The Gene Repertoire of G protein-coupled Receptors : New Genes, Phylogeny, and Evolution

Abstract: The superfamily of G protein-coupled receptors (GPCRs) is one of the largest protein families of mammalian genomes and can be divided into five main families; Glutamate, Rhodopsin, Adhesion, Frizzled, and Secretin. GPCRs participate in most major physiological functions, contributing to the fact that they are important targets in drug discovery. In paper I we mined the human and mouse genomes for new Adhesion GPCR genes. We found two new human genes (GPR133 and GPR144) and 17 mouse Adhesion genes, bringing the number up to 33 human and 31 mouse genes. In paper II we describe 53 new splice variants for human Adhesion receptors supported by expressed sequence tags (EST) data. 29 of these variants seem to code for functional proteins, several of which lack one or more functional domains in the N-termini. Lack of certain domains is likely to affect ligand binding or interaction with other proteins. Paper III describes the Glutamate GPCR in human, mouse, Fugu, and zebrafish. We gathered a total of 22 human, 79 mouse, 30 Fugu, and 32 zebrafish sequences and grouped these into eight clans using phylogenetic methods. The report provides an overview of the expansion or deletions among the different branches of the Glutamate receptor family. Paper IV focuses on the trace amine (TA) clan of Rhodopsin GPCRs. We identified 18 new rodent genes, 57 zebrafish genes, and eight Fugu genes belonging to the clan. Chromosomal mapping together with phylogenetic relationships suggests that the family arose through several mechanisms involving tetraploidisation, block duplications, and local duplication events. Paper V provides a comprehensive dataset of the GPCR superfamily of human and mouse containing 495 mouse and 400 human non-olfactory GPCRs. Phylogenetic analyses showed that 329 of the receptors are found in one-to-one orthologous pairs, whereas other receptors may have originated from species-specific expansions.