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X chromosome regulation: diverse patterns in development, tissues and disease

Key Points

  • Functional specialization of the gene content of the X chromosome occurs in mammals: the X chromosome is highly enriched in male-specific genes (which are expressed in the testes), as well as in female-biased genes and brain-specific genes.

  • Diverse molecular mechanisms are involved in upregulation of expressed genes on the active X chromosome to balance gene expression with the autosomes (which are present in two copies).

  • Initiation of X chromosome inactivation (XCI) is not conserved in early development of mammalian species, which leads to early embryonic sex-specific differences before gonadal development.

  • Genes that escape XCI show sex biases in gene expression levels.

  • The peculiar modes of X chromosome regulation, especially mosaicism and skewing of XCI, influence the severity of diseases caused by X-linked mutations.

Abstract

Genes on the mammalian X chromosome are present in one copy in males and two copies in females. The complex mechanisms that regulate the X chromosome lead to evolutionary and physiological variability in gene expression between species, the sexes, individuals, developmental stages, tissues and cell types. In early development, delayed and incomplete X chromosome inactivation (XCI) in some species causes variability in gene expression. Additional diversity stems from escape from XCI and from mosaicism or XCI skewing in females. This causes sex-specific differences that manifest as differential gene expression and associated phenotypes. Furthermore, the complexity and diversity of X dosage regulation affect the severity of diseases caused by X-linked mutations.

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Figure 1: Variable gene content and dosage upregulation of the mammalian X chromosome.
Figure 2: XCI initiation varies in mammals.
Figure 3: Escape from XCI varies between cell types and tissue in mice.
Figure 4: Variability of X-linked gene expression and sex bias.

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Acknowledgements

This work was supported by grants GM046883, GM098039, MH083949, and MH099628 from the US National Institutes of Health.

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Correspondence to Christine M. Disteche.

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PowerPoint slides

Glossary

X upregulation

A process to increase X-linked gene expression levels to balance expression between the X chromosome and autosomes.

X chromosome inactivation

(XCI). A process to silence one X chromosome in females to achieve similar expression levels between the sexes.

Sex biases in gene expression

Differential gene expression between males and females.

Allele-specific gene expression

Specific expression from the maternal or paternal allele that can be assayed by single-nucleotide polymorphisms.

Genes that escape XCI

A subset of X-linked genes that are biallelically expressed in female somatic cells.

XCI skewing

Preferential inactivation of one X chromosome.

Sexual antagonism

Evolution of alleles that are beneficial to one sex but detrimental to the other.

Meiotic sex chromosome inactivation

(MSCI). A process to silence both X-linked and Y-linked genes during male meiosis.

X reactivation

A process to reactivate the silenced X chromosome at different developmental stages (for example, in the mouse inner cell mass and in female germ cells).

Turner syndrome

Syndrome in females with a single X chromosome (that is, 45,X).

XCI initiation

Onset of chromosome-wide X-linked gene silencing that is controlled by a master regulatory locus known as the X inactivation centre.

Inactive X specific transcripts

(Xist). Long non-coding RNAs transcribed from the X inactivation centre that function as the master regulator of mouse X chromosome inactivation.

X conserved region

(XCR). A region on the mammalian X chromosome that is found on chicken orthologous autosome 4 and on the marsupial X chromosome.

X added region

(XAR). A region on the mammalian X chromosome that is found on chicken orthologous autosome 1 and that was added since the divergence between eutherian mammals and marsupials.

Mosaicism for X allele expression

A mixture of somatic cells that carry an active paternal or maternal X chromosome owing to random X chromosome inactivation.

Pseudoautosomal regions

(PARs). Regions of homology and pairing on the sex chromosomes.

X–Y gene pairs

Genes with paralogues located on the X and Y chromosomes.

X chromosome controlling element

(Xce). A locus at the X inactivation centre that controls the choice of a particular X chromosome to be inactivated or to remain active.

Haploinsufficiency

Insufficiency due to the presence of a single copy instead of two copies of a gene in a diploid cell.

Klinefelter's syndrome

A syndrome in males that carry an additional X chromosome (that is, 47,XXY).

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Deng, X., Berletch, J., Nguyen, D. et al. X chromosome regulation: diverse patterns in development, tissues and disease. Nat Rev Genet 15, 367–378 (2014). https://doi.org/10.1038/nrg3687

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