Independent HHsearch, Needleman--Wunsch-based, and motif analyses reveal the overall hierarchy for most of the G protein-coupled receptor families.

Several families of G protein-coupled receptors (GPCRs) show no significant sequence similarities to each other, and it has been debated which of them share a common origin. We developed and performed integrated and independent HHsearch, Needleman--Wunsch-based and motif analyses on more than 6,600 unique GPCRs from 12 species. Moreover, we mined the evolutionary important Trichoplax adhaerens, Nematostella vectensis, Thalassiosira pseudonana, and Strongylocentrotus purpuratus genomes, revealing remarkably rich vertebrate-like GPCR repertoires already in the early Metazoan species. We found strong evidence that the Adhesion and Frizzled families are children to the cyclic AMP (cAMP) family with HHsearch homology probabilities of 99.8% and 99.4%, respectively, also supported by the Needleman--Wunsch analysis and several motifs. We also found that the large Rhodopsin family is likely a child of the cAMP family with an HHsearch homology probability of 99.4% and conserved motifs. Therefore, we suggest that the Adhesion and Frizzled families originated from the cAMP family in an event close to that which gave rise to the Rhodopsin family. We also found convincing evidence that the Rhodopsin family is parent to the important sensory families; Taste 2 and Vomeronasal type 1 as well as the Nematode chemoreceptor families. The insect odorant, gustatory, and Trehalose receptors, frequently referred to as GPCRs, form a separate cluster without relationship to the other families, and we propose, based on these and others' results, that these families are ligand-gated ion channels rather than GPCRs. Overall, we suggest common descent of at least 97% of the GPCRs sequences found in humans.

[1]  L. Holm,et al.  The Pfam protein families database , 2005, Nucleic Acids Res..

[2]  Robert Fredriksson,et al.  Mapping the human membrane proteome : a majority of the human membrane proteins can be classified according to function and evolutionary origin , 2015 .

[3]  Jianzhi Zhang,et al.  Origin of the genetic components of the vomeronasal system in the common ancestor of all extant vertebrates. , 2009, Molecular biology and evolution.

[4]  Robert Fredriksson,et al.  The Secretin GPCRs descended from the family of Adhesion GPCRs. , 2008, Molecular biology and evolution.

[5]  H. Schiöth,et al.  The G protein-coupled receptor subset of the dog genome is more similar to that in humans than rodents , 2009, BMC Genomics.

[6]  Leszek Rychlewski,et al.  The Phaeodactylum genome reveals the evolutionary history of diatom genomes , 2008, Nature.

[7]  Martin Madera,et al.  Profile Comparer: a program for scoring and aligning profile hidden Markov models , 2008, Bioinform..

[8]  James H. Thomas,et al.  The Caenorhabditis chemoreceptor gene families , 2008, BMC Biology.

[9]  Nicholas H. Putnam,et al.  The Trichoplax genome and the nature of placozoans , 2008, Nature.

[10]  Kazutaka Katoh,et al.  Recent developments in the MAFFT multiple sequence alignment program , 2008, Briefings Bioinform..

[11]  Nicholas H. Putnam,et al.  The amphioxus genome and the evolution of the chordate karyotype , 2008, Nature.

[12]  Leslie B. Vosshall,et al.  Insect olfactory receptors are heteromeric ligand-gated ion channels , 2008, Nature.

[13]  Regine Heller,et al.  Drosophila odorant receptors are both ligand-gated and cyclic-nucleotide-activated cation channels , 2008, Nature.

[14]  W. Sadee,et al.  Evolutionary relationships among G protein-coupled receptors using a clustered database approach , 2001, AAPS PharmSci.

[15]  N. Manoj,et al.  The repertoire of G protein-coupled receptors in the sea squirt Ciona intestinalis , 2008, BMC Evolutionary Biology.

[16]  H. Schiöth,et al.  The amphioxus (Branchiostoma floridae) genome contains a highly diversified set of G protein-coupled receptors , 2008, BMC Evolutionary Biology.

[17]  H. Schiöth,et al.  The G protein-coupled receptor subset of the rat genome , 2007, BMC Genomics.

[18]  Nicholas H. Putnam,et al.  Sea Anemone Genome Reveals Ancestral Eumetazoan Gene Repertoire and Genomic Organization , 2007, Science.

[19]  A. Edgar.  Human GPR107 and murine Gpr108 are members of the LUSTR family of proteins found in both plants and animals, having similar topology to G-protein coupled receptors , 2007, DNA sequence : the journal of DNA sequencing and mapping.

[20]  Tatiana Tatusova,et al.  NCBI Reference Sequence (RefSeq): a curated non-redundant sequence database of genomes, transcripts and proteins , 2004, Nucleic Acids Res..

[21]  Andrew R. Jackson,et al.  The Genome of the Sea Urchin Strongylocentrotus purpuratus , 2006, Science.

[22]  Ludwig Eichinger,et al.  The Dictyostelium repertoire of seven transmembrane domain receptors. , 2006, European journal of cell biology.

[23]  David E. Gloriam,et al.  Comprehensive repertoire and phylogenetic analysis of the G protein-coupled receptors in human and mouse. , 2006, Genomics.

[24]  Adam Godzik,et al.  Cd-hit: a fast program for clustering and comparing large sets of protein or nucleotide sequences , 2006, Bioinform..

[25]  David E. Gloriam,et al.  The G Protein–Coupled Receptor Subset of the Chicken Genome , 2006, PLoS Comput. Biol..

[26]  Silke Sachse,et al.  Atypical Membrane Topology and Heteromeric Function of Drosophila Odorant Receptors In Vivo , 2006, PLoS biology.

[27]  Robert D. Finn,et al.  Pfam: clans, web tools and services , 2005, Nucleic Acids Res..

[28]  Ramanathan Sowdhamini,et al.  Genome wide survey of G protein-coupled receptors in Tetraodon nigroviridis , 2005, BMC Evolutionary Biology.

[29]  David L. Steffen,et al.  The genome of the social amoeba Dictyostelium discoideum , 2005, Nature.

[30]  H. Schiöth,et al.  The Repertoire of G-Protein–Coupled Receptors in Fully Sequenced Genomes , 2005, Molecular Pharmacology.

[31]  Johannes Söding,et al.  Protein homology detection by HMM?CHMM comparison , 2005, Bioinform..

[32]  F. Delsuc,et al.  The timing of eukaryotic evolution: does a relaxed molecular clock reconcile proteins and fossils? , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[33]  Nicholas H. Putnam,et al.  The Genome of the Diatom Thalassiosira Pseudonana: Ecology, Evolution, and Metabolism , 2004, Science.

[34]  R. Lefkowitz.  Historical review: a brief history and personal retrospective of seven-transmembrane receptors. , 2004, Trends in pharmacological sciences.

[35]  A. Krogh,et al.  A combined transmembrane topology and signal peptide prediction method. , 2004, Journal of molecular biology.

[36]  Geoffrey J. Barton,et al.  The Jalview Java alignment editor , 2004, Bioinform..

[37]  H. Schiöth,et al.  The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints. , 2003, Molecular pharmacology.

[38]  Yusuke Nakamura,et al.  Inhibition of Experimental Intimal Thickening in Mice Lacking a Novel G-Protein–Coupled Receptor , 2003, Circulation.

[39]  Gert Vriend,et al.  GPCRDB information system for G protein-coupled receptors , 2003, Nucleic Acids Res..

[40]  W. J. Kent,et al.  BLAT--the BLAST-like alignment tool. , 2002, Genome research.

[41]  Timothy B. Stockwell,et al.  The Sequence of the Human Genome , 2001, Science.

[42]  J. V. Moran,et al.  Initial sequencing and analysis of the human genome. , 2001, Nature.

[43]  T. Brody,et al.  Drosophila melanogasterG Protein–Coupled Receptors , 2000, The Journal of cell biology.

[44]  I. Longden,et al.  EMBOSS: the European Molecular Biology Open Software Suite. , 2000, Trends in genetics : TIG.

[45]  L. Josefsson,et al.  Evidence for kinship between diverse G-protein coupled receptors. , 1999, Gene.

[46]  N. M. Brooke,et al.  A molecular timescale for vertebrate evolution , 1998, Nature.

[47]  Sean R. Eddy,et al.  Profile hidden Markov models , 1998, Bioinform..

[48]  Cori Bargmann,et al.  Divergent seven transmembrane receptors are candidate chemosensory receptors in C. elegans , 1995, Cell.

[49]  R. Axel,et al.  A novel family of genes encoding putative pheromone receptors in mammals , 1995, Cell.

[50]  A. Ballabio,et al.  Cloning of the gene for ocular albinism type 1 from the distal short arm of the X chromosome , 1995, Nature Genetics.

[51]  T K Attwood,et al.  Fingerprinting G-protein-coupled receptors. , 1994, Protein engineering.

[52]  Kolakowski Lf.  GCRDB: A G-PROTEIN-COUPLED RECEPTOR DATABASE , 1994 .

[53]  E. Myers,et al.  Basic local alignment search tool. , 1990, Journal of molecular biology.

[54]  P. Devreotes,et al.  A chemoattractant receptor controls development in Dictyostelium discoideum. , 1988, Science.

[55]  Leland H. Hartwell,et al.  The yeast α-factor receptor: structural properties deduced from the sequence of the STE2 gene , 1985 .

[56]  S. B. Needleman,et al.  A general method applicable to the search for similarities in the amino acid sequence of two proteins. , 1970, Journal of molecular biology.