Gender-Specific Gene Expression in Post-Mortem Human Brain: Localization to Sex Chromosomes (original) (raw)

• Complicated Case Study
• Published: 29 October 2003
• Simon Evans2,5 na1,
• Prabhakara Choudary3,5 na1,
• Hiroaki Tomita1,5 na1,
• Jim Meador-Woodruff2,
• Margherita Molnar3,5,
• Jun Li4,5,
• Juan F Lopez2,5,
• Rick Myers4,5,
• David Cox4,
• Stanley J Watson2,5,
• Huda Akil2,5,
• Edward G Jones3,5 &
• …
• William E Bunney1,5

Neuropsychopharmacology volume 29, pages 373–384 (2004)Cite this article

• 6381 Accesses
• 197 Citations
• 18 Altmetric
• Metrics details

Abstract

Gender differences in brain development and in the prevalence of neuropsychiatric disorders such as depression have been reported. Gender differences in human brain might be related to patterns of gene expression. Microarray technology is one useful method for investigation of gene expression in brain. We investigated gene expression, cell types, and regional expression patterns of differentially expressed sex chromosome genes in brain. We profiled gene expression in male and female dorsolateral prefrontal cortex, anterior cingulate cortex, and cerebellum using the Affymetrix oligonucleotide microarray platform. Differentially expressed genes between males and females on the Y chromosome (DBY, SMCY, UTY, RPS4Y, and USP9Y) and X chromosome (XIST) were confirmed using real-time PCR measurements. In situ hybridization confirmed the differential expression of gender-specific genes and neuronal expression of XIST, RPS4Y, SMCY, and UTY in three brain regions examined. The XIST gene, which silences gene expression on regions of the X chromosome, is expressed in a subset of neurons. Since a subset of neurons express gender-specific genes, neural subpopulations may exhibit a subtle sexual dimorphism at the level of differences in gene regulation and function. The distinctive pattern of neuronal expression of XIST, RPS4Y, SMCY, and UTY and other sex chromosome genes in neuronal subpopulations may possibly contribute to gender differences in prevalence noted for some neuropsychiatric disorders. Studies of the protein expression of these sex-chromosome-linked genes in brain tissue are required to address the functional consequences of the observed gene expression differences.

Similar content being viewed by others

References

• American Psychiatric Association (1994). Diagnostic and Statistical Manual of Mental Disorders 4th edn American Psychiatric Association: Washington, DC.
• Andreasen NC, Flaum M, Swayze II V, O'Leary DS, Alliger R, Cohen G et al (1993). Intelligence and brain structure in normal individuals. Am J Psychiatry 150: 130–134.
  Article CAS Google Scholar
• Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM et al (2000). Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet 25: 25–29.
  Article CAS Google Scholar
• Brockdorff N, Ashworth A, Kay GF, Cooper P, Smith S, McCabe VM et al (1991). Conservation of position and exclusive expression of mouse Xist from the inactive X chromosome. Nature 351: 329–331.
  Article CAS Google Scholar
• Brown CJ, Hendrich BD, Rupert JL, Lafreniere RG, Xing Y, Lawrence J et al (1992). The human XIST gene: analysis of a 17 kb inactive X-specific RNA that contains conserved repeats and is highly localized within the nucleus. Cell 71: 527–542.
  Article CAS Google Scholar
• Carruth LL, Reisert I, Arnold AP (2002). Sex chromosome genes directly affect brain sexual differentiation. Nat Neurosci 5: 933–934.
  Article CAS Google Scholar
• Dennis Jr G, Sherman BT, Hosack DA, Yang J, Gao W, Lane HC et al (2003). DAVID: database for annotation, visualization, and integrated discovery. Genome Biol 4: 1–11(Article R60).
  Article Google Scholar
• Eriksson A, Wahlestedt C, Nordqvist K (1999). Isolation of sex-specific cDNAs from fetal mouse brain using mRNA differential display and representational difference analysis. Brain Res Mol Brain Res 74: 91–97.
  Article CAS Google Scholar
• Escalona PR, McDonald WM, Doraiswamy PM, Boyko OB, Husain MM, Figiel GS et al (1991). In vivo stereological assessment of human cerebellar volume: effects of gender and age. AJNR Am J Neuroradiol 12: 927–929.
  CAS PubMed Google Scholar
• Fisher EM, Beer-Romero P, Brown LG, Ridley A, McNeil JA, Lawrence JB et al (1990). Homologous ribosomal protein genes on the human X and Y chromosomes: escape from X inactivation and possible implications for Turner syndrome. Cell 63: 1205–1218.
  Article CAS Google Scholar
• Gee CE, Chen CL, Roberts JL, Thompson R, Watson SJ (1983). Identification of proopiomelanocortin neurones in rat hypothalamus by in situ cDNA-mRNA hybridization. Nature 306: 374–376.
  Article CAS Google Scholar
• Giedd JN, Snell JW, Lange N, Rajapakse JC, Casey BJ, Kozuch PL et al (1996). Quantitative magnetic resonance imaging of human brain development: ages 4–18. Cereb Cortex 6: 551–560.
  Article CAS Google Scholar
• Graves JA (1995). The evolution of mammalian sex chromosomes and the origin of sex determining genes. Philos Trans R Soc Lond B Biol Sci 350: 305–311; discussion 311–312.
  Article CAS Google Scholar
• Gur RC, Mozley PD, Resnick SM, Gottlieb GL, Kohn M, Zimmerman R et al (1991). Gender differences in age effect on brain atrophy measured by magnetic resonance imaging. Proc Natl Acad Sci USA 88: 2845–2849.
  Article CAS Google Scholar
• Jones EG, Hendry SH, Liu XB, Hodgins S, Potkin SG, Tourtellotte WW (1992). A method for fixation of previously fresh-frozen human adult and fetal brains that preserves histological quality and immunoreactivity. J Neurosci Methods 44: 133–144.
  Article CAS Google Scholar
• Kanehisa M, Goto S (2000). KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids Res 28: 27–30.
  Article CAS Google Scholar
• Lahn BT, Page DC (1997). Functional coherence of the human Y chromosome. Science 278: 675–680.
  Article CAS Google Scholar
• Li C, Wong WH (2001). Model-based analysis of oligonucleotide arrays: expression index computation and outlier detection. Proc Natl Acad Sci USA 98: 31–36.
  Article CAS Google Scholar
• Mayer A, Lahr G, Swaab DF, Pilgrim C, Reisert I (1998). The Y-chromosomal genes SRY and ZFY are transcribed in adult human brain. Neurogenetics 1: 281–288.
  Article CAS Google Scholar
• Meador-Woodruff JH, Mansour A, Bunzow JR, Van Tol HH, Watson Jr SJ, Civelli O (1989). Distribution of D2 dopamine receptor mRNA in rat brain. Proc Natl Acad Sci USA 86: 7625–7628.
  Article CAS Google Scholar
• Pakkenberg B, Pelvig D, Marner L, Bundgaard MJ, Gundersen HJ, Nyengaard JR et al (2003). Aging and the human neocortex. Exp Gerontol 38: 95–99.
  Article Google Scholar
• Rabinowicz T, Petetot JM, Gartside PS, Sheyn D, Sheyn T, de CM (2002). Structure of the cerebral cortex in men and women. J Neuropathol Exp Neurol 61: 46–57.
  Article Google Scholar
• Reisert I, Pilgrim C (1991). Sexual differentiation of monoaminergic neurons—genetic or epigenetic? Trends Neurosci 14: 468–473.
  Article CAS Google Scholar
• Sibug R, Kuppers E, Beyer C, Maxson SC, Pilgrim C, Reisert I (1996). Genotype-dependent sex differentiation of dopaminergic neurons in primary cultures of embryonic mouse brain. Brain Res Dev Brain Res 93: 136–142.
  Article CAS Google Scholar
• Skaletsky H, Kuroda-Kawaguchi T, Minx PJ, Cordum HS, Hillier L, Brown LG et al (2003). The male-specific region of the human Y chromosome is a mosaic of discrete sequence classes. Nature 423: 825–837.
  Article CAS Google Scholar
• Su A, Cooke M, Ching K, Hakak Y, Walker J, Wiltshire T et al (2002). Large-scale analysis of the human and mouse transcriptomes. Proc Natl Acad Sci USA 99: 4465–4470.
  Article CAS Google Scholar
• Sudbrak R, Wieczorek G, Nuber UA, Mann W, Kirchner R, Erdogan F et al (2001). X chromosome-specific cDNA arrays: identification of genes that escape from X-inactivation and other applications. Hum Mol Genet 10: 77–83.
  Article CAS Google Scholar
• Tighilet B, Huntsman MM, Hashikawa T, Murray KD, Isackson PJ, Jones EG (1998). Cell-specific expression of type II calcium/calmodulin-dependent protein kinase isoforms and glutamate receptors in normal and visually deprived lateral geniculate nucleus of monkeys. J Comp Neurol 390: 278–296.
  Article CAS Google Scholar
• Vogt MH, van den Muijsenberg JW, Goulmy E, Spierings E, Kluck P, Kester MG et al (2002). The DBY gene codes for an HLA-DQ5-restricted human male-specific minor histocompatibility antigen involved in graft-versus-host disease. Blood 99: 3027–3032.
  Article CAS Google Scholar
• Xu J, Burgoyne PS, Arnold AP (2002). Sex differences in sex chromosome gene expression in mouse brain. Hum Mol Genet 11: 1409–1419.
  Article CAS Google Scholar
• Xu J, Kobayashi S, Yamaguchi S, Iijima K, Okada K, Yamashita K (2000). Gender effects on age-related changes in brain structure. AJNR Am J Neuroradiol 21: 112–118.
  CAS PubMed Google Scholar

Download references

Acknowledgements

We appreciate the assistance of Richard Stein, PhD, David Walsh, PsyD, and Preston Cartagena, PsyD for their contributions to post-mortem clinical characterization of subjects and Kathleen Burke for procurement of brain tissue, as well as Jacque Berndt and the investigators and medical examiners at the Orange County Coroners Office. We also appreciate the technical contributions of Erick Ferran, Karen Lopez, Sharon Burke, and Phong Nguyen. F Warren Lovell, MD, performed a neuropathological evaluation of the post-mortem brains. Tissue specimens were processed and stored at the Human Brain and Spinal Fluid Resource Center, Veterans Medical Center, Los Angeles under the direction of Wallace W Tourtellotte, MD, PhD. This project is supported by the NIMH Conte Center Grant P50 MH60398, Pritzker Neuropsychiatric Disorders Research Consortium, William Lion Penzner Foundation (UCI), Della Martin Foundation (UCI), NIMH Grant #MH54844 (EGJ), WM Keck Foundation (EGJ), and the NIMH Program Project MH42251 (SJW and HA).

Author information

Author notes

1. Marquis P Vawter, Simon Evans, Prabhakara Choudary and Hiroaki Tomita: These authors made equal contributions.

Authors and Affiliations

1. Department of Psychiatry, University of California, Irvine, CA, USA
   Marquis P Vawter, Hiroaki Tomita & William E Bunney
2. MHRI, University of Michigan, Ann Arbor, MI, USA
   Simon Evans, Jim Meador-Woodruff, Juan F Lopez, Stanley J Watson & Huda Akil
3. Center for Neuroscience, University of California, Davis, CA, USA
   Prabhakara Choudary, Margherita Molnar & Edward G Jones
4. Stanford Human Genome Center, Stanford University, Palo Alto, CA, USA
   Jun Li, Rick Myers & David Cox
5. The Pritzker Neuropsychiatric Disorders Research Consortium,
   Marquis P Vawter, Simon Evans, Prabhakara Choudary, Hiroaki Tomita, Margherita Molnar, Jun Li, Juan F Lopez, Rick Myers, Stanley J Watson, Huda Akil, Edward G Jones & William E Bunney

Authors

1. Marquis P Vawter
2. Simon Evans
3. Prabhakara Choudary
4. Hiroaki Tomita
5. Jim Meador-Woodruff
6. Margherita Molnar
7. Jun Li
8. Juan F Lopez
9. Rick Myers
10. David Cox
11. Stanley J Watson
12. Huda Akil
13. Edward G Jones
14. William E Bunney

Corresponding author

Correspondence toMarquis P Vawter.

Supplementary information

Rights and permissions

About this article

Cite this article

Vawter, M., Evans, S., Choudary, P. et al. Gender-Specific Gene Expression in Post-Mortem Human Brain: Localization to Sex Chromosomes.Neuropsychopharmacol 29, 373–384 (2004). https://doi.org/10.1038/sj.npp.1300337

Download citation

• Received: 27 December 2002
• Revised: 03 September 2003
• Accepted: 17 September 2003
• Published: 29 October 2003
• Issue date: 01 February 2004
• DOI: https://doi.org/10.1038/sj.npp.1300337

Keywords

This article is cited by