Skip to main content
SpringerLink
Log in

Implications of the gene balance hypothesis for dosage compensation

  • Review
  • Published:
Frontiers in Biology

Abstract

Dosage compensation refers to the equal expression between the sexes despite the fact that the dosage of the X chromosome is different in males and females. In Drosophila there is a twofold upregulation of the single male X. In triple X metafemales, there is also dosage compensation, which occurs by a two-thirds downregulation. There is a concomitant reduction in expression of many autosomal genes in metafemales. The male specific lethal (MSL) complex is present on the male X chromosome. Evidence is discussed showing that the MSL complex sequesters a histone acetyltransferase to the X chromosome to mute an otherwise increased expression by diminishing the histone acetylation on the autosomes. Several lines of evidence indicate that a constraining activity occurs from the MSL complex to prevent overcompensation on the X that might otherwise occur from the high level of acetylation present. Together, the evidence suggests that dosage compensation is a modification of a regulatory inverse dosage effect that is a reflection of intrinsic gene regulatory mechanisms and that the MSL complex has evolved in reaction in order to equalize the expression on both the X and autosomes of males and females.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Aït Yahya-Graison E, Aubert J, Dauphinot L, Rivals I, Prieur M, Golfier G, Rossier J, Personnaz L, Creau N, Bléhaut H, Robin S, Delabar J M, Potier M C (2007). Classification of human chromosome 21 geneexpression variations in Down syndrome: impact on disease phenotypes. Am J Hum Genet, 81(3): 475–491

    Article  PubMed  Google Scholar 

  • Akhtar A, Becker P B (2000). Activation of transcription through histone H4 acetylation by MOF, an acetyltransferase essential for dosage compensation in Drosophila. Mol Cell, 5(2): 367–375

    Article  PubMed  CAS  Google Scholar 

  • Altug-Teber O, Bonin M, Walter M, Mau-Holzmann U A, Dufke A, Stappert H, Tekesin I, Heilbronner H, Nieselt K, Riess O (2007). Specific transcriptional changes in human fetuses with autosomal trisomies. Cytogenet Genome Res, 119(3–4): 171–184

    Article  PubMed  CAS  Google Scholar 

  • Arkhipova I R, Li J, Meselson M (1997). On the mode of gene-dosage compensation in Drosophila. Genetics, 145(3): 729–736

    PubMed  CAS  Google Scholar 

  • Badenhorst P, Voas M, Rebay I, Wu C (2002). Biological functions of the ISWI chromatin remodeling complex NURF. Genes Dev, 16(24): 3186–3198

    Article  PubMed  CAS  Google Scholar 

  • Bahn S, Mimmack M, Ryan M, Caldwell M A, Jauniaux E, Starkey M, Svendsen C N, Emson P (2002). Neuronal target genes of the neuronrestrictive silencer factor in neurospheres derived from fetuses with Down’s syndrome: a gene expression study. Lancet, 359(9303): 310–315

    Article  PubMed  CAS  Google Scholar 

  • Belote JM, Lucchesi J C (1980). Control of X chromosome transcription by the maleless gene in Drosophila. Nature, 285(5766): 573–575

    Article  PubMed  CAS  Google Scholar 

  • Bhadra M P, Bhadra U, Kundu J, Birchler J A (2005). Gene expression analysis of the function of the male-specific lethal complex in Drosophila. Genetics, 169(4): 2061–2074

    Article  PubMed  CAS  Google Scholar 

  • Bhadra U, Pal-Bhadra M, Birchler J A (1999). Role of the male specific lethal (msl) genes in modifying the effects of sex chromosomal dosage in Drosophila. Genetics, 152(1): 249–268

    PubMed  CAS  Google Scholar 

  • Bhadra U, Pal-Bhadra M, Birchler J A (2000). Histone acetylation and gene expression analysis of sex lethal mutants in Drosophila. Genetics, 155(2): 753–763

    PubMed  CAS  Google Scholar 

  • Birchler J A (1979). A study of enzyme activities in a dosage series of the long arm of chromosome one in maize. Genetics, 92(4): 1211–1229

    PubMed  CAS  Google Scholar 

  • Birchler J A (1981). The genetic basis of dosage compensation of alcohol dehydrogenase-1 in maize. Genetics, 97(3–4): 625–637

    PubMed  CAS  Google Scholar 

  • Birchler J A (1984). Genetic analysis of a modifier of the sexual dimorphism of glass in Drosophila melanogaster. Genet Res, 44(02): 125–132

    Article  Google Scholar 

  • Birchler J A (1992). Expression of cis-regulatory mutations of the white locus in metafemales of Drosophila melanogaster. Genet Res, 59(1): 11–18

    Article  PubMed  CAS  Google Scholar 

  • Birchler J A (1996). X chromosome dosage compensation in Drosophila. Science, 272(5265): 1190–1191

    Article  PubMed  CAS  Google Scholar 

  • Birchler J A (2010). Reflections on studies of gene expression in aneuploids. Biochem J, 426(2): 119–123

    Article  PubMed  CAS  Google Scholar 

  • Birchler J A, Bhadra U, Bhadra M P, Auger D L (2001). Dosage-dependent gene regulation in multicellular eukaryotes: implications for dosage compensation, aneuploid syndromes, and quantitative traits. Dev Biol, 234(2): 275–288

    Article  PubMed  CAS  Google Scholar 

  • Birchler J A, Hiebert J C, Krietzman M (1989). Gene expression in adult metafemales of Drosophila melanogaster. Genetics, 122(4): 869–879

    PubMed  CAS  Google Scholar 

  • Birchler J A, Hiebert J C, Paigen K (1990). Analysis of autosomal dosage compensation involving the alcohol dehydrogenase locus in Drosophila melanogaster. Genetics, 124(3): 679–686

    PubMed  CAS  Google Scholar 

  • Birchler J A, Newton K J (1981). Modulation of protein levels in chromosomal dosage series of maize: the biochemical basis of aneuploid syndromes. Genetics, 99(2): 247–266

    PubMed  CAS  Google Scholar 

  • Birchler J A, Riddle N C, Auger D L, Veitia R A (2005). Dosage balance in gene regulation: biological implications. Trends Genet, 21(4): 219–226

    Article  PubMed  CAS  Google Scholar 

  • Birchler J A, Veitia R A (2007). The gene balance hypothesis: from classical genetics to modern genomics. Plant Cell, 19(2): 395–402

    Article  PubMed  CAS  Google Scholar 

  • Birchler J A, Veitia R A (2010). The gene balance hypothesis: implications for gene regulation, quantitative traits and evolution. New Phytol, 186(1): 54–62

    Article  PubMed  CAS  Google Scholar 

  • Bone J R, Lavender J, Richman R, Palmer M J, Turner B M, Kuroda M I (1994). Acetylated histone H4 on the male X chromosome is associated with dosage compensation in Drosophila. Genes Dev, 8(1): 96–104

    Article  PubMed  CAS  Google Scholar 

  • Brehm A, Längst G, Kehle J, Clapier C R, Imhof A, Eberharter A, Müller J, Becker P B (2000). dMi-2 and ISWI chromatin remodelling factors have distinct nucleosome binding and mobilization properties. EMBO J, 19(16): 4332–4341

    Article  PubMed  CAS  Google Scholar 

  • Corona D F, Clapier C R, Becker P B, Tamkun J W (2002). Modulation of ISWI function by site-specific histone acetylation. EMBO Rep, 3(3): 242–247

    Article  PubMed  CAS  Google Scholar 

  • Delattre M, Spierer A, Jaquet Y, Spierer P (2004). Increased expression of Drosophila Su(var)3-7 triggers Su(var)3-9-dependent heterochromatin formation. J Cell Sci, 117(Pt 25): 6239–6247

    Article  PubMed  CAS  Google Scholar 

  • Deuring R, Fanti L, Armstrong J A, Sarte M, Papoulas O, Prestel M, Daubresse G, Verardo M, Moseley S L, Berloco M, Tsukiyama T, Wu C, Pimpinelli S, Tamkun J W (2000). The ISWI chromatinremodeling protein is required for gene expression and the maintenance of higher order chromatin structure in vivo. Mol Cell, 5(2): 355–365

    Article  PubMed  CAS  Google Scholar 

  • Devlin R H, Holm D G, Grigliatti T A (1982). Autosomal dosage compensation Drosophila melanogaster strains trisomic for the left arm of chromosome 2. Proc Natl Acad Sci U S A, 79(4): 1200–1204

    Article  PubMed  CAS  Google Scholar 

  • Devlin R H, Holm D G, Grigliatti T A (1988). The influence of whole-arm trisomy on gene expression in Drosophila. Genetics, 118(1): 87–101

    PubMed  CAS  Google Scholar 

  • Dreesen T D, Henikoff S, Loughney K (1991). A pairing-sensitive element that mediates trans-inactivation is associated with the Drosophila brown gene. Genes Dev, 5(3): 331–340

    Article  PubMed  CAS  Google Scholar 

  • Gergen J P (1987). Dosage compensation in Drosophila: Evidence that daughterless and Sex-lethal control X chromosome activity at the blastoderm stage of embryogenesis. Genetics, 117(3): 477–485

    PubMed  CAS  Google Scholar 

  • Grell E H (1962). The dose effect of ma-l+ and ry+ on xanthine dehydrogenase activity in Drosophila melanogaster. Z Vererbungsl, 93(3): 371–377

    Article  Google Scholar 

  • Guo M, Birchler J A (1994). Trans-acting dosage effects on the expression of model gene systems in maize aneuploids. Science, 266(5193): 1999–2002

    Article  PubMed  CAS  Google Scholar 

  • Gupta V, Parisi M, Sturgill D, Nuttall R, Doctolero M, Dudko O K, Malley J D, Eastman P S, Oliver B (2006). Global analysis of X-chromosome dosage compensation. J Biol, 5(1): 3

    Article  PubMed  Google Scholar 

  • Hiebert J C, Birchler J A (1994). Effects of the maleless mutation on X and autosomal gene expression in Drosophila melanogaster. Genetics, 136(3): 913–926

    PubMed  CAS  Google Scholar 

  • Hilfiker A, Hilfiker-Kleiner D, Pannuti A, Lucchesi J C (1997). mof, a putative acetyl transferase gene related to the Tip60 and MOZ human genes and to the SAS genes of yeast, is required for dosage compensation in Drosophila. EMBO J, 16(8): 2054–2060

    Article  PubMed  CAS  Google Scholar 

  • Jin Y, Wang Y, Johansen J, Johansen KM (2000). JIL-1, a chromosomal kinase implicated in regulation of chromatin structure, associates with the male specific lethal (MSL) dosage compensation complex. J Cell Biol, 149(5): 1005–1010

    Article  PubMed  CAS  Google Scholar 

  • Jin Y, Wang Y, Walker D L, Dong H, Conley C, Johansen J, Johansen K M (1999). JIL-1: a novel chromosomal tandem kinase implicated in transcriptional regulation in Drosophila. Mol Cell, 4(1): 129–135

    Article  PubMed  CAS  Google Scholar 

  • Kelley R L, Kuroda M I (1995). Equality for X chromosomes. Science, 270(5242): 1607–1610

    Article  PubMed  CAS  Google Scholar 

  • Kind J, Vaquerizas J M, Gebhardt P, Gentzel M, Luscombe N M, Bertone P, Akhtar A (2008). Genome-wide analysis reveals MOF as a key regulator of dosage compensation and gene expression in Drosophila. Cell, 133(5): 813–828

    Article  PubMed  CAS  Google Scholar 

  • Kuroda M I, Kernan M J, Kreber R, Ganetzky B, Baker B S (1991). The maleless protein associates with the X chromosome to regulate dosage compensation in Drosophila. Cell, 66(5): 935–947

    Article  PubMed  CAS  Google Scholar 

  • Lucchesi J C, Belote J M, Maroni G (1977). X-linked gene activity in metamales (XY;3A) of Drosophila. Chromosoma, 65(1): 1–7

    Article  CAS  Google Scholar 

  • Lucchesi J C, Kelly W G, Panning B (2005). Chromatin remodeling in dosage compensation. Annu Rev Genet, 39(1): 615–651

    Article  PubMed  CAS  Google Scholar 

  • Lucchesi J C, Rawls J M Jr (1973a). Regulation of gene function: a comparison of enzyme activity levels in relation to gene dosage in diploids and triploids of Drosophila melanogaster. Biochem Genet, 9(1): 41–51

    Article  PubMed  CAS  Google Scholar 

  • Lucchesi J C, Rawls J M Jr, Maroni G (1974). Gene dosage compensation in metafemales (3X;2A) of Drosophila. Nature, 248(449): 564–567

    Article  PubMed  CAS  Google Scholar 

  • Lucchesi J C, Rawls R M Jr (1973b). Regulation of gene function: a comparison of X-linked enzyme activity levels in normal and intersexual triploids of Drosophila melanogaster. Genetics, 73(3): 459–464

    PubMed  CAS  Google Scholar 

  • Lyle R, Gehrig C, Neergaard-Henrichsen C, Deutsch S, Antonarakis S E (2004). Gene expression from the aneuploid chromosome in a trisomy mouse model of down syndrome. Genome Res, 14(7): 1268–1274

    Article  PubMed  CAS  Google Scholar 

  • Margolis O S (1934). The effect of a supernumerary X chromosome on members of the Bar series of Drosophila. Genetics, 19(1): 18–24

    PubMed  CAS  Google Scholar 

  • Maroni G, Plaut W (1973). Dosage compensation in Drosophila melanogaster triploids. I. Autoradiographic study. Chromosoma, 40(4): 361–377

    Article  PubMed  CAS  Google Scholar 

  • Meller V H, Rattner B P (2002). The roX genes encode redundant malespecific lethal transcripts required for targeting of the MSL complex. EMBO J, 21(5): 1084–1091

    Article  PubMed  CAS  Google Scholar 

  • Meller V H, Wu K H, Roman G, Kuroda M I, Davis R L (1997). roX1 RNA paints the X chromosome of male Drosophila and is regulated by the dosage compensation system. Cell, 88(4): 445–457

    Article  PubMed  CAS  Google Scholar 

  • Muller H J (1932). Further studies on the nature and causes of gene mutations. Proc 6th Int Congr Genetics, 1: 213–255

    Google Scholar 

  • Okuno T, Satou T, Oishi K (1984). Studies on the sex-specific lethals of Drosophila melanogaster. VII. Sex-specific lethals that do not affect dosage compensation. Jpn J Genet, 59(3): 237–247

    Article  Google Scholar 

  • Pal-Bhadra M, Bhadra U, Birchler J A (1997). Cosuppression in Drosophila: gene silencing of Alcohol dehydrogenase by white-Adh transgenes is Polycomb dependent. Cell, 90(3): 479–490

    Article  PubMed  CAS  Google Scholar 

  • Pal-Bhadra M, Bhadra U, Birchler J A (1999). Cosuppression of nonhomologous transgenes in Drosophila involves mutually related endogenous sequences. Cell, 99(1): 35–46

    Article  PubMed  CAS  Google Scholar 

  • Pal Bhadra M, Bhadra U, Birchler J A (2006). Misregulation of Sexlethal and disruption of MSL localization in Drosophila species hybrids. Genetics, 174: 1151–1159

    Article  PubMed  Google Scholar 

  • Parisi M, Nuttall R, Naiman D, Bouffard G, Malley J, Andrews J, Eastman S, Oliver B (2003). Paucity of genes on the Drosophila X chromosome showing male-biased expression. Science, 299(5607): 697–700

    Article  PubMed  CAS  Google Scholar 

  • Phillips J L, Hayward S W, Wang Y, Vasselli J, Pavlovich C, Padilla-Nash H, Pezullo J R, Ghadimi B M, Grossfeld G D, Rivera A, Linehan W M, Cunha G R, Ried T (2001). The consequences of chromosomal aneuploidy on gene expression profiles in a cell line model for prostate carcinogenesis. Cancer Res, 61(22): 8143–8149

    PubMed  CAS  Google Scholar 

  • Prestel M, Feller C, Straub T, Mitlöhner H, Becker P B (2010). The activation potential of MOF is constrained for dosage compensation. Mol Cell, 38(6): 815–826

    Article  PubMed  CAS  Google Scholar 

  • Qian S, Pirrotta V (1995). Dosage compensation of the Drosophila white gene requires both the X chromosome environment and multiple intragenic elements. Genetics, 139(2): 733–744

    PubMed  CAS  Google Scholar 

  • Rabinow L, Nguyen-Huynh A T, Birchler J A (1991). A trans-acting regulatory gene that inversely affects the expression of the white, brown and scarlet loci in Drosophila. Genetics, 129(2): 463–480

    PubMed  CAS  Google Scholar 

  • Rastelli L, Kuroda M I (1998). An analysis of maleless and histone H4 acetylation in Drosophila melanogaster spermatogenesis. Mech Dev, 71(1–2): 107–117

    Article  PubMed  CAS  Google Scholar 

  • Roseman R R, Swan J M, Geyer P K (1995). A Drosophila insulator protein facilitates dosage compensation of the X chromosome minwhite gene located at autosomal insertion sites. Development, 121(11): 3573–3582

    PubMed  CAS  Google Scholar 

  • Ruiz M F, Esteban M R, Doñoro C, Goday C, Sánchez L (2000). Evolution of dosage compensation in Diptera: the gene maleless implements dosage compensation in Drosophila (Brachycera suborder) but its homolog in Sciara (Nematocera suborder) appears to play no role in dosage compensation. Genetics, 156(4): 1853–1865

    PubMed  CAS  Google Scholar 

  • Sabl J F, Birchler J A (1993). Dosage dependent modifiers of white alleles in Drosophila melanogaster. Genet Res, 62(1): 15–22

    Article  PubMed  CAS  Google Scholar 

  • Saran N G, Pletcher M T, Natale J E, Cheng Y, Reeves R H (2003). Global disruption of the cerebellar transcriptome in a Down syndrome mouse model. Hum Mol Genet, 12(16): 2013–2019

    Article  PubMed  CAS  Google Scholar 

  • Smith P D, Lucchesi J C (1969). The role of sexuality in dosage compensation in Drosophila. Genetics, 61(3): 607–618

    PubMed  CAS  Google Scholar 

  • Spierer A, Seum C, Delattre M, Spierer P (2005). Loss of the modifiers of variegation Su(var)3-7 or HP1 impacts male X polytene chromosome morphology and dosage compensation. J Cell Sci, 118(Pt 21): 5047–5057

    Article  PubMed  CAS  Google Scholar 

  • Stern C (1960). Dosage compensation-development of a concept and new facts. Can J Genet Cytol, 2: 105–118

    Google Scholar 

  • Sun X, Birchler J A (2009). Interaction study of the male specific lethal (MSL) complex and trans-acting dosage effects in metafemales of Drosophila melanogaster. Cytogenet Genome Res, 124(3–4): 298–311

    Article  PubMed  CAS  Google Scholar 

  • Turner B M, Birley A J, Lavender J (1992). Histone H4 isoforms acetylated at specific lysine residues define individual chromosomes and chromatin domains in Drosophila polytene nuclei. Cell, 69(2): 375–384

    Article  PubMed  CAS  Google Scholar 

  • Veitia R A, Birchler J A (2010). Dominance and gene dosage balance in human health and disease. J Pathol, 220: 174–185

    PubMed  CAS  Google Scholar 

  • Veitia R A, Bottani S, Birchler J A (2008). Cellular reactions to gene dosage imbalance: genomic, transcriptomic and proteomic effects. Trends Genet, 24(8): 390–397

    Article  PubMed  CAS  Google Scholar 

  • Wang Y, Zhang W, Jin Y, Johansen J, Johansen K M (2001). The JIL-1 tandem kinase mediates histone H3 phosphorylation and is required for maintenance of chromatin structure in Drosophila. Cell, 105(4): 433–443

    Article  PubMed  CAS  Google Scholar 

  • Weiler K S, Wakimoto B T (1995). Heterochromatin and gene expression in Drosophila. Annu Rev Genet, 29(1): 577–605

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Biological Sciences University of Missouri, Columbia, MO, 65211, USA

    James A. Birchler, Lin Sun, Ryan Donohue, Abhijit Sanyal & Weiwu Xie

Authors
  1. James A. Birchler
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lin Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ryan Donohue
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Abhijit Sanyal
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Weiwu Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to James A. Birchler.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Birchler, J.A., Sun, L., Donohue, R. et al. Implications of the gene balance hypothesis for dosage compensation. Front. Biol. 6, 118–124 (2011). https://doi.org/10.1007/s11515-011-1121-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11515-011-1121-y

Keywords

Search

Navigation