Elsevier

Gene

Volume 246, Issues 1–2, 4 April 2000, Pages 239-245
Gene

Gene conversion among chemokine receptors

https://doi.org/10.1016/S0378-1119(00)00072-XGet rights and content

Abstract

It has been proposed that proteins which are involved in host defence and susceptibility undergo accelerated evolution. Chemokine receptors have roles as pro-inflammatory agents acting in response to infection, and in addition are receptors for entry of viruses and other pathogens into cells. Consistent with this, their rate of evolution is higher than that for other members of the seven-transmembrane domain receptor family. The pattern of evolution of the chemokine receptors was examined in detail. Both chromosomal clusters of chemokine receptors (CC and CXC) showed evidence of a number of gene conversions. These are likely to have resulted in protein sequence changes, which could possibly alter function. 45% of a control group of clustered genes also showed evidence of conversion. Thus, the fixation of a gene conversion is not in itself sufficiently unusual in tandemly repeated genes and cannot be taken as strong evidence of a selection for a novel function. However, the degree of amino acid difference between the chemokine receptors CCR1 and CCR3 was greater than that for any of the control genes. Such changes could have functional implications for inter-species differences in chemokine receptor interactions with pathogens.

Introduction

Plants lack a specific immune response, so that the emergence of a novel variant in a pathogen gene is frequently followed by selection for a novel variant in a plant host gene that spreads as a resistance factor through the population, leading to the observed gene-for-gene relationship (Keen, 1990). The specific immune system of mammals buffers the non-specific immune system from many pathogen challenges. Therefore, fewer changes of the mammalian non-specific immune system are likely during evolution. However, there are numerous human polymorphisms that are associated with resistance to malaria and other infections (Hill and Motulsky, 1999), indicating that there are still evolutionary pressures on mammalian host components in response to pathogen pressures (Marrack and Kappler, 1994). It has been proposed (Murphy, 1993) that the high rate of evolution of host defence components reflects positive selection for novel host variants which confer an advantage with respect to particular pathogen challenges arising at particular times during evolution. However, a high evolutionary rate in a protein may just as well be associated with a low level of functional constraint. Extreme rates of protein change driven by positive selection will result in an excess of non-synonymous over synonymous changes when species are compared. Some host defence proteins, such as the eosinophilic ribonucleases (Rosenberg et al., 1995) and the hemopoietin family of cytokines (Shields et al., 1996), do in fact show such excesses. This suggests that their high rates of evolution result partly from positive selection of novel adaptive variants.

However, the evolutionary rates of many host defence proteins are not so rapid that non-synonymous rates exceed synonymous rates, yet adaptive changes may still be occurring. Another clue that indicates adaptive evolution is acceleration in an evolutionary lineage which is consistent with adaptive changes. While the rate of nearly neutral changes in a protein should be approximately constant over time, it would be predicted that adaptive changes will occur in bursts, often in one lineage and not in the other.

The chemokine receptors (CRs) CCR5 and Duffy are respectively known to be receptors of HIV and malaria vivax (Fauci, 1996). Population null variants of CCR5 occur in both human and sooty mangabey populations, leading to the hypothesis that transient selection pressures have acted strongly on these proteins in the recent evolutionary past (Palacios et al., 1998). CRs additionally mediate the signalling of host immune responses, and are pirated by herpesviral genomes. Their rates of evolution appear faster than those of other seven-transmembrane domain receptors (Shields et al., 1996). In this study, we investigate whether the pathogen-related roles may have influenced their mode of evolution, by investigating the evolution of the group of chemokine receptors (CCRs) specific for ‘CC’ chemokines, the related ‘CXC’ chemokine receptors (CXCRs), and a number of related receptors.

Section snippets

Materials and methods

The gene names used here are those of the CCR and CXCR numbering system, and where a CR has not been assigned any such name (usually because its ligand binding specificity is unknown) the SWISSPROT database ID has been used instead. The mouse SwissProt entry CKRY_MOUSE has been termed CCR2_MOUSE, on the basis of phylogenetic similarity with the human CCR2 protein. For human CCR2, the alternative splice variant has been chosen which confers greater similarity to the mouse CCR2 sequence. CRs from

Rates of amino acid replacement

The tree of seven-transmembrane receptors with broad similarity to the chemokine receptors in Fig. 1 is not a perfect representation of the true branching order. Firstly, gene conversion among sequences complicates the pattern (see below); secondly, there is low statistical support (not shown) for many branches, particularly those that are separated only by small distances on the tree. However, the broad features of the tree are of relevance to the question of how host CRs are evolving in

Conclusions

The approach used here in investigating gene conversion has a number of limitations: it assumes equal rates of nucleotide substitution, equal mutation rates among species, and lack of convergent selection for shared function among amino acid residues carried at homologous sites on different proteins. The approach has also limited itself to CRs which are in known gene clusters. Many of these limitations have been imposed in order to ensure that the study has sufficient power to detect

Acknowledgements

This work was supported by the Higher Education Authority (Ireland) and the Wellcome Trust (039618/Z/93/Z). I thank Andrew Lloyd and Ken Wolfe for discussion.

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