Evolution of the Neuropeptide Y Receptor Family: Gene and Chromosome Duplications Deduced from the Cloning and Mapping of the Five Receptor Subtype Genes in Pig

Abstract

Neuropeptide Y (NPY) receptors mediate a variety of physiological responses including feeding and vasoconstriction. To investigate the evolutionary events that have generated this receptor family, we have sequenced and determined the chromosomal localizations of all five presently known mammalian NPY receptor subtype genes in the domestic pig, Sus scrofa (SSC). The orthologs of the Y 1 and Y 2 subtypes display high amino acid sequence identities between pig, human, and mouse (92%-94%), whereas the Y 4 , Y 5 , and y 6 subtypes display lower identities (76%-87%). The lower identity of Y 5 is due to high sequence divergence in the large third intracellular loop. The NPY1R, NPY2R, and NPY5R receptor genes were localized to SSC8, the NPY4R to SSC14, and NPY6R to SSC2. Our comparisons strongly suggest that the tight cluster of NPY1R, NPY2R, and NPY5R on human chromosome 4 (HSA4) represents the ancestral configuration, whereas the porcine cluster has been split by two inversions on SSC8. These 3 genes, along with adjacent genes from 14 other gene families, form a cluster on HSA4 with extensive similarities to a cluster on HSA5, where NPY6R and >13 other paralogs reside, as well as another large cluster on HSA10 that includes NPY4R. Thus, these gene families have expanded through large-scale duplications. The sequence comparisons show that the NPY receptor triplet NPY1R-NPY2R-NPY5R existed before these large-scale duplications.

The Human Hox-bearing Chromosome Regions Did Arise by Block or Chromosome (or Even Genome) Duplications

“…Included among the 40 sequences were also two NPY-family receptors (on non-Hox chromosomes). These arose before the proposed chromosome duplications, although they still bind the same ligands (Wraith et al 2000). Other NPY-family receptors (Wraith et al 2000) as well as dopamine receptors D1 and D5 and adrenergic receptors support chromosome duplications, albeit a different paralogon than the one discussed here.…”

“…These arose before the proposed chromosome duplications, although they still bind the same ligands (Wraith et al 2000). Other NPY-family receptors (Wraith et al 2000) as well as dopamine receptors D1 and D5 and adrenergic receptors support chromosome duplications, albeit a different paralogon than the one discussed here. Thus, the analysis performed by Hughes et al cannot be taken as evidence for or against block duplications.…”

To Predict Human Biomarker for the Obesity Using Mouse Homologous Expression Data at Different Theiler Stages

“…The comparative genomics and proteomics analysis has led to identification of biomarker by comparing it with already known human and mouse biomarker. It has been concluded that both the proteins are plasma membrane proteins and also both NPY1R and MC4R belongs to same familyof GPCR (Gprotein-coupled receptors) [19] [20], NPY1R bears greater similarity to MC4R in its domain organization. And both proteins are structurally and functionally similar.…”

Pancreatic Polypeptide Is Recognized by Two Hydrophobic Domains of the Human Y4 Receptor Binding Pocket

“…Physiologically, the Y 4 R is involved in the regulation of food intake (9), colonic anion transport (10), and adipose tissue and bone formation synergistically with Y 2 R (11). The Y 4 R sequence is one of the least conserved members of the NPYR family among different species, making it the fastest evolving functional member of the family (12). This makes it difficult to transfer conclusions from other Y receptor members to this subtype.…”

“…It is secreted after food ingestion in proportion to its caloric content (14), and it promotes appetite suppression and inhibition of gastric emptying (15). This ligand was already found in ancient tetrapod evolution and appears to be one of the fastest developing peptides of the family (12). Because of its role in appetite suppression, this system is a very attractive target for the design of new therapeutic compounds for fighting obesity.…”