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Journal of Molecular Evolution

, Volume 65, Issue 3, pp 267–276 | Cite as

Tempo and Mode in the Endocannaboinoid System

  • John M. McPartlandEmail author
  • Ryan W. Norris
  • C. William Kilpatrick
Article

Abstract

The best-known endocannabinoid ligands, anandamide and 2-AG, signal at least seven receptors and involve ten metabolic enzymes. Genes for the receptors and enzymes were examined for heterogeneities in tempo (relative rate of evolution, RRE) and mode (selection pressure, Ka/Ks) in six organisms with sequenced genomes. BLAST identified orthologs as reciprocal best hits, and nucleotide alignments were performed with ClustalX and MacClade. Two bioinformatics platforms, LiKaKs (a distance-based LWL85 model) and SNAP (a parsimony-based NG86 model) made pairwise comparisons of orthologs in murids (rat and mouse) and primates (human and macaque). Mean RRE of the 18 endocannabinoid genes was significantly greater in murids than primates, whereas mean Ka/Ks did not differ significantly. Next we used FUGE (tree-based maximum-likelihood model) to compute human lineage-specific Ka/Ks calculations for 18 genes, which ranged from 1.11 to 0.00, in rank order from highest to lowest: PTPN22, NAAA, TRPV1, TRPA1, NAPE-PLD, MAGL, PPARγ, FAAH1, COX2, FAAH2, ABDH4, CB2, GPR55, DAGLβ, PPARα, TRPV4, CB1, DAGLα; differences were significant (p < 0.0001). Rat and mouse presented different rank orders (e.g., GPR55 generated the greatest Ka/Ks ratio). The 18 genes were then tested for recent positive selection (within 10,000 yr) using an extended haplotype homozygosity analysis of SNP data from the HapMap database. Significant evidence (p < 0.05) of a positive “selective sweep” was exhibited by PTPN22, TRPV1, NAPE-PLD, and DAGLα. In conclusion, the endocannabinoid system is collectively under strong purifying selection, although some genes show evidence of adaptive evolution.

Keywords

Relative rate of evolution Selection pressure Ka/Ks ratio dN/dS ratio Linkage disequilibrium Cannabinoid receptor Vanilloid receptor Peroxisome proliferator-activated receptor Fatty acid amide hydrolase Cyclooxygenase-2 

Notes

Acknowledgments

This work was partially supported by an unrestricted grant from GW Pharmaceuticals, Salisbury, UK.

Supplementary material

239_2007_9004_MOESM1_ESM.doc (301 kb)
Supplementary material

References

  1. Abel EL (1980) Marihuana, the first twelve thousand years. Plenum Press, New YorkGoogle Scholar
  2. Akey JM, Zhang G, Zhang K, Jin L, Shriver MD (2002) Interrogating a high-density SNP map for signatures of natural selection. Genome Res 12:1805–1814PubMedCrossRefGoogle Scholar
  3. Altschul SF, Madden TL, Schaffer AA, Zhang J, Zhang Z, Miller W, Lipman DJ (1997) Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res 25:3389–3402PubMedCrossRefGoogle Scholar
  4. Baker D, Pryce G, Davies WL, Hiley CR (2006) In silico patent searching reveals a new cannabinoid receptor. Trends Pharmacol Sci 27:1–4PubMedCrossRefGoogle Scholar
  5. Benton MJ, Donoghue PCJ (2007) Paleontological evidence to date the tree of life. Mol Biol Evol 24:26–53PubMedCrossRefGoogle Scholar
  6. Bisogno T, Howell F, Williams G, Minassi A, Cascio MG, Ligresti A, Matias I, Schiano-Moriello A, Paul P, Williams EJ, et al. (2003) Cloning of the first sn1-DAG lipases points to the spatial and temporal regulation of endocannabinoid signaling in the brain. J Cell Biol 163:463–468PubMedCrossRefGoogle Scholar
  7. Bustamante CD, Fledel-Alon A, Williamson S, Nielsen R, Hubisz MT, Glanowski S, Tanenbaum DM, White TJ, Sninsky JJ, Hernandez RD, Civello D, Adams MD, Cargill M, Clark AG (2005) Natural selection on protein-coding genes in the human genome. Nature 437:1153–1157PubMedCrossRefGoogle Scholar
  8. Chimpanzee Sequencing, Analysis Consortium (2005) Initial sequence of the chimpanzee genome and comparison with the human genome. Nature 437:69–87CrossRefGoogle Scholar
  9. Clark AG, Glanowski S, Nielsen R, Thomas PD, Kejariwal A, Todd MA, Tanenbaum DM, Civello D, Lu F, Murphy B, Ferriera S, Wang G, Zheng X, White TJ, Sninsky JJ, Adams MD, Cargill M (2003) Inferring nonneutral evolution from human-chimp-mouse orthologous gene trios. Science 302:1960–1963PubMedCrossRefGoogle Scholar
  10. Clark AG, Hubisz MJ, Bustamante CD, Williamson SH, Nielsen R (2005) Ascertainment bias in studies of human genome-wide polymorphism. Genome Res 15:1496–1502PubMedCrossRefGoogle Scholar
  11. Cravatt BF, Giang DK, Mayfield SP, Boger DL, Lerner RA, Gilula NB (1996) Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature 384:83–87PubMedCrossRefGoogle Scholar
  12. Deutsch DG, Ueda N, Yamamoto S (2002) The fatty acid amide hydrolase (FAAH). Prostaglandins Leukotrienes Essential Fatty Acids 66:201–210CrossRefGoogle Scholar
  13. Dinh TP, Carpenter D, Leslie FM, Freund TF, Katona I, Sensi SL, Kathuria S, Piomelli D (2002) Brain monoglyceride lipase participating in endocannabinoid inactivation. Proc Natl Acad Sci U S A 99:10819–10824PubMedCrossRefGoogle Scholar
  14. Dorus S, Vallender EJ, Evans PD, Anderson JR, Gilbert SL, Mahowald M, Wyckoff GJ, Malcom CM, Lahn BT (2004) Accelerated evolution of nervous system genes in the origin of Homo sapiens. Cell 119:1027–1040PubMedCrossRefGoogle Scholar
  15. Enard W, Przeworski M, Fisher SE, Lai CS, Wiebe V, Kitano T, Monaco AP, Paabo S (2002) Molecular evolution of FOXP2, a gene involved in speech and language. Nature 418:869–872PubMedCrossRefGoogle Scholar
  16. Gibbs RA, Weinstock GM, Metzker ML, Muzny DM, Sodergren EJ, Scherer S, et al. (2004) Genome sequence of the Brown Norway rat yields insights into mammalian evolution. Nature 428:493–521PubMedCrossRefGoogle Scholar
  17. Hurst LD (2002) The Ka/Ks ratio: diagnosing the form of sequence evolution. Trends Genet 18:486–487PubMedCrossRefGoogle Scholar
  18. Jeanmougin F, Thompson JD, Gouy M, Higgins DG, Gibson TJ (1998) Multiple sequence alignment with Clustal X. Trends Biochem Sci 23:403–405PubMedCrossRefGoogle Scholar
  19. Jordt SE, Julius D (2002) Molecular basis for species-specific sensitivity to “hot” chili peppers. Cell 108:421–430PubMedCrossRefGoogle Scholar
  20. Jordt SE, Bautista DM, Chuang HH, McKemy DD, Zygmunt PM, Hogestatt ED, Meng ID, Julius D (2004) Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1. Nature 427:260–265PubMedCrossRefGoogle Scholar
  21. Kozak KR, Rowlinson SW, Marnett LJ (2000) Oxygenation of the endocannabinoid, 2-arachidonylglycerol, to glyceryl prostaglandins by cyclooxygenase-2. J Biol Chem 275:33744–33749PubMedCrossRefGoogle Scholar
  22. Kozak KR, Crews BC, Morrow JD, Wang LH, Ma YH, Weinander R, Jakobsson PJ, Marnett LJ (2002) Metabolism of the endocannabinoids, 2-arachidonylglycerol and anandamide, into prostaglandin, thromboxane, and prostacyclin glycerol esters and ethanolamides. J Biol Chem 277:44877–44885PubMedCrossRefGoogle Scholar
  23. Liu J, Wang L, Harvey-White J, Osei-Hyiaman D, Razdan R, Gong Q, Chan AC, Zhou Z, Huang BX, Kim HY, Kunos G (2006) A biosynthetic pathway for anandamide. Proc Natl Acad Sci U S A 103:13345–13350PubMedCrossRefGoogle Scholar
  24. Lynch M, Conery JS (2000) The evolutionary fate and consequences of duplicate genes. Science 290:1151–1155PubMedCrossRefGoogle Scholar
  25. Maddison WP, Maddison DR (1989) Interactive analysis of phylogeny and character evolution using the computer program MacClade. Folia Primatol 53:190–202PubMedCrossRefGoogle Scholar
  26. McPartland JM, Glass M (2003) Functional mapping of cannabinoid receptor homologs in mammals, other vertebrates, and invertebrates. Gene 312:297–303PubMedCrossRefGoogle Scholar
  27. McPartland JM, Matias I, DiMarzo V, Glass G (2006) Evolutionary origins of the endocannabinoid system. Gene 370:64–74PubMedCrossRefGoogle Scholar
  28. Mechoulam R, Fride E, Di Marzo V (1998) Endocannabinoids. Eur J Pharmacol 359:1–18PubMedCrossRefGoogle Scholar
  29. Nielsen R, Bustamante C, Clark AG, Glanowski S, Sackton TB, Hubisz MJ, Fledel-Alon A, Tanenbaum DM, Civello D, White TJ, Sninsky J, Adams MD, Cargill M (2005) A scan for positively selected genes in the genomes of humans and chimpanzees. PLoS Biol 3(6):e170PubMedCrossRefGoogle Scholar
  30. Okamoto Y, Morishita J, Tsuboi K, Tonai T, Ueda N (2004) Molecular characterization of a phospholipase D generating anandamide and its congeners. J Biol Chem 279:5298–5305PubMedCrossRefGoogle Scholar
  31. O'Sullivan SE, Tarling EJ, Bennett AJ, Kendall DA, Randall MD (2005) Novel time-dependent vascular actions of Delta9-tetrahydrocannabinol mediated by peroxisome proliferator-activated receptor gamma. Biochem Biophys Res Commun 337:824–831PubMedCrossRefGoogle Scholar
  32. Rockman MV, Hahn MW, Soranzo N, Zimprich F, Goldstein DB, Wray GA (2005) Ancient and recent positive selection transformed opioid cis-regulation in humans. PLoS Biol 3(12):e387PubMedCrossRefGoogle Scholar
  33. Rockwell CE, Kaminski NE (2004) A cyclooxygenase metabolite of anandamide causes inhibition of interleukin-2 secretion in murine splenocytes. J Pharmacol Exp Ther 311:683–690PubMedCrossRefGoogle Scholar
  34. Rockwell CE, Snider NT, Thompson JT, Vanden Heuvel JP, Kaminski NE (2006) Interleukin-2 suppression by 2-arachidonyl glycerol is mediated through peroxisome proliferator-activated receptor gamma independently of cannabinoid receptors 1 and 2. Mol Pharmacol 70:101–111PubMedGoogle Scholar
  35. Sabeti PC, Schaffner SF, Fry B, Lohmueller J, Varilly P, Shamovsky O, Palma A, Mikkelsen TS, Altshuler D, Lander ES (2006) Positive natural selection in the human lineage. Science 312:1614–1620PubMedCrossRefGoogle Scholar
  36. Simon GM, Cravatt BF (2006) Endocannabinoid biosynthesis proceeding through glycerophospho-N-acyl ethanolamine and a role for alpha/beta-hydrolase 4 in this pathway. J Biol Chem 281:26465–26472PubMedCrossRefGoogle Scholar
  37. Simpson GG (1944) Tempo and Mode in Evolution. Columbia University Press, New YorkGoogle Scholar
  38. Smith NG, Eyre-Walker A (2003) Partitioning the variation in mammalian substitution rates. Mol Biol Evol 20:10–17PubMedGoogle Scholar
  39. Straiker A, Mackie K (2007) Metabotropic suppression of excitation in murine autaptic hippocampal neurons. J Physiol 578:773–785PubMedCrossRefGoogle Scholar
  40. Sun Y, Alexander SPH, Kendall DA, Bennett AJ (2006) Cannabinoids and PPARα signalling. Biochem Soc Trans 34:1095–1097PubMedCrossRefGoogle Scholar
  41. Tsuboi K, Sun YX, Okamoto Y, Araki N, Tonai T, Ueda N (2005) Molecular characterization of N-acylethanolamine- hydrolyzing acid amidase, a novel member of the choloylglycine hydrolase family with structural and functional similarity to acid ceramidase. J Biol Chem 280:11082–11092PubMedCrossRefGoogle Scholar
  42. Tzeng YH, Pan R, Li WH (2004) Comparison of three methods for estimating rates of synonymous and nonsynonymous nucleotide substitutions. Mol Biol Evol 21:2290–2298PubMedCrossRefGoogle Scholar
  43. Voight BF, Kudaravalli S, Wen X, Pritchard JK (2006) A map of recent positive selection in the human genome. PLoS Biol 4(3):e72PubMedCrossRefGoogle Scholar
  44. Watanabe H, Vriens J, Prenen J, Droogmans G, Voets T, Nilius B (2003) Anandamide and arachidonic acid use epoxyeicosatrienoic acids to activate TRPV4 channels. Nature 424:434–438PubMedCrossRefGoogle Scholar
  45. Wei BQ, Mikkelsen TS, McKinney MK, Lander ES, Cravatt BF (2006) A second fatty acid amide hydrolase with variable distribution among placental mammals. J Biol Chem 281:36569–36578PubMedCrossRefGoogle Scholar
  46. Yang Z, Nielsen R, Goldman N, Pedersen AM (2000) Codon-substitution models for heterogeneous selection pressure at amino acid sites. Genetics 155:431–449PubMedGoogle Scholar
  47. Zhang J, Webb DM, Podlaha O (2002) Accelerated protein evolution and origins of human-specific features: Foxp2 as an example. Genetics 162:1825–1835PubMedGoogle Scholar
  48. Zhang P, Gu Z, Li WH (2003) Different evolutionary patterns between young duplicate genes in the human genome. Genome Biol 4(9):R56PubMedCrossRefGoogle Scholar
  49. Zygmunt PM, Petersson J, Andersson DA, Chuang H, Sorgard M, Di Marzo V, Julius D, Hogestatt ED (1999) Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature 400:452–457PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • John M. McPartland
    • 1
    Email author
  • Ryan W. Norris
    • 2
  • C. William Kilpatrick
    • 2
  1. 1.GW Pharmaceuticals, Ltd.MiddleburyUSA
  2. 2.Department of BiologyUniversity of VermontBurlingtonUSA

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