Equality of the Sexes: Mammalian Dosage Compensation

ABSTRACT

X chromosome inactivation achieves dosage equivalence for most X-linked genes between the two X chromosomes in females and the single X chromosome in males. In this article the evidence for random inactivation of an X chromosome is reviewed, along with the exceptions that result in nonrandom inactivation. Another exception to X chromosome inactivation is the presence of genes that escape inactivation and are expressed from both the active and inactive X chromosomes. The phenotypic consequences of such expression from the inactive X chromosome are discussed. The major players in the process of inactivation are presented. Initiation of inactivation requires the functional RNA, XIST, and the subsequent stable inactivation of the X chromosome relies upon the recruitment of many other factors, the majority of which are generally associated with heterochromatin.

KEYWORD

X chromosome inactivation - dosage compensation - XIST

REFERENCES

• 1 Lyon M F. Gene action in the X-chromosome of the mouse (Mus musculus L.)  Nature . 1961;  190 372-373
• 2 Barr M L, Bertram E G. A morphological distinction between neurones of the male and female, and the behaviour of the nucleolar satellite during accelerated nucleoprotein synthesis.  Nature . 1949;  163 676-677
• 3 Ohno S, Kaplan W D, Kinosita R. Formation of the sex chromatin by a single X-chromosome in liver cells of Rattus norvegicus Exp Cell Res .  1959;  18 415-418
• 4 Davidson R G, Nitowsky H M, Childs B. Demonstration of two populations of cells in the human female heterozygous for glucose-6-phosphate dehydrogenase variants.  Proc Natl Acad Sci U S A . 1963;  50 481-485
• 5 Lahn B T, Page D C. Four evolutionary strata on the human X chromosome.  Science . 1999;  286 964-967
• 6 Jegalian K, Page D C. A proposed path by which genes common to mammalian X and Y chromosomes evolve to become X inactivated.  Nature . 1998;  394 776-780
• 7 Franke A, Baker B S. Dosage compensation rox! Curr Opin Cell Biol .  2000;  12 351-354
• 8 Meyer B J. Sex in the worm: counting and compensating X-chromosome dose.  Trends Genet . 2000;  16 247-253
• 9 Adler D A, Rugarli E I, Lingenfelter P A. Evidence of evolutionary up-regulation of the single active X chromosome in mammals based on Clc4 expression levels in Mus spretus and Mus musculus Proc Natl Acad Sci U S A .  1997;  94 9244-9248
• 10 Brown C J, Robinson W P. The causes and consequences of random and non-random X chromosome inactivation in humans.  Clin Genet . 2000;  58 353-363
• 11 Belmont J W. Genetic control of X inactivation and processes leading to X-inactivation skewing.  Am J Hum Genet . 1996;  58 1101-1108
• 12 Migeon B R. Non-random X chromosome inactivation in mammalian cells.  Cytogenet Cell Genet . 1998;  80 142-148
• 13 Cooper D W, Johnston P G, Watson J M, Graves J AM. X- inactivation in marsupials and monotremes.  Semin Dev Biol . 1993;  4 117-128
• 14 Takagi N, Sasaki M. Preferential inactivation of the paternally derived X chromosome in the extraembryonic membranes of the mouse.  Nature . 1975;  256 640-642
• 15 West J D, Frels W I, Chapman V M, Papaioannou V E. Preferential expression of the maternally derived X chromosome in the mouse yolk sac.  Cell . 1977;  12 873-882
• 16 Harrison K B, Warburton D. Preferential X-chromosome activity in human female placental tissues.  Cytogenet Cell Genet . 1986;  41 163-168
• 17 Harrison K B. X-chromosome inactivation in the human cytotrophoblast.  Cytogenet Cell Genet . 1989;  52 37-41
• 18 Migeon B R, Do T T. In search of non-random X inactivation: studies of fetal membranes heterozygous for glucose-6-phosphate dehydrogenase.  Am J Hum Genet . 1979;  31 581-585
• 19 Ropers H-H, Wolff G, Hitzeroth H W. Preferential X inactivation in human placenta membranes: is the paternal X active in early embryonic development of female mammals?.  Hum Genet . 1978;  43 265-273
• 20 Mohandas T K, Passage M B, Williams J W, Sparkes R S, Yen P H, Shapiro L J. X-chromosome inactivation in cultured cells from human chorionic villi.  Somat Cell Mol Genet . 1989;  15 131-136
• 21 Bamforth F, Machin G, Innes M. X-chromosome inactivation is mostly random in placental tissues of female monozygotic twins and triplets.  Am J Med Genet . 1996;  61 209-215
• 22 Looijenja L, Gillis A, Verkerk A, van Putten W, Oosterhuis J. Heterogeneous X inactivation in trophoblastic cells of human full-term female placentas.  Am J Hum Genet . 1999;  64 1445-1452
• 23 Uehara S, Tamura M, Nata M. X-chromosome inactivation in the human trophoblast of early pregnancy.  J Hum Genet . 2000;  45 119-126
• 24 Cattanach B M. Control of chromosome inactivation.  Annu Rev Genet . 1975;  9 1-18
• 25 Naumova A K, Olien L, Bird L M. Genetic mapping of X-linked loci involved in skewing of X chromosome inactivation in the human.  Eur J Hum Genet . 1998;  6 552-562
• 26 Plenge R M, Hendrich B D, Schwartz C. A promoter mutation in the XIST gene in two unrelated families with skewed X-chromosome inactivation.  Nat Genet . 1997;  17 353-356
• 27 Nance W E. Genetic tests with a sex-linked marker: glucose-6-phosphate dehydrogenase.  Cold Spring Harbor Symp Quant Biol . 1964;  29 415-424
• 28 Puck J M, Stewart C C, Nussbaum R L. 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 . 1992;  50 742-748
• 29 Monteiro J, Derom C, Vlietinck R, Kohn N, Lesser M, Gregersen P K. Commitment to X inactivation precedes the twinning event in monochorionic MZ twins.  Am J Hum Genet . 1998;  63 339-346
• 30 Lau A W, Brown C J, Penaherrera M, Langlois S, Kalousek D K, Robinson W P. Skewed X-chromosome inactivation is common in fetuses or newborns associated with confined placental mosaicism.  Am J Hum Genet . 1997;  61 1353-1361
• 31 Vogelstein B, Fearon E R, Hamilton S R. Clonal analysis using recombinant DNA probes from the X-chromosome.  Cancer Res . 1987;  47 4806-4813
• 32 Puck J M, Nussbaum R L, Conley M E. Carrier detection in X-linked severe combined immunodeficiency based on patterns of X chromosome inactivation.  J Clin Invest . 1987;  79 1395-1400
• 33 Allen R C, Zoghbi H Y, Moseley A B, Rosenblatt H M, Belmont J W. Methylation of HpaII and HhaI sites near the polymorphic CAG repeat in the human androgen-receptor gene correlates with X chromosome inactivation.  Am J Hum Genet . 1992;  51 1229-1239
• 34 Kutsche R, Brown C J. Determination of X-chromosome inactivation status using X-linked expressed polymorphisms identified by database searching.  Genomics . 2000;  65 9-15
• 35 Lyon M F. Sex chromatin and gene action in the mammalian X-chromosome.  Am J Hum Genet . 1962;  14 135-145
• 36 Carrel L, Cottle A A, Goglin K C, Willard H F. A first-generation X-inactivation profile of the human X chromosome.  Proc Natl Acad Sci U S A . 1999;  96 14440-14444
• 37 Sudbrak R, Wieczorek G, Nuber U A. X chromosome- specific cDNA arrays: identification of genes that escape from X-inactivation and other applications.  Hum Mol Genet . 2001;  10 77-83
• 38 Disteche C M. Escapees on the X chromosome.  Proc Natl Acad Sci U S A . 1999;  96 14180-14182
• 39 Tsuchiya K D, Willard H F. Chromosomal domains and escape from X inactivation: comparative X inactivation analysis in mouse and human.  Mamm Genome . 2000;  11 849-854
• 40 Lingenfelter P A, Adler D A, Poslinski D. Escape from X inactivation of Smcx is preceded by silencing during mouse development.  Nat Genet . 1998;  18 212-213
• 41 Zinn A, Page D, Fisher E. Turner syndrome: the case of the missing sex chromosome.  Trends Genet . 1993;  9 90-93
• 42 Rouyer F, Simmler M C, Johnsson C, Vergnaud G, Cooke H J, Weissenbach J. A gradient of sex linkage in the pseudoautosomal region of the human sex chromosomes.  Nature . 1986;  319 291-295
• 43 Horwitz M, Wiernik P H. Pseudoautosomal linkage of Hodgkin disease.  Am J Hum Genet . 1999;  65 1413-1422
• 44 Chance P F, Gartler S M. Evidence for a dosage effect at the X-linked steroid sulfatase locus in human tissues.  Am J Hum Genet . 1983;  35 234-240
• 45 Migeon B R, Shapiro L J, Norum R A, Mohandas T, Axelman J, Dabora R L. Differential expression of steroid sulphatase locus on active and inactive human X chromosome.  Nature . 1982;  299 838-840
• 46 Anderson C, Brown C J. Polymorphic X-chromosome inactivation of the human TIMP1 gene.  Am J Hum Genet . 1999;  65 699-708
• 47 Carrel L, Willard H F. 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 U S A . 1999;  96 7364-7369
• 48 Brown C J, Ballabio A, Rupert J L. A gene from the region of the human X inactivation centre is expressed exclusively from the inactive X chromosome.  Nature . 1991;  349 38-44
• 49 Brown C J, Hendrich B D, Rupert J L. 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 . 1992;  71 527-542
• 50 Penny G D, Kay G F, Sheardown S A, Rastan S, Brockdorff N. Requirement for Xist in X chromosome inactivation.  Nature . 1996;  379 131-137
• 51 Marahrens Y, Panning B, Dausman J, Strauss W, Jaenisch R. Xist-deficient mice are defective in dosage compensation but not spermatogenesis.  Genes Dev . 1997;  11 156-166
• 52 Lee J T, Strauss W M, Dausman J A, Jaenisch R. A 450 kb transgene displays properties of the mammalian X-inactivation center.  Cell . 1996;  86 83-94
• 53 Herzing L BK, Romer J T, Horn J M, Ashworth A. Xist has properties of the X-chromosome inactivation centre.  Nature . 1997;  386 272-275
• 54 Wutz A, Jaenisch R. A shift from reversible to irreversible X inactivation is triggered during ES cell differentiation.  Mol Cell . 2000;  5 695-705
• 55 Avner P, Heard E. X-chromosome inactivation: counting, choice and initiation.  Nat Rev Genet . 2001;  2 59-67
• 56 Keohane A M, Lavender J S, O'Neill L P, Turner B M. Histone acetylation and X inactivation.  Dev Genet . 1998;  22 65-73
• 57 Costanzi C, Stein P, Worrad D M, Schultz R M, Pehrson J R. Histone macroH2A1 is concentrated in the inactive X chromosome of female preimplantation mouse embryos.  Development . 2000;  127 2283-2289
• 58 Tai H H, Gordon J, McBurney M W. Xist is expressed in female embryonal carcinoma cells with two active X chromosomes.  Somat Cell Mol Genet . 1994;  20 171-182
• 59 Kay G F, Penny G D, Patel D, Ashworth A, Brockdorff N, Rastan S. Expression of Xist during mouse development suggests a role in the initiation of X chromosome inactivation.  Cell . 1993;  72 171-182
• 60 Sheardown S A, Duthie S M, Johnston C M. Stabilisation of Xist RNA mediates initiation of X chromosome inactivation.  Cell . 1997;  91 99-107
• 61 Panning B, Dausman J, Jaenisch R. X chromosome inactivation is mediated by RNA stabilization.  Cell . 1997;  90 907-916
• 62 Lee J T, Davidow L S, Warshawsky D. Tsix, a gene antisense to Xist at the X-inactivation center.  Nat Genet . 1999;  21 400-404
• 63 Clerc P, Avner P. Role of the region 3′ to Xist exon 6 in the counting process of X-chromosome inactivation.  Nat Genet . 1998;  19 249-253.
• 64 Lee J T, Lu N. Targeted mutagenesis of Tsix leads to nonrandom X inactivation.  Cell . 1999;  99 47-57
• 65 White W M, Willard H F, Van Dyke L D, Wolff D J. 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 . 1998;  63 20-28
• 66 Keohane A M, Barlow A L, Waters J, Bourn D, Turner B M. H4 acetylation, XIST RNA and replication timing are coincident and define X/autosome boundaries in two abnormal X chromosomes.  Hum Mol Genet . 1999;  8 377-383
• 67 Gartler S M, Riggs A D. Mammalian X-chromosome inactivation.  Annu Rev Genet . 1983;  17 155-190
• 68 Lyon M F. X-chromosome inactivation: a repeat hypothesis.  Cytogenet Cell Genet . 1998;  80 133-137
• 69 Bailey J A, Carrel L, Chakravarti A, Eichler E. Molecular evidence for a relationship between LINE-1 elements and X chromosome inactivation: the Lyon repeat hypothesis.  Proc Natl Acad Sci U S A . 2000;  97 6634-6639
• 70 Duthie S M, Nesterova T B, Formstone E J. Xist RNA exhibits a banded localization on the inactive X chromosome and is excluded from autosomal material in cis.  Hum Mol Genet . 1999;  8 195-204
• 71 Rack K A, Chelly J, Gibbons R J. Absence of the XIST gene from late-replicating isodicentric X chromosomes in leukemia.  Hum Mol Genet . 1994;  3 1053-1059
• 72 Brown C J, Willard H F. The human X inactivation center is not required for maintenance of X inactivation.  Nature . 1994;  368 154-156
• 73 Tinker A V, Brown C J. Induction of XIST expression from the human active X chromosome in mouse/human somatic cell hybrids by DNA demethylation.  Nucleic Acids Res . 1998;  26 2935-2940
• 74 Hansen R S, Canfield T K, Stanek A M, Keitges E A, Gartler S M. Reactivation of XIST in normal fibroblasts and a somatic cell hybrid: abnormal localization of XIST RNA in hybrid cells.  Proc Natl Acad Sci U S A . 1998;  95 5133-5138
• 75 Csankovski G, Panning B, Bates B, Pehrson J R, Jaenisch R. Conditional deletion of Xist disrupts histone macroH2A localization but not maintenance of X inactivation.  Nat Genet . 1999;  22 323-324
• 76 Brown S W. Heterochromatin.  Science . 1966;  151 417-425
• 77 Eils R, Dietzel S, Bertin E. Three-dimensional reconstruction of painted human interphase chromosomes: active and inactive X chromosome territories have similar volumes but differ in shape and surface structure.  J Cell Biol . 1996;  135 1427-1440
• 78 Walker C L, Cargile C B, Floy K M, Delannoy M, Migeon B R. The Barr body is a looped X chromosome formed by telomere association.  Proc Natl Acad Sci U S A . 1991;  88 6191-6195
• 79 Dyer K A, Canfield T K, Gartler S M. Molecular cytological differentiation of active from inactive X domains in interphase: implications for X chromosome inactivation.  Cytogenet Cell Genet . 1989;  50 116-120
• 80 Lima-de-Faria, Jaworksa H. Late DNA synthesis in heterochromatin.  Nature . 1968;  217 138-142
• 81 Willard H F, Latt S A. Analysis of deoxyribonucleic acid replication in human X chromosomes by fluorescence microscopy.  Am J Hum Genet . 1976;  28 213-227
• 82 Gartler S M, Goldman M A. Reactivation of inactive X-linked genes.  Dev Genet . 1994;  15 504-514
• 83 Okano M, Bell D W, Haber D A, Li E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development.  Cell . 1999;  99 247-257
• 84 Hansen R S, Wijmenga C, Luo P. The DNMT3B DNA methyltransferase gene is mutated in the ICF immunodeficiency syndrome.  Proc Natl Acad Sci U S A . 1999;  96 14412-14417
• 85 Belyaev N D, Keohane A M, Turner B M. Differential underacetylation of histones H2A, H3 and H4 on the inactive X chromosome in human female cells.  Hum Genet . 1996;  97 573-578
• 86 Jeppeson P, Turner B. The inactive X chromosome in female mammals is distinguished by a lack of histone H4 acetylation, a cytogenetic marker for gene expression.  Cell . 1993;  74 281-189
• 87 Gilbert S L, Sharp P A. Promoter-specific hypoacetylation of X-inactivated genes.  Proc Natl Acad Sci U S A . 1999;  96 13825-13830
• 88 Costanzi C, Pehrson J R. Histone macroH2A1 is concentrated in the inactive X chromosome of female mammals.  Nature . 1998;  393 599-601
• 89 Perche P-Y, Vourc'h C, Konecny L. Higher concentrations of histone macroH2A in the Barr body are correlated with higher nucleosome density.  Curr Biol . 2000;  10 1531-1534
• 90 Akhtar A, Zink D, Becker P B. Chromodomains are protein-RNA interaction modules.  Nature . 2000;  407 405-409
• 91 Salido E C, Yen P H, Mohandas T K, Shapiro L J. Expression of the X-inactivation-associated gene XIST during spermatogenesis.  Nat Genet . 1992;  2 196-199
• 92 Armstrong S J, Hulten M A, Keohane A M, Turner B M. Different strategies of X-inactivation in germinal and somatic cells: histone H4 underacetylation does not mark the inactive X chromosome in mouse male germline.  Exp Cell Res . 1997;  230 399-402
• 93 Richler C, Dhara S K, Wahrman J. Histone macroH2A1.2 is concentrated in the XY compartment of mammalian male meiotic nuclei.  Cytogenet Cell Genet . 2000;  89 118-120
• 94 Yoshida I, Kashio N, Takagi N. Cell fusion-induced quick change in replication time of the inactive mouse X chromosome: an implication for the maintenance mechanism of late replication.  EMBO J . 1993;  12 4397-4405
• 95 Migeon B R. X-chromosome inactivation: molecular mechanisms and genetic consequences.  Trends Genet . 1994;  10 230-235
• 96 Leal C A, Ayala-Madrigal M L, Figuera L E, Medina C. Histone H4 acetylation analyses in patients with polysomy X: implications for the mechanisms of X inactivation.  Hum Genet . 1998;  103 29-33
• 97 Clemson C M, Chow J C, Brown C J, Lawrence J B. Stabilization and localization of Xist RNA are controlled by separate mechanisms and are not sufficient for X inactivation.  J Cell Biol . 1998;  142 13-23
• 98 Gregory P, Greene C, Shapira E, Wang E. Alterations in the time of X chromosome replication induced by 5-azacytidine in a patient with 48,XXXY/47,XXY.  Cytogenet Cell Genet . 1985;  39 234-236
• 99 Jones P L, Veenstra G JC, Wade P A. Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription.  Nat Genet . 1998;  19 187-191