The Role of Genomic Data in the Discovery, Annotation and Evolutionary Interpretation of the Interferon-Lambda Family

Brian A Fox,Patrick J O'Hara,Paul O Sheppard,Laurent Rénia

doi:10.1371/journal.pone.0004933

Abstract

BackgroundType-I interferons, type-II interferons, and the IL-10 family are helical cytokines with similar three-dimensional folds. However, their homologous relationship is difficult to detect on the basis of sequence alone. We have previously described the discovery of the human type-III interferons (IFN lambda-1, -2, -3 or IL-29, IL-28A, IL-28B), which required a combination of manual and computational techniques applied to predicted protein sequences.Principal FindingsHere we describe how the use of gene structure analysis and comparative genomics enabled a more extensive understanding of these genes early in the discovery process. More recently, additional mammalian genome sequences have shown that there are between one and potentially nine copies of interferon lambda genes in each genome, and that several species have single exon versions of the interferon lambda gene.SignificanceThe variable number of single exon type-I interferons in mammals, along with recently identified genes in zebrafish homologous to interferons allows a story of interferon evolution to be proposed. This model suggests that the gene duplications and single exon retrotransposons of mammalian type-III interferons are positively selected for within a genome. These characteristics are also shared with the fish interferons and could be responsible for the generation of the IL10 family and also the single exon type-I interferons.

Highlights

The use of sequence similarity between proteins to infer a functional relationship helped to define the beginnings of bioinformatics
Due to the sequence diversity of the helical cytokine fold, the type-III interferons are very difficult to detect as homologs using standard bioinformatics tools
As reported earlier [7], only the combined use of specialized software to detect a helical cytokine fold [4], other protein sequence filters, and manual knowledgebased multiple sequence alignments, allowed us to identify these family members as novel helical cytokines

Summary

Introduction

The use of sequence similarity between proteins to infer a functional relationship helped to define the beginnings of bioinformatics. This model suggests that the gene duplications and single exon retrotransposons of mammalian type-III interferons are positively selected for within a genome. Later developments to this technique include using a combination of protein similarity and exon-intron gene structure to characterize many diverse members of the helical cytokine family [5], and to identify evolutionary subclasses within this family.

Results

Conclusion