X‐Chromosome Dosage Compensation


The X and Y chromosomes of placental and marsupial mammals originated from a pair of autosomes. Ohno hypothesised nearly 50 years ago that the expression levels of X‐linked genes should be doubled to compensate for the degeneration of their Y‐linked homologues during sex chromosome evolution. The advent of microarray and RNA (ribonucleic acid) sequencing technologies in the past decade prompted a series of empirical tests of Ohno's hypothesis. Surprisingly, X‐chromosome dosage compensation is found to be largely absent in mammals. Studies of multiple independently evolved sex chromosome systems from a variety of species revealed a large variation in sex‐chromosome dosage compensation, ranging from absence of compensation to complete compensation, although further scrutiny is required because of the high heterogeneities in expression data acquisition and analysis methods among studies. The lack of sex chromosome dosage compensation in at least some lineages has important implications for understanding gene expression evolution and sex chromosome evolution.

Key Concepts

  • Ohno proposed that the expression levels of mammalian X‐linked genes should be doubled to compensate for the degeneration of their Y‐linked homologues during sex chromosome evolution.
  • Initial microarray studies of genome‐wide gene expression levels found an X : AA ratio of ∼1, consistent with Ohno's hypothesis.
  • Subsequent analysis of transcriptomic data generated by the more sensitive RNA sequencing method found an X : AA ratio of ∼0.5, inconsistent with Ohno's hypothesis.
  • Some argued that Ohno's hypothesis is supported because X : AA is about 1 for actively expressed genes, but this assertion is caused by a common misunderstanding of Ohno's hypothesis.
  • A direct comparison between human X‐linked genes and their one‐to‐one orthologues located in chicken autosomes that are homologous to the mammalian proto‐X found no upregulation in mammalian X‐linked gene expression, refuting Ohno's hypothesis.
  • A human proteomic analysis found no evidence for a twofold upregulation of protein concentrations of X‐linked genes.
  • Transcriptome analyses of multiple species with independently evolved sex chromosomes revealed a large variation in the presence/absence and degree of sex chromosome dosage compensation, but further scrutiny is required due to the high heterogeneities in the data and methods used in the published studies.
  • The lack of sex chromosome dosage compensation in at least some lineages suggests that halving the expression level of a gene usually has no appreciable fitness consequences.

Keywords: dosage compensation; sex chromosome; autosome; evolution; gene expression; mammals; birds

Figure 1. The prevailing evolutionary model of mammalian X‐chromosome dosage compensation that has recently been tested and challenged. Each arrowhead represents the expression of one allele, with the height of the arrowhead indicating the expression level of the allele.
Figure 2. Comparison of expression levels of orthologous genes from human and chicken. (A) Human X : chicken XX expression ratios for one‐to‐one orthologues in six male (M) or four female (F) tissues, when the medians of human AA : chicken AA expression ratios are normalised to 1. The null hypothesis of X : XX = AA : AA is rejected in each tissue (P < 10−9, Mann–Whitney U‐test). There are 325 gene pairs for calculating X : XX and 10 171 gene pairs for calculating AA : AA. The central bold line shows the median, the box encompasses 50% of genes, and the error bars include 90% of genes. Reproduced with permission from Lin et al. (2012) © Proceedings of the National Academy of Sciences of the United States of America.


Adler DA, Rugarli EI, Lingenfelter PA, et al. (1997) Evidence of evolutionary up‐regulation of the single active X chromosome in mammals based on Clc4 expression levels in Mus spretus and Mus musculus. Proceedings of the National Academy of Sciences of the United States of America 94: 9244–9248.

Albritton SE, Kranz AL, Rao P, et al. (2014) Sex‐biased gene expression and evolution of the X chromosome in nematodes. Genetics 197: 865–883.

Bull JJ (1983) Evolution of Sex Determining Mechanisms. Menlo Park, CA: Benjamin‐Cummings.

Charlesworth B (1978) Model for evolution of Y chromosomes and dosage compensation. Proceedings of the National Academy of Sciences of the United States of America 75: 5618–5622.

Charlesworth B (1996) The evolution of chromosomal sex determination and dosage compensation. Current Biology 6: 149–162.

Charlesworth B and Charlesworth D (2000) The degeneration of Y chromosomes. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences 355: 1563–1572.

Chen X and Zhang J (2015) No X‐chromosome dosage compensation in human proteomes. Molecular Biology and Evolution 32: 1456–1460.

Deng X, Hiatt JB, Nguyen DK, et al. (2011) Evidence for compensatory upregulation of expressed X‐linked genes in mammals, Caenorhabditis elegans and Drosophila melanogaster. Nature Genetics 43: 1179–1185.

Deutschbauer AM, Jaramillo DF, Proctor M, et al. (2005) Mechanisms of haploinsufficiency revealed by genome‐wide profiling in yeast. Genetics 169: 1915–1925.

Gammerdinger WJ, Conte MA, Acquah EA, Roberts RB and Kocher TD (2014) Structure and decay of a proto‐Y region in Tilapia, Oreochromis niloticus. BMC Genomics 15: 975.

Gupta V, Parisi M, Sturgill D, et al. (2006) Global analysis of X‐chromosome dosage compensation. Journal of Biology 5: 3.

He X, Chen X, Xiong Y, et al. (2011) He et al. reply. Nature Genetics 43: 1171–1172.

Hough J, Hollister JD, Wang W, Barrett SC and Wright SI (2014) Genetic degeneration of old and young Y chromosomes in the flowering plant Rumex hastatulus. Proceedings of the National Academy of Sciences of the United States of America 111: 7713–7718.

Jaquiery J, Rispe C, Roze D, et al. (2013) Masculinization of the X chromosome in the pea aphid. PLoS Genetics 9: e1003690.

Jiang X, Biedler JK, Qi Y, Hall AB and Tu Z (2015) Complete dosage compensation in Anopheles stephensi and the evolution of sex‐biased genes in mosquitoes. Genome Biology and Evolution 7: 1914–1924.

Julien P, Brawand D, Soumillon M, et al. (2012) Mechanisms and evolutionary patterns of mammalian and avian dosage compensation. PLoS Biology 10: e1001328.

Kharchenko PV, Xi R and Park PJ (2011) Evidence for dosage compensation between the X chromosome and autosomes in mammals. Nature Genetics 43: 1167–1169; author reply 1171–1162.

Lahn BT, Pearson NM and Jegalian K (2001) The human Y chromosome, in the light of evolution. Nature Reviews Genetics 2: 207–216.

Lehner B (2008) Selection to minimise noise in living systems and its implications for the evolution of gene expression. Molecular Systems Biology 4: 170.

Liao BY and Zhang J (2006) Evolutionary conservation of expression profiles between human and mouse orthologous genes. Molecular Biology and Evolution 23: 530–540.

Lin H, Halsall JA, Antczak P, et al. (2011) Relative overexpression of X‐linked genes in mouse embryonic stem cells is consistent with Ohno's hypothesis. Nature Genetics 43: 1169–1170; author reply 1171–1162.

Lin F, Xing K, Zhang J and He X (2012) Expression reduction in mammalian X chromosome evolution refutes Ohno's hypothesis of dosage compensation. Proceedings of the National Academy of Sciences of the United States of America 109: 11752–11757.

Lyon MF (1961) Gene action in the X‐chromosome of the mouse (Mus musculus L.) Nature 190: 372–373.

Mahajan S and Bachtrog D (2015) Partial dosage compensation in Strepsiptera, a sister group of beetles. Genome Biology and Evolution 7: 591–600.

Mank JE (2013) Sex chromosome dosage compensation: definitely not for everyone. Trends in Genetics 29: 677–683.

Moore KL and Barr ML (1953) Morphology of the nerve cell nucleus in mammals, with special reference to the sex chromatin. Journal of Comparative Neurology 98: 213–231.

Nguyen DK and Disteche CM (2006) Dosage compensation of the active X chromosome in mammals. Nature Genetics 38: 47–53.

Nozawa M, Fukuda N, Ikeo K and Gojobori T (2014) Tissue‐ and stage‐dependent dosage compensation on the neo‐X chromosome in Drosophila pseudoobscura. Molecular Biology and Evolution 31: 614–624.

Ohno S, Kaplan WD and Kinosita R (1959) Formation of the sex chromatin by a single X‐chromosome in liver cells of Rattus norvegicus. Experimental Cell Research 18: 415–418.

Ohno S (1967) Sex Chromosomes and Sex‐Linked Genes. New York: Springer‐Verlag.

Papp B, Pal C and Hurst LD (2003) Dosage sensitivity and the evolution of gene families in yeast. Nature 424: 194–197.

Pessia E, Makino T, Bailly‐Bechet M, McLysaght A and Marais GA (2012) Mammalian X chromosome inactivation evolved as a dosage‐compensation mechanism for dosage‐sensitive genes on the X chromosome. Proceedings of the National Academy of Sciences of the United States of America 109: 5346–5351.

Shao C, Li Q, Chen S, et al. (2014) Epigenetic modification and inheritance in sexual reversal of fish. Genome Research 24: 604–615.

Smith G, Chen YR, Blissard GW and Briscoe AD (2014) Complete dosage compensation and sex‐biased gene expression in the moth Manduca sexta. Genome Biology and Evolution 6: 526–537.

Uebbing S, Kunstner A, Makinen H and Ellegren H (2013) Transcriptome sequencing reveals the character of incomplete dosage compensation across multiple tissues in flycatchers. Genome Biology and Evolution 5: 1555–1566.

Veyrunes F, Waters PD, Miethke P, et al. (2008) Bird‐like sex chromosomes of platypus imply recent origin of mammal sex chromosomes. Genome Research 18: 965–973.

Vicoso B, Emerson JJ, Zektser Y, Mahajan S and Bachtrog D (2013) Comparative sex chromosome genomics in snakes: differentiation, evolutionary strata, and lack of global dosage compensation. PLoS Biology 11: e1001643.

Vicoso B and Bachtrog D (2015) Numerous transitions of sex chromosomes in Diptera. PLoS Biology 13: e1002078.

Walters JR, Hardcastle TJ and Jiggins CD (2015) Sex chromosome dosage compensation in heliconius butterflies: global yet still incomplete? Genome Biology and Evolution 7: 2545–2559.

Wang Z, Gerstein M and Snyder M (2009) RNA‐seq: a revolutionary tool for transcriptomics. Nature Reviews Genetics 10: 57–63.

Wright AE, Moghadam HK and Mank JE (2012) Trade‐off between selection for dosage compensation and masculinization on the avian Z chromosome. Genetics 192: 1433–1445.

Xiong Y, Chen X, Chen Z, et al. (2010) RNA sequencing shows no dosage compensation of the active X‐chromosome. Nature Genetics 42: 1043–1047.

Further Reading

Graves JA (2016) Evolution of vertebrate sex chromosomes and dosage compensation. Nature Reviews Genetics 17: 33–46.

Lucchesi JC and Kuroda MI (2015) Dosage compensation in Drosophila. Cold Spring Harbor Perspectives in Biology 7.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
He, Xionglei, and Zhang, Jianzhi(May 2016) X‐Chromosome Dosage Compensation. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0026517]