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Comprehensive repertoire and phylogenetic analysis of the G-protein-coupled receptors in human and mouse
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. (Farmakologi 3)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. (Farmakologi 3)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. (Farmakologi 3)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. (Farmakologi 3)
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2006 (English)In: Genomics, ISSN 0888-7543, E-ISSN 1089-8646, Vol. 88, no 3, 263-273 p.Article in journal (Refereed) Published
Abstract [en]

Understanding differences in the repertoire of orthologous gene pairs is vital for interpretation of pharmacological and physiological experiments if conclusions are conveyed between species. Here we present a comprehensive dataset for G protein-coupled receptors (GPCRs) in both human and mouse with a phylogenetic road map. We performed systematic searches applying several search tools such as BLAST, BLAT, and Hidden Markov models and searches in literature data. We aimed to gather a full-length version of each human or mouse GPCR in only one copy referring to a single chromosomal position. Moreover, we performed detailed phylogenetic analysis of the transmembrane regions of the receptors to establish accurate orthologous pairs. The results show the identity of 495 mouse and 400 human functional nonolfactory GPCRs. Overall, 329 of the receptors are found in one-to-one orthologous pairs, while 119 mouse and 31 human receptors originate from species-specific expansions or deletions. The average percentage similarity of the orthologue pairs is 85%, while it varies between the main GRAFS families from an average of 59 to 94%. The orthologous pairs for the lipid-binding GPCRs had the lowest levels of conservation, while the biogenic amines had highest levels of conservation. Moreover, we searched for expressed sequence tags (ESTs) and identified more than 17,000 ESTs matching GPCRs in mouse and human, providing information about their expression patterns. On the whole, this is the most comprehensive study of the gene repertoire that codes for human and mouse GPCRs. The datasets are available for downloading.

Place, publisher, year, edition, pages
2006. Vol. 88, no 3, 263-273 p.
Keyword [en]
GPCR, glutamate, rhodopsin, adhesion, frizzled, taste2, secretin
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-94124DOI: 10.1016/j.ygeno.2006.04.001ISI: 000240371500002PubMedID: 16753280OAI: oai:DiVA.org:uu-94124DiVA: diva2:167870
Available from: 2006-03-22 Created: 2006-03-22 Last updated: 2011-06-17Bibliographically approved
In thesis
1. The Gene Repertoire of G protein-coupled Receptors: New Genes, Phylogeny, and Evolution
Open this publication in new window or tab >>The Gene Repertoire of G protein-coupled Receptors: New Genes, Phylogeny, and Evolution
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 65 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 121
Keyword
Pharmacology, Bioinformatics, Evolution, GPCR, Phylogeny, Farmakologi
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-6627 (URN)91-554-6489-0 (ISBN)
Public defence
2006-04-12, Room B21, BMC, Husargatan 3, Uppsala, 09:15
Opponent
Supervisors
Available from: 2006-03-22 Created: 2006-03-22 Last updated: 2013-04-04Bibliographically approved
2. G Protein-Coupled Receptors; Discovery of New Human Members and Analyses of the Entire Repertoires in Human, Mouse and Rat
Open this publication in new window or tab >>G Protein-Coupled Receptors; Discovery of New Human Members and Analyses of the Entire Repertoires in Human, Mouse and Rat
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

G protein-coupled receptors (GPCRs) are signal mediators that have a prominent role in the regulation of physiological processes and they make up the targets for 30-45% of all drugs.

Papers I and II describe the discovery of new human GPCRs belonging to the Rhodopsin family, a family which contains many common drug targets. The new receptors have only weak relationships to previously known GPCRs. However, they have been evolutionary conserved in several species and most of them display distinct expression patterns.

In paper III we identified new human GPCRs belonging to the Adhesion family, which is characterised by very long N-termini containing conserved domains. The different compositions of conserved domains as well as the expression patterns suggest that the Adhesions can have several different functions.

In paper IV we revealed remarkable species variations in the repertoires of Trace Amine-Associated Receptors (TAARs), which are relatives of the biogenic amine receptors. The human, mouse and rat TAAR genes are located in only one locus and are therefore most likely the result of gene tandem duplications. 47 of the 57 zebrafish TAARs were mapped to nine different loci on six chromosomes containing from 1 to 27 genes each. This study suggests that the TAARs arose through several different mechanisms involving tetraploidisation, block duplications, and local duplication events.

Papers V and VI are overall analyses of the repertoires of GPCRs in humans, mice and rats; which contain approximately 800, 1800 and 1900 members, respectively. The repertoires were compared to distinguish between species-specific and common (orthologous) members, something which is important for example when predicting drug effects from experiments in rodents. The Glutamate, Adhesion, Frizzled and Secretin families show no or very little variation between human and rodents, whereas the repertoires of olfactory, vomeronasal and Taste2 receptors display large differences between all three species.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 46 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 133
Keyword
Bioinformatics, G protein-coupled receptor, GPCR, Bioinformatics, Evolution, Orphan, Rhodopsin, Adhesion, Phylogeny, Bioinformatik
Identifiers
urn:nbn:se:uu:diva-6745 (URN)91-554-6522-6 (ISBN)
Public defence
2006-04-28, Room B21, BMC, Husargatan 3, Uppsala, 09:15
Opponent
Supervisors
Available from: 2006-04-07 Created: 2006-04-07 Last updated: 2011-06-17Bibliographically approved

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