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Evolution of the Neuropeptide Y and Opioid Systems and Their Genomic

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Evolution of the Neuropeptide Y and Opioid Systems and Their Genomic It's time to try Defying gravity I think I'll try Defying gravity And you can't pull me down Wicked List of Papers This thesis is based on the following papers, which are referred to in the text by their Roman numerals. I Sundström G, Larsson TA, Brenner S, Venkatesh B, Larham- mar D. (2008) Evolution of the neuropeptide Y family: new genes by chromosome duplications in early vertebrates and in teleost fishes. General and Comparative Endocrinology Feb 1;155(3):705-16. II Sundström G, Larsson TA, Xu B, Heldin J, Lundell I, Lar- hammar D. (2010) Interactions of zebrafish peptide YYb with the neuropeptide Y-family receptors Y4, Y7, Y8a and Y8b. Manuscript III Sundström G, Xu B, Larsson TA, Heldin J, Bergqvist CA, Fredriksson R, Conlon JM, Lundell I, Denver RJ, Larhammar D. (2010) Characterization of the neuropeptide Y system's three peptides and six receptors in the frog Silurana tropicalis. Manu- script IV Dreborg S, Sundström G, Larsson TA, Larhammar D. (2008) Evolution of vertebrate opioid receptors. Proc Natl Acad Sci USA Oct 7;105(40):15487-92. V Sundström G, Dreborg S, Larhammar D. (2010) Concomitant duplications of opioid peptide and receptor genes before the origin of jawed vertebrates. PLoS One May 6;5(5):e10512. VI Sundström G, Larsson TA, Larhammar D. (2008) Phylogenet- ic and chromosomal analyses of multiple gene families syntenic with vertebrate Hox clusters. BMC Evolutionary Biology Sep 19;8:254. VII Widmark J, Sundström G, Ocampo Daza D, Larhammar D. (2010) Differential evolution of voltage-gated sodium channels in tetrapods and teleost fishes. Submitted VIII Ocampo Daza D, Sundström G, Bergqvist CA, Duan C, Lar- hammar D. (2010) Evolution of the insulin-like growth factor binding protein (IGFBP) family. Submitted Additional publications • Larsson TA, Tay BH, Sundström G, Fredriksson R, Brenner S, Lar- hammar D, Venkatesh B. (2009) Neuropeptide Y-family peptides and receptors in the elephant shark, Callorhinchus milii confirm gene dupli- cations before the gnathostome radiation. Genomics. Mar;93(3):254-60. • Larsson TA, Olsson F, Sundström G, Lundin LG, Brenner S, Venka- tesh B, Larhammar D. (2008) Early vertebrate chromosome duplications and the evolution of the neuropeptide Y receptor gene regions. BMC Evolutionary Biology Jun 25;8:184. Contents Introduction ..................................................................................................... 9 Gene and genome duplication .................................................................. 10 The neuropeptide Y family of receptors ................................................... 15 The neuropeptide Y family of peptides .................................................... 19 The opioid receptor family ....................................................................... 21 The opioid peptide family ........................................................................ 24 Hox-cluster regions .................................................................................. 27 Aims .............................................................................................................. 30 Materials and Methods .................................................................................. 31 Genomes examined .................................................................................. 31 Database searches and sequence identification ........................................ 34 Sequence alignments and phylogenetic analysis ...................................... 35 Cloning and Sequencing ........................................................................... 35 Receptor binding studies .......................................................................... 36 RT-PCR .................................................................................................... 36 RNA extraction and quantitative real time PCR ...................................... 36 Results and discussion .................................................................................. 38 Paper I ...................................................................................................... 38 Paper II ..................................................................................................... 39 Paper III .................................................................................................... 39 Paper IV and V ......................................................................................... 40 Paper VI, VII and VIII ............................................................................. 41 Conclusions and perspectives ....................................................................... 43 Svensk sammanfattning (Swedish summary) ............................................... 46 Acknowledgements ....................................................................................... 49 References ..................................................................................................... 51 Abbreviations 2R Two rounds of genome duplication 3R Third round of genome duplication BLAST Basic Local Alignment Search Tool cAMP Cyclic adenosine monophosphate GPCR G-protein coupled receptor G-protein Guanine nucleotide binding protein HEK Human embryonic kidney cells IGFBP Insulin-like growth factor binding protein NJ Neighbor-joining NPY Neuropeptide Y (Y = tyrosine) PDYN Prodynorphin PENK Proenkephalin PhyML Phylogenetic maximum likelihood PNOC Proorphanin POMC Proopiomelanocortin PP Pancreatic polypeptide PYY, 125I-pPYY Peptide YY (Y = tyrosine), iodinated porcine PYY QP Quartet puzzling maximum likelihood RT-PCR Reverse transcriptase PCR SCN Sodium channel TM Transmembrane Y1, Y2, … Y7, Y8 Neuropeptide Y receptor Yn Introduction Cells in our body communicate through numerous systems of receptors and ligands. In some cases, the ligands are exogenous signals such as for the opsins (light receptors), gustatory receptors (salt, sugar etc.) and olfactory receptors (odorants). Ligands used for signalling internally can be small molecules such as acetylcholine and dopamine or peptides that derive from precursor proteins produced from genes. The receptors as well as their ligands often belong to gene families with multiple members, particularly in vertebrates. Several ligands of the same family are frequently able to bind to the same receptor. The repertoire of ligands and receptors often varies between species and sometimes ligand- receptor preferences also differ. Therefore it is important to distinguish be- tween orthologs; genes separated by a speciation event, and paralogs; genes separated by a duplication event, when comparing functions of genes from different organisms. Furthermore, some of the receptor-ligand complexes execute their functions in a wide range of different tissues including the brain as well as peripheral tissues. This distribution may differ between spe- cies. Examples of this type of complex systems are the neuropeptide Y system of receptors and peptides with 4 to 7 receptors and 3 to 4 ligands (depending on species) and the opioid system with four receptors and four ligands in mammals. Several receptor and ligand families have expanded in the vertebrate line- age. Gene duplication followed by mutation, in contrast to direct mutation of a gene, allows for change in one gene copy with the other copy still intact and able to perform the original function. The higher complexity of many ligand-receptor systems in vertebrates compared with invertebrates has been attributed to both local gene duplications and whole genome duplications, i.e. tetraploidizations, early in vertebrate evolution. 9 Gene and genome duplication Gene and genome duplications have been promoted as the main mechanisms that can lead to the emergence of new genes and gene functions. In the 1970s Susumu Ohno argued that big leaps in evolution required new (duplicate) sets of genes. However, even before him there had been suggestions that it was not enough to modify and mutate already existing genes (Ohno, 1970). There are several well known molecular mechanisms by which new genes can be formed, including classical gene duplication and retroposition (Long et al., 2003). Data from several eukaryotic species have shown that gene duplications occur frequently and that the probability of duplication of a gene is at least 1% per million years (Lynch and Conery, 2003). Estimations of the number of gene duplications in different lineages have also been conducted. The duplication rates range from 0.27 and 0.8 per million years in chicken and frog up to 7.27 and 9.05 per million years in mouse and zebrafish. These estimates are however based on predicted genes in the genome databases and the extreme values might reflect the quality of genome assembly and not the true duplication rate. A low value might also be an indication of a high rate of gene loss and not only a low duplication rate (Blomme et al., 2006). Other studies have shown that humans and chimpanzees have a three-fold higher rate of gene gain and loss than other mammals (Hahn et al., 2007), and both segmental duplication and copy number variation seem to have played im- portant roles in the evolution of the primate genomes (Bailey and Eichler, 2006; Demuth and Hahn, 2009). When a gene has been duplicated, one of the gene copies is sufficient to maintain the function, while the other copy may evolve new functions (see below). Alternatively, the duplicate could easily become a pseudogene through accumulation of deleterious mutations due to reduced selective pres- sure (Kellogg,
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