Human Genetics

, Volume 115, Issue 5, pp 377–386 | Cite as

Positive selection in MAOA gene is human exclusive: determination of the putative amino acid change selected in the human lineage

  • Aida M. Andrés
  • Marta Soldevila
  • Arcadi Navarro
  • Kenneth K. Kidd
  • Baldomero Oliva
  • Jaume BertranpetitEmail author
Original Investigation


Monoamine oxidase A (MAOA) is the X-linked gene responsible for deamination and subsequent degradation of several neurotransmitters and other amines. Among other activities, the gene has been shown to play a role in locomotion, circadian rhythm, and pain sensitivity and to have a critical influence on behavior and cognition. Previous studies have reported a non-neutral evolution of the gene attributable to positive selection in the human lineage. To determine whether this selection was human-exclusive or shared with other species, we performed a population genetic analysis of the pattern of nucleotide variation in non-human species, including bonobo, chimpanzee, gorilla, and orangutan. Footprints of positive selection were absent in all analyzed species, suggesting that positive selection has been recent and unique to humans. To determine which human-unique genetic changes could have been responsible for this differential evolution, the coding region of the gene was compared between human, chimpanzee, and gorilla. Only one human exclusive non-conservative change is present in the gene: Glu151Lys. This human substitution affects protein dimerization according to a three-dimensional structural model that predicts a non-negligible functional shift. This is the only candidate position at present to have been selected to fixation in humans during an episode of positive selection. Divergence analysis among species has shown that, even under positive selection in the human lineage, the MAOA gene did not experience accelerated evolution in any of the analyzed lineages, and that tools such as Ka/Ks would not have detected the selective history of the gene.


Ancestral Sequence Human Lineage Variability Level Gorilla Gorilla Hydrophilic Amino Acid 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The authors thank Monica Vallés (UPF) for technical support, Coralie de Hemptinne for sequencing assistance, and Judith R. Kidd (Yale University) for her invaluable help with primate DNA samples. We are indebted to Jorune Balciuniene and Elena Vazin (University of Minnesota) for sharing sequences from MAOA exons in chimpanzees and gorillas. We are also grateful to Yoav Gilad (Yale University) and Molly Przeworski (Brown University) for useful discussion, Francesc Calafell and David Comas (UPF) for valuable comments on the manuscript, and Tomàs Marquès (UPF) for help with RRTree program. Some primate samples were kindly supplied by the Barcelona Zoo (under the agreement of the Primate DNA Bank with Pompeu Fabra University). This study was supported by the Spanish Government (grant BCM 2001-0772) and by the Departament d’Universitats, Recerca i Societat de la Informació de la Generalitat de Catalunya (both to J.B.), and BOS2003-08070 (to A.N.). A.M.A. was financially supported by a fellowship from Generalitat de Catalunya (2000FI 00686).


  1. Bach AW, Lan NC, Johnson DL, Abell CW, Bembenek ME, Kwan SW, Seeburg PH, Shih JC (1988) cDNA cloning of human liver monoamine oxidase A and B: molecular basis of differences in enzymatic properties. Proc Natl Acad Sci USA 85:4934–4938PubMedGoogle Scholar
  2. Balciuniene J, Syvanen AC, McLeod HL, Pettersson U, Jazin EE (2001) The geographic distribution of monoamine oxidase haplotypes supports a bottleneck during the dispersion of modern humans from Africa. J Mol Evol 52:157–163PubMedGoogle Scholar
  3. Berger W, Meindl A, Pol TJ van de, Cremers FP, Ropers HH, Doerner C, Monaco A, Bergen AA, Lebo R, Warburg M, et al (1992) Isolation of a candidate gene for Norrie disease by positional cloning. Nat Genet 1:199–203CrossRefPubMedGoogle Scholar
  4. Binda C, Newton-Vinson P, Hubalek F, Edmondson DE, Mattevi A (2002) Structure of human monoamine oxidase B, a drug target for the treatment of neurological disorders. Nat Struct Biol 9:22–26CrossRefPubMedGoogle Scholar
  5. Boeckmann B, Bairoch A, Apweiler R, Blatter MC, Estreicher A, Gasteiger E, Martin MJ, Michoud K, O’Donovan C, et al (2003) The SWISS-PROT protein knowledgebase and its supplement TrEMBL in 2003. Nucleic Acids Res 31:365–370CrossRefPubMedGoogle Scholar
  6. Boffelli D, McAuliffe J, Ovcharenko D, Lewis KD, Ovcharenko I, Pachter L, Rubin EM (2003) Phylogenetic shadowing of primate sequences to find functional regions of the human genome. Science 299:1391–1394CrossRefPubMedGoogle Scholar
  7. Brunner HG, Nelen M, Breakefield XO, Ropers HH, Oost van BA (1993) Abnormal behavior associated with a point mutation in the structural gene for monoamine oxidase A. Science 262:578–580PubMedGoogle Scholar
  8. Cann HM, Toma C de, Cazes L, Legrand MF, Morel V, Piouffre L, Bodmer J, Bodmer WF, Bonne-Tamir B, Cambon-Thomsen A, et al (2002) A human genome diversity cell line panel. Science 296:261–262CrossRefPubMedGoogle Scholar
  9. Cases O, Seif I, Grimsby J, Gaspar P, Chen K, Pournin S, Muller U, Aguet M, Babinet C, Shih JC, et al (1995) Aggressive behavior and altered amounts of brain serotonin and norepinephrine in mice lacking MAOA. Science 268:1763–1766PubMedGoogle Scholar
  10. Chen FC, Li WH (2001) Genomic divergences between humans and other hominoids and the effective population size of the common ancestor of humans and chimpanzees. Am J Hum Genet 68:444–456CrossRefPubMedGoogle Scholar
  11. Clarimon J, Andres AM, Bertranpetit J, Comas D (2004) Comparative analysis of Alu insertion sequences in the APP 5′flanking region in humans and other primates. J Mol Evol 58:722–731Google Scholar
  12. Ebersberger I, Metzler D, Schwarz C, Paabo S (2002) Genomewide comparison of DNA sequences between humans and chimpanzees. Am J Hum Genet 70:1490–1497CrossRefPubMedGoogle Scholar
  13. 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 418:869–872CrossRefPubMedGoogle Scholar
  14. Eswar N, John B, Mirkovic N, Fiser A, Ilyin VA, Pieper U, Stuart AC, Marti-Renom MA, Madhusudhan MS, Yerkovich B, Sali A (2003) Tools for comparative protein structure modeling and analysis. Nucleic Acids Res 31:3375–3380CrossRefPubMedGoogle Scholar
  15. Evans PD, Anderson JR, Vallender EJ, Gilbert SL, Malcom CM, Dorus S, Lahn BT (2004) Adaptive evolution of ASPM, a major determinant of cerebral cortical size in humans. Hum Mol Genet 13:489–494Google Scholar
  16. Fay JC, Wu CI (2000) Hitchhiking under positive Darwinian selection. Genetics 155:1405–1413PubMedGoogle Scholar
  17. Fu YX, Li WH (1993) Statistical tests of neutrality of mutations. Genetics 133:693–709PubMedGoogle Scholar
  18. Gargallo R, Hunenberger PH, Aviles FX, Oliva B (2003) Molecular dynamics simulation of highly charged proteins: comparison of the particle–particle particle–mesh and reaction field methods for the calculation of electrostatic interactions. Protein Sci 12:2161–2172CrossRefPubMedGoogle Scholar
  19. Gilad Y, Rosenberg S, Przeworski M, Lancet D, Skorecki K (2002) Evidence for positive selection and population structure at the human MAO-A gene. Proc Natl Acad Sci USA 99:862–867CrossRefPubMedGoogle Scholar
  20. Grimsby J, Chen K, Wang LJ, Lan NC, Shih JC (1991) Human monoamine oxidase A and B genes exhibit identical exon-intron organization. Proc Natl Acad Sci USA 88:3637–3641PubMedGoogle Scholar
  21. Gunsteren WV, Billeter S, Eising A, Hünenberger P, Früger, P, Mark A, Scott W, Tironi I (1996) Biomolecular simulation: the GROMOS96 manual and user guide. Verlag der Fachvereine, ZürichGoogle Scholar
  22. Hall TA (1999) BioEdit: a user-friendly biological sequence alignment editor and analysis program for Windows 95/98/NT. Nucleic Acids Symp Ser 41:95–98Google Scholar
  23. Holschneider DP, Chen K, Seif I, Shih JC (2001) Biochemical, behavioral, physiologic, and neurodevelopmental changes in mice deficient in monoamine oxidase A or B. Brain Res Bull 56:453–462Google Scholar
  24. Hudson RR, Kreitman M, Aguade M (1987) A test of neutral molecular evolution based on nucleotide data. Genetics 116:153–159PubMedGoogle Scholar
  25. Hunenberger PH, van Gunsteren WF (1998) Alternative schemes for the inclusion of a reaction-field correction into molecular dynamics simulations: influence on the simulated energetic, structural, and dielectric properties of liquid water. J Chem Phys 108:6117–6134CrossRefGoogle Scholar
  26. Kaessmann H, Wiebe V, Paabo S (1999) Extensive nuclear DNA sequence diversity among chimpanzees. Science 286:1159–1162CrossRefPubMedGoogle Scholar
  27. Kaessmann H, Wiebe V, Weiss G, Paabo S (2001) Great ape DNA sequences reveal a reduced diversity and an expansion in humans. Nat Genet 27:155–156CrossRefPubMedGoogle Scholar
  28. Kim JJ, Shih JC, Chen K, Chen L, Bao S, Maren S, Anagnostaras SG, Fanselow MS, De Maeyer E, Seif I, Thompson RF (1997) Selective enhancement of emotional, but not motor, learning in monoamine oxidase A-deficient mice. Proc Natl Acad Sci USA 94:5929–5933CrossRefPubMedGoogle Scholar
  29. Kitano T, Schwarz C, Nickel B, Paabo S (2003) Gene diversity patterns at 10 X-chromosomal loci in humans and chimpanzees. Mol Biol Evol 20:1281–1289CrossRefPubMedGoogle Scholar
  30. Kräutler V, Gunsteren, WF, Hünenberger P (2001) A fast SHAKE algorithm to solve distance constraint equations for small molecules in molecular dynamics simulations. J Comput Chem 22:501–508CrossRefGoogle Scholar
  31. Mcdonald JH, Kreitman M (1991) Adaptive protein evolution at the Adh locus in Drosophila. Nature 351:652–654CrossRefPubMedGoogle Scholar
  32. Messier W, Stewart CB (1997) Episodic adaptative evolution of primate lysozymes. Nature 385:151–154CrossRefPubMedGoogle Scholar
  33. Robinson-Rechavi M, Huchon D (2000) RRTree: relative-rate tests between groups of sequences on a phylogenetic tree. Bioinformatics 16:296–297CrossRefPubMedGoogle Scholar
  34. Rozas J, Rozas R (1999) DnaSP version 3: an integrated program for molecular population genetics and molecular evolution analysis. Bioinformatics 15:174–175CrossRefPubMedGoogle Scholar
  35. Russell RB, Barton GJ (1992) Multiple protein-sequence alignment from tertiary structure comparison—assignment of global and residue confidence levels. Proteins Struct Funct Genet 14:309–323PubMedGoogle Scholar
  36. Sanchez R, Pieper U, Melo F, Eswar N, Marti-Renom MA, Madhusudhan MS, Mirkovic N, Sali A (2000) Protein structure modeling for structural genomics. Nat Struct Biol 7(Suppl):986–990CrossRefPubMedGoogle Scholar
  37. Shih JC, Thompson RF (1999) Monoamine oxidase in neuropsychiatry and behavior. Am J Hum Genet 65:593–598CrossRefPubMedGoogle Scholar
  38. Shih JC, Chen K, Ridd MJ (1999) Monoamine oxidase: from genes to behavior. Annu Rev Neurosci 22:197–217CrossRefPubMedGoogle Scholar
  39. Sims KB, Chapelle A de la, Norio R, Sankila EM, Hsu YP, Rinehart WB, Corey TJ, Ozelius L, Powell JF, Bruns G, et al (1989) Monoamine oxidase deficiency in males with an X chromosome deletion. Neuron 2:1069–1076PubMedGoogle Scholar
  40. Subramanian S, Kumar S (2003) Neutral substitutions occur at a faster rate in exons than in noncoding DNA in primate genomes. Genome Res 13:838–844CrossRefPubMedGoogle Scholar
  41. Swanson WJ, Yang Z, Wolfner MF, Aquadro CF (2001) Positive Darwinian selection drives the evolution of several female reproductive proteins in mammals. Proc Natl Acad Sci USA 98:2509–2514CrossRefPubMedGoogle Scholar
  42. Tajima F (1989) Statistical method for testing the neutral mutation hypothesis by DNA polymorphism. Genetics 123:585–595PubMedGoogle Scholar
  43. Westbrook J, Feng Z, Chen L, Yang H, Berman HM (2003) The Protein Data Bank and structural genomics. Nucleic Acids Res 31:489–491CrossRefPubMedGoogle Scholar
  44. Wiehe T, Guigo R, Miller W (2000) Genome sequence comparisons: hurdles in the fast lane to functional genomics. Brief Bioinform 1:381–388PubMedGoogle Scholar
  45. Wyckoff GJ, Wang W, Wu CI (2000) Rapid evolution of male reproductive genes in the descent of man. Nature 403:304–309 CrossRefPubMedGoogle Scholar
  46. Yang Z (1997) PAML: a program package for phylogenetic analysis by maximum likelihood. Comput Appl Biosci 13:555–556PubMedGoogle Scholar
  47. Yu N, Jensen-Seaman MI, Chemnick L, Kidd JR, Deinard AS, Ryder O, Kidd KK, Li WH (2003) Low nucleotide diversity in chimpanzees and bonobos. Genetics 164:1511–1518PubMedGoogle Scholar
  48. Zhang J (2003) Evolution of the human ASPM gene, a major determinant of brain size. Genetics 165:2063–2070PubMedGoogle Scholar
  49. 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

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Aida M. Andrés
    • 1
    • 4
  • Marta Soldevila
    • 1
  • Arcadi Navarro
    • 1
  • Kenneth K. Kidd
    • 2
  • Baldomero Oliva
    • 3
  • Jaume Bertranpetit
    • 1
    Email author
  1. 1.Unitat de Biologia Evolutiva, Departament de Ciències Experimentals i de la SalutUniversitat Pompeu Fabra (UPF)BarcelonaSpain
  2. 2.Department of GeneticsYale University School of MedicineNew HavenUSA
  3. 3.Laboratori de Bioinformàtica Estructural (GRIB)Universitat Pompeu FabraBarcelonaSpain
  4. 4.Department of Molecular Biology and GeneticsCornell UniversityIthacaUSA

Personalised recommendations