Pseudogenization of the MCP-2/CCL8 chemokine gene in European rabbit (genus Oryctolagus), but not in species of Cottontail rabbit (Sylvilagus) and Hare (Lepus)

Wessel Van Der Loo,Ana De Matos,Joana Abrantes,Pedro J Esteves,Sandra Afonso

doi:10.1186/1471-2156-13-72

Abstract

BackgroundRecent studies in human have highlighted the importance of the monocyte chemotactic proteins (MCP) in leukocyte trafficking and their effects in inflammatory processes, tumor progression, and HIV-1 infection. In European rabbit (Oryctolagus cuniculus) one of the prime MCP targets, the chemokine receptor CCR5 underwent a unique structural alteration. Until now, no homologue of MCP-2/CCL8a, MCP-3/CCL7 or MCP-4/CCL13 genes have been reported for this species. This is interesting, because at least the first two genes are expressed in most, if not all, mammals studied, and appear to be implicated in a variety of important chemokine ligand-receptor interactions. By assessing the Rabbit Whole Genome Sequence (WGS) data we have searched for orthologs of the mammalian genes of the MCP-Eotaxin cluster.ResultsWe have localized the orthologs of these chemokine genes in the genome of European rabbit and compared them to those of leporid genera which do (i.e. Oryctolagus and Bunolagus) or do not share the CCR5 alteration with European rabbit (i.e. Lepus and Sylvilagus). Of the Rabbit orthologs of the CCL8, CCL7, and CCL13 genes only the last two were potentially functional, although showing some structural anomalies at the protein level. The ortholog of MCP-2/CCL8 appeared to be pseudogenized by deleterious nucleotide substitutions affecting exon1 and exon2. By analyzing both genomic and cDNA products, these studies were extended to wild specimens of four genera of the Leporidae family: Oryctolagus, Bunolagus, Lepus, and Sylvilagus. It appeared that the anomalies of the MCP-3/CCL7 and MCP-4/CCL13 proteins are shared among the different species of leporids. In contrast, whereas MCP-2/CCL8 was pseudogenized in every studied specimen of the Oryctolagus - Bunolagus lineage, this gene was intact in species of the Lepus - Sylvilagus lineage, and was, at least in Lepus, correctly transcribed.ConclusionThe biological function of a gene was often revealed in situations of dysfunction or gene loss. Infections with Myxoma virus (MYXV) tend to be fatal in European rabbit (genus Oryctolagus), while being harmless in Hares (genus Lepus) and benign in Cottontail rabbit (genus Sylvilagus), the natural hosts of the virus. This communication should stimulate research on a possible role of MCP-2/CCL8 in poxvirus related pathogenicity.

Highlights

Recent studies in human have highlighted the importance of the monocyte chemotactic proteins (MCP) in leukocyte trafficking and their effects in inflammatory processes, tumor progression, and Human Immunodeficiency Virus (HIV)-1 infection
The genes of the CC chemokine ligands (CCL) RANTES/ CCL5, Macrophage inflammatory proteins (MIP)-1a/CCL3, and MIP-1b/CCL4 are documented for Rabbit (Oryctolagus cuniculus) [GenBank: NC_013687_REGION:24922000..25085000]
True orthologs of mammalian MCP-3/CCL7, MCP2/CCL8, and MCP-4/CCL13 have not yet been identified

Summary

Introduction

Recent studies in human have highlighted the importance of the monocyte chemotactic proteins (MCP) in leukocyte trafficking and their effects in inflammatory processes, tumor progression, and HIV-1 infection. The introduction of Myxoma virus (MYXV) during the midst of last century as a method of rabbit pest control had devastating effects on populations of European rabbit with reported mortality rates approaching 100% in Europe and Australia [7]. This was in sharp contrast to the very mild pathology caused by the virus in its natural host and reservoir, i.e. species of the genus Sylvilagus [8,9]. This results in a generalized leukocyte depletion, particular of CD4+ T cells, which leads to a systemic immunodepression with fatal outcome i.e. myxomatosis [11,12]

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