist and be functionally important in several nonhuman mammals. In this study, we present ...[more]

PMID: 26308395

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Project description:BackgroundAccurate determination of orthology is central to comparative genomics. For vertebrates in particular, very large gene families, high rates of gene duplication and loss, multiple mechanisms of gene duplication, and high rates of retrotransposition all combine to make inference of orthology between genes difficult. Many methods have been developed to identify orthologous genes, mostly based upon analysis of the inferred protein sequence of the genes. More recently, methods have been proposed that use genomic context in addition to protein sequence to improve orthology assignment in vertebrates. Such methods have been most successfully implemented in fungal genomes and have long been used in prokaryotic genomes, where gene order is far less variable than in vertebrates. However, to our knowledge, no explicit comparison of synteny and sequence based definitions of orthology has been reported in vertebrates, or, more specifically, in mammals.ResultsWe test a simple method for the measurement and utilization of gene order (local synteny) in the identification of mammalian orthologs by investigating the agreement between coding sequence based orthology (Inparanoid) and local synteny based orthology. In the 5 mammalian genomes studied, 93% of the sampled inter-species pairs were found to be concordant between the two orthology methods, illustrating that local synteny is a robust substitute to coding sequence for identifying orthologs. However, 7% of pairs were found to be discordant between local synteny and Inparanoid. These cases of discordance result from evolutionary events including retrotransposition and genome rearrangements.ConclusionsBy analyzing cases of discordance between local synteny and Inparanoid we show that local synteny can distinguish between true orthologs and recent retrogenes, can resolve ambiguous many-to-many orthology relationships into one-to-one ortholog pairs, and might be used to identify cases of non-orthologous gene displacement by retroduplicated paralogs.

Dataset Information

Comparative Functional Analysis of 12 Mammalian IFN-?4 Orthologs.

Publications

Comparative Functional Analysis of 12 Mammalian IFN-λ4 Orthologs.

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