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Molecular evolution of CXC chemokines and receptors
Update
TRENDS in Immunology
Vol.24 No.7 July 2003
355
Molecular evolution of CXC chemokines and receptors Denis C. Shields Department of Clinical Pharmacology and Institute of Biopharmaceutical Sciences, Royal College of Surgeons in Ireland, 123 St Stephen’s Green, Dublin 2, Ireland
The Opinion by Huising et al. [1] in the June issue of Trends in Immunology makes two interesting speculations about the evolution of CXC chemokines. First, they propose that the large radiation of mammalian CXC chemokines since the divergence from the common ancestor with fish might be linked to the development of a number of features of the adaptive immune system, including the distinctlymphoid architecture, the more complex thymus and the control of Th1 – Th2 responses. Second, they suggest that because the central nervous system (CNS) pre-existed the immune system, the ancestral chemokines might have had a CNS role and subsequently acquired an inflammatory role. The first difficulty with the evolutionary analysis is the absence of any clear outgroup sequences to the set of sequences analysed. Thus, even if the tree is correct, it is difficult to prove which branching in the tree is the most ancient. Therefore, the claim that the chemokine and receptor with CNS roles (CXCL12 and CXCR4) are ancestral is speculative and not confirmed or denied by the evolutionary trees. The assertion that limited structural change predicts a vital function is not necessarily true: it might be instead that genes with a role in host defense are under selection pressure for adaptive change [2], and other genes evolve more slowly by comparison. If the ancestral receptor were a slowly evolving CNS gene, it might be expected that an orthologue of the slowly evolving CXCR4 receptor would be detectable in the primitive chordate Ciona intestinalis (the sea squirt), whose genome has recently been sequenced [3] and which has a CNS. However, a search of the CXCR4 protein against the Ciona genome (http://genome.jgi-psf.org/ciona4) failed to identify a conserved orthologous CXCR4-like protein. A simple explanation is that the common ancestor of the CXCR chemokines had an immune role and a rapid evolutionary rate, and that CXCR4 subsequently developed a CNS role and accordingly a slower rate of evolution. The idea that the ancestral role was an immune one is also suggested by the similarities of the CXC family and receptors to the CC chemokines and their receptors, which also have roles in immunity. The second difficulty with the evolutionary analysis is that the chemokines are too short to provide a large enough sample size to determine the branching order of major groups. Therefore, the data can neither confirm nor deny many orthologies, and the assumption that the fish chemokines, CXCa, b and c, form a single group has no clear basis. The receptor tree is also sensitive to incomplete sequences. If the trees are redrawn exluding four incomplete sequences, there is 75% bootstrap support for Corresponding author: Denis C. Shields ([email protected]). http://treimm.trends.com
the grouping of pufferfish CXCRa and CXCRb with mammalian CXCR3. This suggests a possible orthology that was not seen in the original analysis. Incomplete sequences might reflect incorrect gene predictions [4] and a thorough phylogenetic analysis requires complete cDNA sequences from each gene. Incorrect sequences reduce the chance of identifying true orthologues. The third difficulty with their analysis of chemokine receptors is that there is documented evidence that these receptors have undergone frequent gene conversion events within the chromosomally clustered genes [5]. In this scenario, a tree cannot properly represent the relationships among sequences and evolutionary inference is difficult. The effect of this gene conversion is to make sequences from within a species or grouping of species more similar. Again, this can confuse definition of orthology. The fourth difficulty is that their model of chemokine duplication during genome duplication is not supported by evidence from extant human chromosomal block duplications, which are thought to have arisen through genome duplication. Although the location of CXCL14 on chromosome 5 is spanned by a block of 10 genes duplicated on chromosome 10, there are no CXC chemokines in this region of chromosome 10 [6] (http://wolfe.gen.tcd.ie/dup/human1.0/). Although absence from a preserved and visible chromosomally duplicated block does not prove that the duplications are not associated with genome duplication, it does provide circumstantial evidence against it. Although the evolutionary evidence given is consistent with the model of Huising et al., it is equally consistent with a great many other models. In common with many other gene families, interesting evolutionary events are veiled in a fog of uncertainty. Accumulation of more sequences from intermediate species, such as the lamprey, could shed further light. In the meantime it is certainly stimulating to consider what those evolutionary histories might have been. References 1 Huising, M.O. et al. (2003) Molecular evolution of CXC chemokines: extant CXC chemokines originate from the CNS. Trends Immunol., 24 2 Murphy, P.M. (1993) Molecular mimicry and the generation of host defense protein diversity. Cell 72, 823– 826 3 Dehal, P. et al. (2002) The draft genome of Ciona intestinalis: insights into chordate and vertebrate origins. Science 298, 2157 – 2167 4 Wiehe, T. et al. (2001) SGP-1: prediction and validation of homologous genes based on sequence alignments. Genome Res. 11, 1574 – 1583 5 Shields, D.C. (2000) Gene conversion among chemokine receptors. Gene 246, 239 – 245 6 McLysaght, A. et al. (2002) Extensive genomic duplication during early chordate evolution. Nat. Genet. 31, 200 – 204
1471-4906/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S1471-4906(03)00138-8
TRENDS in Immunology
Vol.24 No.7 July 2003
355
Molecular evolution of CXC chemokines and receptors Denis C. Shields Department of Clinical Pharmacology and Institute of Biopharmaceutical Sciences, Royal College of Surgeons in Ireland, 123 St Stephen’s Green, Dublin 2, Ireland
The Opinion by Huising et al. [1] in the June issue of Trends in Immunology makes two interesting speculations about the evolution of CXC chemokines. First, they propose that the large radiation of mammalian CXC chemokines since the divergence from the common ancestor with fish might be linked to the development of a number of features of the adaptive immune system, including the distinctlymphoid architecture, the more complex thymus and the control of Th1 – Th2 responses. Second, they suggest that because the central nervous system (CNS) pre-existed the immune system, the ancestral chemokines might have had a CNS role and subsequently acquired an inflammatory role. The first difficulty with the evolutionary analysis is the absence of any clear outgroup sequences to the set of sequences analysed. Thus, even if the tree is correct, it is difficult to prove which branching in the tree is the most ancient. Therefore, the claim that the chemokine and receptor with CNS roles (CXCL12 and CXCR4) are ancestral is speculative and not confirmed or denied by the evolutionary trees. The assertion that limited structural change predicts a vital function is not necessarily true: it might be instead that genes with a role in host defense are under selection pressure for adaptive change [2], and other genes evolve more slowly by comparison. If the ancestral receptor were a slowly evolving CNS gene, it might be expected that an orthologue of the slowly evolving CXCR4 receptor would be detectable in the primitive chordate Ciona intestinalis (the sea squirt), whose genome has recently been sequenced [3] and which has a CNS. However, a search of the CXCR4 protein against the Ciona genome (http://genome.jgi-psf.org/ciona4) failed to identify a conserved orthologous CXCR4-like protein. A simple explanation is that the common ancestor of the CXCR chemokines had an immune role and a rapid evolutionary rate, and that CXCR4 subsequently developed a CNS role and accordingly a slower rate of evolution. The idea that the ancestral role was an immune one is also suggested by the similarities of the CXC family and receptors to the CC chemokines and their receptors, which also have roles in immunity. The second difficulty with the evolutionary analysis is that the chemokines are too short to provide a large enough sample size to determine the branching order of major groups. Therefore, the data can neither confirm nor deny many orthologies, and the assumption that the fish chemokines, CXCa, b and c, form a single group has no clear basis. The receptor tree is also sensitive to incomplete sequences. If the trees are redrawn exluding four incomplete sequences, there is 75% bootstrap support for Corresponding author: Denis C. Shields ([email protected]). http://treimm.trends.com
the grouping of pufferfish CXCRa and CXCRb with mammalian CXCR3. This suggests a possible orthology that was not seen in the original analysis. Incomplete sequences might reflect incorrect gene predictions [4] and a thorough phylogenetic analysis requires complete cDNA sequences from each gene. Incorrect sequences reduce the chance of identifying true orthologues. The third difficulty with their analysis of chemokine receptors is that there is documented evidence that these receptors have undergone frequent gene conversion events within the chromosomally clustered genes [5]. In this scenario, a tree cannot properly represent the relationships among sequences and evolutionary inference is difficult. The effect of this gene conversion is to make sequences from within a species or grouping of species more similar. Again, this can confuse definition of orthology. The fourth difficulty is that their model of chemokine duplication during genome duplication is not supported by evidence from extant human chromosomal block duplications, which are thought to have arisen through genome duplication. Although the location of CXCL14 on chromosome 5 is spanned by a block of 10 genes duplicated on chromosome 10, there are no CXC chemokines in this region of chromosome 10 [6] (http://wolfe.gen.tcd.ie/dup/human1.0/). Although absence from a preserved and visible chromosomally duplicated block does not prove that the duplications are not associated with genome duplication, it does provide circumstantial evidence against it. Although the evolutionary evidence given is consistent with the model of Huising et al., it is equally consistent with a great many other models. In common with many other gene families, interesting evolutionary events are veiled in a fog of uncertainty. Accumulation of more sequences from intermediate species, such as the lamprey, could shed further light. In the meantime it is certainly stimulating to consider what those evolutionary histories might have been. References 1 Huising, M.O. et al. (2003) Molecular evolution of CXC chemokines: extant CXC chemokines originate from the CNS. Trends Immunol., 24 2 Murphy, P.M. (1993) Molecular mimicry and the generation of host defense protein diversity. Cell 72, 823– 826 3 Dehal, P. et al. (2002) The draft genome of Ciona intestinalis: insights into chordate and vertebrate origins. Science 298, 2157 – 2167 4 Wiehe, T. et al. (2001) SGP-1: prediction and validation of homologous genes based on sequence alignments. Genome Res. 11, 1574 – 1583 5 Shields, D.C. (2000) Gene conversion among chemokine receptors. Gene 246, 239 – 245 6 McLysaght, A. et al. (2002) Extensive genomic duplication during early chordate evolution. Nat. Genet. 31, 200 – 204
1471-4906/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S1471-4906(03)00138-8