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J. Biol. Chem., Vol. 280, Issue 35, 31068-31075, September 2, 2005

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The Rise and Fall of the Chemoattractant Receptor GPR33^*

Holger Römpler, Angela Schulz, Christian Pitra, Graham Coop¶, Molly Przeworski||, Svante Pääbo**, and Torsten Schöneberg

From the Institute of Biochemistry, Molecular Biochemistry, Medical Faculty, University of Leipzig, 04103 Leipzig, Germany, the Institute for Zoo and Wildlife Research, Department of Evolutionary Genetics, 10315 Berlin, Germany, the ^¶Department of Statistics, University of Oxford, Oxford, OX1 3TG, United Kingdom, the ^||Department of Ecology and Evolutionary Biology, Brown University, Providence, Rhode Island 02912, and the ^**Max-Planck-Institute of Evolutionary Anthropology, 04103 Leipzig, Germany

Chemokine and chemoattractant receptors are members of the large superfamily of G protein-coupled receptors (GPCR), which control leukocyte chemotaxis. In addition to their physiological role, several chemokine and chemoattractant receptors, such as CCR5 and Duffy, have been directly associated with pathogen entry. GPR33 is an orphan chemoattractant GPCR that was previously identified as a pseudogene in humans. GPR33 evolved in mammals about 125-190 million years ago. The cloning and analysis of more than 120 mammalian GPR33 orthologs from 16 of 18 eutherian orders revealed an inactivation of this chemoattractant GPCR not only in humans, but also in several great ape and rodent species. Intriguingly, in all ape and some rodent species where the inactivation occurred, samples harbored both pseudogene and intact gene variants. The analysis of over 1200 human individuals representing all major linguistic groups revealed that the intact allele of GPR33 is still present in the human population. Estimates of the age of the human alleles suggest inactivation in the past 1 million years. Similarly, analysis of more than 120 wild-caught gray rats (Rattus norvegicus), revealed that inactivation of gpr33 is worldwide fixed and occurred in less than 0.7 million years ago. The coincidental inactivation and its fixation in several species of distantly related mammalian orders suggest a selective pressure on this chemoattractant receptor gene.

Received for publication, April 1, 2005 , and in revised form, June 29, 2005.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AY490569-AY490743, AY493989-AY494004, AY502103, AY502104, and AY528865 (supplemental materials Table S1).

^* This work was supported by the Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, Fonds der Chemischen Industrie, and IZKF Leipzig. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains additional text, Tables S1–S7, and Fig. S1.

To whom correspondence should be addressed: Institute of Biochemistry, Molecular Biochemistry (Max-Planck-Institute Interim), Medical Faculty, University of Leipzig, Deutscher Platz 6, 04103 Leipzig, Germany. Tel.: 49-341-3550-850; Fax: 49-341-3550-855; E-mail: schoberg{at}medizin.uni-leipzig.de.

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