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Human Genetics

, Volume 119, Issue 3, pp 267–275 | Cite as

Inactivation status of PCDH11X: sexual dimorphisms in gene expression levels in brain

  • Alexandra M. Lopes
  • Norman Ross
  • James Close
  • Adam Dagnall
  • António Amorim
  • Timothy J. Crow
Original Investigation

Abstract

Genes escaping X-inactivation are predicted to contribute to differences in gene dosage between the sexes and are the prime candidates for being involved in the phenotype observed in individuals with X chromosome aneuploidies. Of particular interest is ProtocadherinX (PCDH11X or PCDHX), a recently described gene expressed in brain. In humans, PCDH11X has a homologue on the Y chromosome and is predicted to escape from X-inactivation. Employing bisulphite sequencing analysis we found absence of CpG island methylation on both the active and the inactive X chromosomes, providing a strong indication that PCDH11X escapes inactivation in humans. Furthermore, a sexual dimorphism in levels of expression in brain tissue was observed by quantitative real-time PCR, with females presenting an up to 2-fold excess in the abundance of PCDH11X transcripts. We relate these findings to sexually dimorphic traits in the human brain. Interestingly, PCDH11X/Y gene pair is unique to Homo sapiens, since the X-linked gene was transposed to the Y chromosome after the human–chimpanzee lineages split. Although no differences in promoter methylation were found between humans and chimpanzees, evidence of an upregulation of PCDH11X in humans deserves further investigation.

Keywords

Methylation Level Lymphoblastoid Cell Line Human Female Female Chimpanzee Inactivation Status 
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.

Notes

Acknowledgments

The authors would like to acknowledge Patricia Blanco-Arias and Carole Sargent for their valuable contribution to this work. We also would like to thank Luís Teixeira da Costa and Raquel Seruca for scientific advice and Luís Cirnes and Marta Novais for technical support. We are grateful to Dr. P. Khaitovitch, Dr. P. A. Morin and Dr. S. Paabo for kindly providing chimpanzee samples. We also thank the anonymous reviewers for their comments, which have contributed to the improvement of the manuscript. This work was partially supported by Fundação para a Ciência e Tecnologia (through grant SFRH/BD/7006/2001 and POCTI, Programa Operacional Ciência, Tecnologia e Inovação). Norman Ross, James Close, Adam Dagnal and Tim Crow are grateful to the UK Medical Research Council, TJ Crow Psychosis Research Trust, Stanley Foundation and SANE for support.

Supplementary material

439_2006_134_MOESM1_ESM.xls (18 kb)
Supplementary material

References

  1. Arnold AP (2004) Sex chromosomes and brain gender. Nat Rev Neurosci 5(9):701–708PubMedCrossRefGoogle Scholar
  2. Barrick TR, Mackay CE, Prima S, Vandermeulen D, Crow TJ, Roberts N (2004) Automatic analysis of cerebral asymmetry: an exploratory study of the relationship between brain torque and planum temporale asymmetry. Neuroimage 24(3):678–691CrossRefGoogle Scholar
  3. Blanco P, Sargent CA, Boucher CA, Mitchell M, Affara NA (2000) Conservation of PCDH11X in mammals; expression of human X/Y genes predominantly in brain. Mamm Genome 11(10):906–914PubMedCrossRefGoogle Scholar
  4. Blanco-Arias P, Sargent CA, Affara NA (2004a) Protocadherin X (PCDH11X) and Y (PCDH11Y) genes; multiple mRNA isoforms encoding variant signal peptides and cytoplasmic domains. Mamm Genome 15(1):41–52CrossRefGoogle Scholar
  5. Blanco-Arias P, Sargent CA, Affara NA (2004b) A comparative analysis of the pig, mouse, and human PCDH11X genes. Mamm Genome 15(4):296–306CrossRefGoogle Scholar
  6. Brown CJ, Greally JM (2003) A stain upon the silence: genes escaping X inactivation. Trends Genet 19(8):432–438PubMedCrossRefGoogle Scholar
  7. Brown CJ, Miller AP, Carrel L, Rupert JL, Davies KE, Willard HF (1995) The DXS423E gene in Xp11.21 escapes X chromosome inactivation. Hum Mol Genet 4(2):251–255PubMedCrossRefGoogle Scholar
  8. Brown CJ, Carrel L, Willard HF (1997) Expression of genes from the human active and inactive X chromosomes. Am J Hum Genet 60(6):1333–1343PubMedCrossRefGoogle Scholar
  9. Cáceres M, Lachuer J, Zapala MA, Redmond JC, Kudo L, Geschwind DH, Lockhart DJ, Preuss TM, Barlow C (2003) Elevated gene expression levels distinguish human from non-human primate brains. Proc Natl Acad Sci 100(22):13030–13035PubMedCrossRefGoogle Scholar
  10. Carrel L, Willard HF (1999) Heterogeneous gene expression from the inactive X chromosome: an X-linked gene that escapes X inactivation in some human cell lines but is inactivated in others. Proc Natl Acad Sci 96(13):7364–7369PubMedCrossRefGoogle Scholar
  11. Carrel L, Willard HF (2005) X-inactivation profile reveals extensive variability in X-linked gene expression in females. Nature 434(7031):400–404PubMedCrossRefGoogle Scholar
  12. Carrel L, Clemson CM, Dunn JM, Miller AP, Hunt PA, Lawrence JB, Willard HF (1996) X inactivation analysis and DNA methylation studies of the ubiquitin activating enzyme E1 and PCTAIRE-1 genes in human and mouse. Hum Mol Genet 5(3):391–401PubMedCrossRefGoogle Scholar
  13. Carrel L, Cottle AA, Goglin KC, Willard HF (1999) A first-generation X-inactivation profile of the human X chromosome. Proc Natl Acad Sci 96(25):14440–14444PubMedCrossRefGoogle Scholar
  14. Carruth LL, Reisert I, Arnold AP (2002) Sex chromosome genes directly affect brain sexual differentiation. Nat Neurosci 5(10):933–934PubMedCrossRefGoogle Scholar
  15. Charlesworth B (1996) The evolution of chromosomal sex determination and dosage compensation. Curr Biol 6(2):149–162PubMedCrossRefGoogle Scholar
  16. Ciccodicola A, D’Esposito M, Esposito T, Gianfrancesco F, Migliaccio C, Miano MG, Matarazzo MR, Vacca M, Franze A, Cuccurese M, Cocchia M, Curci A, Terracciano A, Torino A, Cocchia S, Mercadante G, Pannone E, Archidiacono N, Rocchi M, Schlessinger D, D’Urso M (2000) Differentially regulated and evolved genes in the fully sequenced Xq/Yq pseudoautosomal region. Hum Mol Genet 12:395–401CrossRefGoogle Scholar
  17. Craig IW, Mill J, Craig GM, Loat C, Schalkwyk LC (2004) Application of microarrays to the analysis of the inactivation status of human X-linked genes expressed in lymphocytes. Eur J Hum Genet 12(8):639–646PubMedCrossRefGoogle Scholar
  18. Crow TJ, Crow LR, Done DJ, Leask SJ (1998) Relative hand skill predicts academic ability: global deficits at the point of hemispheric indecision. Neuropsychologia 36(12):1275–1282PubMedCrossRefGoogle Scholar
  19. Csankovszki G, Nagy A, Jaenisch R (2001) Synergism of Xist RNA, DNA methylation, and histone hypoacetylation in maintaining X chromosome inactivation. J Cell Biol 153(4):773–784PubMedCrossRefGoogle Scholar
  20. D’Esposito M, Ciccodicola A, Gianfrancesco F, Esposito T, Flagiello L, Mazzarella R, Schlessinger D, D’Urso M (1996) A synaptobrevin-like gene in the Xq28 pseudoautosomal region undergoes X inactivation. Nat Genet 13(2):227–229PubMedCrossRefGoogle Scholar
  21. D’Esposito M, Matarazzo MR, Ciccodicola A, Strazzullo M, Mazzarella R, Quaderi NA, Fujiwara H, Ko MS, Rowe LB, Ricco A, Archidiacono N, Rocchi M, Schlessinger D, D’Urso M (1997) Differential expression pattern of XqPAR-linked genes SYBL1 and IL9R correlates with the structure and evolution of the region. Hum Mol Genet 6:1917–1923PubMedCrossRefGoogle Scholar
  22. Enard W, Khaitovich P, Klose J, Zollner S, Heissig F, Giavalisco P, Nieselt-Struwe K, Muchmore E, Varki A, Ravid R, Doxiadis GM, Bontrop RE, Paabo S (2002) Intra- and interspecific variation in primate gene expression patterns. Science 296(5566):340–343PubMedCrossRefGoogle Scholar
  23. Fisher EM, Beer-Romero P, Brown LG, Ridley A, McNeil JA, Lawrence JB, Willard HF, Bieber FR, Page DC (1990) Homologous ribosomal protein genes on the human X and Y chromosomes: escape from X inactivation and possible implications for Turner syndrome. Cell 63(6):1205–1218PubMedCrossRefGoogle Scholar
  24. Galfalvy HC, Erraji-Benchekroun L, Smyrniotopoulos P, Pavlidis P, Ellis SP, Mann JJ, Sibille E, Arango V (2003) Sex genes for genomic analysis in human brain: internal controls for comparison of probe level data extraction. BMC Bioinformatics 4:37PubMedCrossRefGoogle Scholar
  25. Jegalian K, Page DC (1998) A proposed path by which genes common to mammalian X and Y chromosomes evolve to become X inactivated. Nature 394(6695):776–780PubMedCrossRefGoogle Scholar
  26. Khaitovich P, Muetzel B, She X, Lachmann M, Hellmann I, Dietzsch J, Steigele S, Do HH, Weiss G, Enard W, Heissig F, Arendt T, Nieselt-Struwe K, Eichler EE, Paabo S (2004) Regional patterns of gene expression in human and chimpanzee brains. Genome Res 14(8):1462–1473PubMedCrossRefGoogle Scholar
  27. Kretschmann HF, Schleicher A, Wingert F, Zilles K, Loeblich HJ (1979) Human brain growth in the 19th and 20th century. J Neurol Sc 40:169–188CrossRefGoogle Scholar
  28. Lee JT, Jaenisch R (1997) The (epi)genetic control of mammalian X-chromosome inactivation. Curr Opin Genet Dev 7(2):274–280PubMedCrossRefGoogle Scholar
  29. Lyon MF (1961) Gene action in the X-chromosome of the mouse (Mus musculus L.). Nature 190:372–373PubMedCrossRefGoogle Scholar
  30. Matarazzo MR, De Bonis ML, Gregory RI, Vacca M, Hansen RS, Mercadante G, D’Urso M, Feil R, D’Esposito M (2002) Allelic inactivation of the pseudoautosomal gene SYBL1 is controlled by epigenetic mechanisms common to the X and Y chromosomes. Hum Mol Genet 11(25):3191–3198PubMedCrossRefGoogle Scholar
  31. Morley M, Molony CM, Weber TM, Devlin JL, Ewens KG, Spielman RS, Cheung VG (2004) Genetic analysis of genome-wide variation in human gene expression. Nature 430(7001):743–747PubMedCrossRefGoogle Scholar
  32. Munton RP, Vizi S, Mansuy IM (2004) The role of protein phosphatase-1 in the modulation of synaptic and structural plasticity. FEBS Lett 567(1):121–128PubMedCrossRefGoogle Scholar
  33. Ohno S (1967) Sex chromosomes and sex-linked genes. Springer, Berlin Heidelberg New YorkGoogle Scholar
  34. Page DC, Harper ME, Love J, Botstein D (1984) Occurrence of a transposition from the X-chromosome long arm to the Y-chromosome short arm during human evolution. Nature 311(5982):119–123PubMedCrossRefGoogle Scholar
  35. Pedone PV, Cosma MP, Ungaro P, Colantuoni V, Bruni CB, Zarrilli R, Riccio A (1994) Parental imprinting of rat insulin-like growth factor II gene promoters is coordinately regulated. J Biol Chem 269(39):23970–23975PubMedGoogle Scholar
  36. Penny GD, Kay GF, Sheardown SA, Rastan S, Brockdorff N (1996) Requirement for Xist in X chromosome inactivation. Nature 379(6561):131–137PubMedCrossRefGoogle Scholar
  37. Redies C, Vanhalst K, Roy FV (2005) delta-Protocadherins: unique structures and functions. Cell Mol Life Sci 62(23):2840–2852CrossRefGoogle Scholar
  38. Schwartz A, Chan DC, Brown LG, Alagappan R, Pettay D, Disteche C, McGillivray B, de la Chapelle A, Page DC (1998) Reconstructing hominid Y evolution: X-homologous block, created by X-Y transposition, was disrupted by Yp inversion through LINE-LINE recombination. Hum Mol Genet 7(1):1–11PubMedCrossRefGoogle Scholar
  39. Simon JL, Resampling Stats, Inc. (2000) “Resampling Stats” Standalone softwareGoogle Scholar
  40. Skaletsky H, Kuroda-Kawaguchi T, Minx PJ, Cordum HS, Hillier L, Brown LG, Repping S, Pyntikova T, Ali J, Bieri T, Chinwalla A, Delehaunty A, Delehaunty K, Du H, Fewell G, Fulton L, Fulton R, Graves T, Hou SF, Latrielle P, Leonard S, Mardis E, Maupin R, McPherson J, Miner T, Nash W, Nguyen C, Ozersky P, Pepin K, Rock S, Rohlfing T, Scott K, Schultz B, Strong C, Tin-Wollam A, Yang SP, Waterston RH, Wilson RK, Rozen S, Page DC (2003) The male-specific region of the human Y chromosome is a mosaic of discrete sequence classes. Nature 423(6942):825–837PubMedCrossRefGoogle Scholar
  41. Sudbrak R, Wieczorek G, Nuber UA, Mann W, Kirchner R, Erdogan F, Brown CJ, Wohrle D, Sterk P, Kalscheuer VM, Berger W, Lehrach H, Ropers HH (2001) X chromosome-specific cDNA arrays: identification of genes that escape from X-inactivation and other applications. Hum Mol Genet 10(1):77–83PubMedCrossRefGoogle Scholar
  42. Uddin M, Wildman DE, Liu G, Xu W, Johnson RM, Hof PR, Kapatos G, Grossman LI, Goodman M (2004) Sister grouping of chimpanzees and humans as revealed by genome-wide phylogenetic analysis of brain gene expression profiles. Proc Natl Acad Sci 101(9):2957–2962PubMedCrossRefGoogle Scholar
  43. Vanhalst K, Kools P, Staes K, van Roy F, Redies C (2005) delta-Protocadherins: a gene family expressed differentially in the mouse brain. Cell Mol Life Sci 62(11):1247–1259PubMedCrossRefGoogle Scholar
  44. Vawter MP, Evans S, Choudary P, Tomita H, Meador-Woodruff J, Molnar M, Li J, Lopez JF, Myers R, Cox D, Watson SJ, Akil H, Jones EG, Bunney WE (2004) Gender-specific gene expression in post-mortem human brain: localization to sex chromosomes. Neuropsychopharmacology 29(2):373–384PubMedCrossRefGoogle Scholar
  45. Vermeesch JR, Petit P, Kermouni A, Renauld JC, Van Den Berghe H, Marynen P (1997) The IL-9 receptor gene, located in the Xq/Yq pseudoautosomal region, has an autosomal origin, escapes X inactivation and is expressed from the Y. Hum Mol Genet 6:1–8PubMedCrossRefGoogle Scholar
  46. Wu Q, Maniatis T (1999) A striking organization of a large family of human neural cadherin-like cell adhesion genes. Cell 97(6):779–790PubMedCrossRefGoogle Scholar
  47. Yagi T, Takeichi M (2000) Cadherin superfamily genes: functions, genomic organization, and neurologic diversity. Genes Dev 14(10):1169–1180PubMedGoogle Scholar
  48. Yan H, Yuan W, Velculescu VE, Vogelstein B, Kinzler KW (2002) Allelic variation in human gene expression. Science 297(5584):1143PubMedCrossRefGoogle Scholar
  49. Yoshida K, Sugano S (1999) Identification of a novel protocadherin gene (PCDH11) on the human XY homology region in Xq21.3. Genomics 62(3):540–543PubMedCrossRefGoogle Scholar
  50. Xu J, Burgoyne PS, Arnold AP (2002) Sex differences in sex chromosome gene expression in mouse brain. Hum Mol Genet 11(12):1409–1419PubMedCrossRefGoogle Scholar
  51. Xu J, Taya S, Kaibuchi K, Arnold AP.( 2005) Sexually dimorphic expression of Usp9x is related to sex chromosome complement in adult mouse brain. Eur J Neurosci 21(11):3017–3022PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Alexandra M. Lopes
    • 1
    • 2
  • Norman Ross
    • 3
  • James Close
    • 3
  • Adam Dagnall
    • 3
  • António Amorim
    • 1
    • 2
  • Timothy J. Crow
    • 3
  1. 1.IPATIMUP, Instituto de Patologia e Imunologia Molecular da Universidade do PortoPortoPortugal
  2. 2.Faculdade de CiênciasUniversidade do PortoPortoPortugal
  3. 3.Department of Psychiatry, POWIC SANE Research CentreUniversity of Oxford, Warneford HospitalOxfordUK

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