The X Chromosome, Dosage Compensation, and X Inactivation

  • Orlando J. Miller
  • Eeva Therman
Chapter

Abstract

The X chromosome is of medium size, making up 5.3% of the haploid karyotype. It is submetacentric, with a centromere index of 0.38 and a distinctive banding pattern (Fig. 17.1). In females, one X chromosome is condensed throughout interphase and is frequently visible in epithelial cells as a Barr body, or X heterochromatin. It is visible as a drumstick-shaped extrusion in 1–5% of polymorphonuclear white blood cells (Fig. 18.1a). The Barr body consists of a loop-shaped X chromosome in which the two telomeres lie close together at the nuclear membrane (Walker et al., 1991). Barr bodies can be scored in cells scraped from the mouth (buccal smears; Fig. 18.1b,c) or vagina, in cultured fibroblasts (Fig. 18.ld,e,f), or in follicle cells attached to a plucked hair. In normal females, a Barr body is visible in only 20–50% of buccal cells, in 30–80% of fibroblasts, and in over 90% of cells in amniotic membranes. In every individual (male or female) with two or more X chromosomes, the maximum number of Barr bodies is one less than the number of X chromosomes. That is, one X remains euchromatic and the additional ones are heterochromatic. The heterochromatic X chromosomes replicate later in S than the euchromatic X, as demonstrated over 35 years ago by autoradiography (Chapter 3). The allocyclic, or out-of-step, behavior of the inactive X chromosome expresses itself in other ways, some described in Chapter 3. In both prophase and metaphase, the inactive X is often more condensed, and thus shorter, than the active X.

Keywords

Leukemia Electrophoresis Sorting Pregnan 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Allderdice PW, Miller OJ, Miller DA, et al. (1978) Spreading of inactivation in an (X;14) translocation. Am J Med Genet 2:233–240PubMedCrossRefGoogle Scholar
  2. Boggs BA, Chinault AC (1994) Analysis of replication timing properties of human X-chromosomal loci by fluorescence in situ hybridization. Proc Natl Acad Sci USA 91:6083–6087PubMedCrossRefGoogle Scholar
  3. Brown CJ, Hendrick BD, Rupert JL, et al. (1992) The human XIST gene: analysis of a 17kb inactive X-specific RNA that contains conserved repeats and is highly localized within the nucleus. Cell 71:527–542PubMedCrossRefGoogle Scholar
  4. Brown CJ, Lafreniere RG, Powers VE, et al. (1991) Localization of the inactivation centre on the human X chromosome in Xql3. Nature 349:82–84PubMedCrossRefGoogle Scholar
  5. Costanzi C, Pehrson JR (1998) Histone macroH2Al is concentrated in the inactive X chromosome of female mammals. Nature 393:599–601PubMedCrossRefGoogle Scholar
  6. Couturier J, Dutrillaux B, Garber P, et al. (1979) Evidence for a correlation between late replication and autosomal gene inactivation in a familial translocation t(X;21). Hum Genet 49:319–326PubMedCrossRefGoogle Scholar
  7. Daniels R, Zuccotti M, Kinis T, et al. (1997) XIST expression in human oocytes and preimplantation embryos. Am J Hum Genet 61:33–39PubMedCrossRefGoogle Scholar
  8. Davidson RG, Nitowsky HM, Childs B (1963) Demonstration of two populations of cells in the human female heterozygous for glucose-6-phosphate dehydrogenase variants. Proc Natl Acad Sci USA 50:481–485PubMedCrossRefGoogle Scholar
  9. Disteche CM (1995) Escape from X-inactivation in human and mouse. Trends Genet 11:17–22PubMedCrossRefGoogle Scholar
  10. Duthie SM, Nesterova TB, Formstone EJ, et al. (1999) Xist RNA exhibits a banded localization on the inactive X chromosome and is excluded from autosomal material in eis. Hum Mol Genet 8:195–204PubMedCrossRefGoogle Scholar
  11. Gartier SM, Goldstein L, Tyler-Freer SE, et al. (1999) The timing of XIST replication: dominance of the domain. Hum Mol Genet 8:1085–1089CrossRefGoogle Scholar
  12. Haaf T, Werner P, Schmid M (1993) 5-Azacytidine distinguishes between active and inactive X chromosome condensation. Cytogenet Cell Genet 63: 160–168PubMedCrossRefGoogle Scholar
  13. Hansen RS, Canfleld TK, Gartier SM (1995) Reverse replication timing for the XIST gene in human fibroblasts. Hum Mol Genet 4:813–820PubMedCrossRefGoogle Scholar
  14. Hellkuhl B, Chapelle A de la, Grzeschik K-H (1982) Different patterns of X chromosome inactivity in lymphocytes and fibroblasts of a human balanced X;autosome translocation. Hum Genet 60:126–129PubMedCrossRefGoogle Scholar
  15. Jeppesen P, Turner BM (1993) The inactive X chromosome in female mammals is distinguished by a lack of histone H4 acetylation, a cytogenetic marker for gene expression. Cell 74:281–289PubMedCrossRefGoogle Scholar
  16. Kaslow DC, Migeon BR (1987) DNA methylation stabilizes X chromosome inactivation in eutherians but not in marsupials: evidence for multistep maintenance of mammalian X dosage compensation. Proc Natl Acad Sci USA 84:6210–6214PubMedCrossRefGoogle Scholar
  17. Keohane AM, Barlow AL, Waters J, et al. (1999) H4 acetylation, XIST RNA and replication timing are coincident and define X;autosome boundaries in two abnormal X chromosomes. Hum Mol Genet 8:377–383PubMedCrossRefGoogle Scholar
  18. Lau AW, Brown CJ, Penaherrera M, et al. (1997) Skewed X-chromosome inactivation is common in fetuses and newborns with confined placental mosaicism. Am J Hum Genet 61:1353–1361PubMedCrossRefGoogle Scholar
  19. Lee JT, Davidow LS, Warshawsky D (1999) Tsix, a gene antisense to Xist at the X-inactivation centre. Nat Genet 21:400–404PubMedCrossRefGoogle Scholar
  20. Lyon MF (1961) Gene action in the X-chromosome of the mouse (Mus musculus L.). Nature 190:372–373PubMedCrossRefGoogle Scholar
  21. Lyon MF (1974) Mechanisms and evolutionary origins of variable X-chromosome activity in mammals. Proc R Soc Lond B 187:243–268PubMedCrossRefGoogle Scholar
  22. Migeon BR (1994) X-chromosome inactivation: molecular mechanisms and genetic consequences. Trends Genet 10:230–235PubMedCrossRefGoogle Scholar
  23. Migeon BR, Schmidt M, Axelman J, et al. (1986) Complete reactivation of X chromosomes from human chorionic villi with a switch to early DNA replication. Proc Natl Acad Sci USA 83:2182–2186PubMedCrossRefGoogle Scholar
  24. Migeon BR, Axelman J, Beur SJ, et al. (1989) Selection against lethal alleles in females heterozygous for incontinentia pigmenti. Am J Hum Genet 44:100–106PubMedGoogle Scholar
  25. Migeon BR, Luo S, Jani M, et al. (1994) The severe phenotype of females with tiny ring X chromosomes is associated with inability of these chromosomes to undergo X inactivation. Am J Hum Genet 55:497–504PubMedGoogle Scholar
  26. Mohandas T, Sparkes RS, Shapiro LJ (1981) Reactivation of an inactive human X-chromosome: evidence for X inactivation by DNA methylation. Science 211:393–396PubMedCrossRefGoogle Scholar
  27. Nagel S, Borisch B, Thein SL, et al. (1995) Somatic mutation detected by mini-and microsatellite DNA markers reveal clonal intratumor heterogeneity in gastrointestinal cancers. Cancer Res 55:2866–2870PubMedGoogle Scholar
  28. Pegoraro E, Whitaker J, Mowery-Rushton P, et al. (1997) Familial skewed X-inactivation: a molecular trait associated with high spontaneous abortion rate maps to Xq28. Am J Hum Genet 61:160–170PubMedCrossRefGoogle Scholar
  29. Puck JM, Stewart CC, Nussbaum RL (1992) Maximum likelihood analysis of human T-cell X chromosome inactivation,patterns: normal women versus carriers of X-linked severe combined immunodeficiency. Am J Hum Genet 50:742–748PubMedGoogle Scholar
  30. Rack KA, Chelly J, Gibbons RJ, et al. (1994) Absence of the XIST gene from late-replicating isodicentric X chromosomes in leukemia. Hum Mol Genet 3:1053–1059PubMedCrossRefGoogle Scholar
  31. Rao E, Weiss B, Fukami M, et al. (1997) Pseudoautosomal deletions encompassing a novel homeobox gene cause growth failure in idiopathic short stature and Turner syndrome. Nat Genet 16:54–63PubMedCrossRefGoogle Scholar
  32. Richter C, Soreq H, Wahrman J (1992) X inactivation in mammalian testis is correlated with inactive X-specific transcription. Nat Genet 2:192–195CrossRefGoogle Scholar
  33. Schmidt M, Migeon BR (1990) Asynchronous replication of homologous loci on human active and inactive X chromosomes. Proc Natl Acad Sci USA 87:3685–3689PubMedCrossRefGoogle Scholar
  34. Sheardown SA, Duthie SM, Johnston CM, et al. (1997) Stabilization of Xist RNA mediates initiation of X chromosome inactivation. Cell 91:99–107PubMedCrossRefGoogle Scholar
  35. Therman E, Sarto GE, Palmer CG, et al. (1979) Position of the human X inactivation center on Xq. Hum Genet 50:59–64PubMedCrossRefGoogle Scholar
  36. Therman E, Susman B (1990) The similarity of phenotypic effects caused by Xp and Xq deletions in the human female: a hypothesis. Hum Genet 85: 175–183PubMedGoogle Scholar
  37. Torchia BS, Call LM, Migeon BR (1994) DNA replication analysis of FMRl, XIST, and factor 8C loci by FISH shows nontranscribed X-linked genes replicate late. Am J Hum Genet 55:96–104PubMedGoogle Scholar
  38. Walker CL, Cargile CB, Floy KM, et al. (1991) The Barr body is a looped X chromosome formed by telomere association. Proc Natl Acad Sci USA 88:6191–6195PubMedCrossRefGoogle Scholar
  39. White WM, Willard HF, Van Dyke DL, et al. (1998) The spreading of X inactivation into autosomal material of an X,autosome translocation: evidence for a difference between autosomal and X chromosomal DNA. Am J Hum Genet 63:20–28PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2001

Authors and Affiliations

  • Orlando J. Miller
    • 1
  • Eeva Therman
    • 2
  1. 1.Center for Molecular Medicine and GeneticsWayne State University School of MedicineDetroitUSA
  2. 2.Laboratory of GeneticsUniversity of WisconsinMadisonUSA

Personalised recommendations