Evolution of X‐Chromosome Inactivation

Abstract

X‐chromosome inactivation is a transcriptional silencing of one of the two X chromosomes that occurs in females of marsupial and eutherian mammals. The process arose and developed as a part of dosage compensation mechanism during differentiation of mammalian X and Y chromosomes. X inactivation started from being imprinted and unstable in marsupials and then was transformed to random and stable in eutherians. The transformation included replacement of the key noncoding nuclear ribonucleic acid master switch gene rsx to xist, and emergency of the X‐inactivation centre responsible for random choice of one of the two X chromosomes. Presumably, further involvement of the xist‐dependent repressive histone modifications together with deoxyribonucleic acid methylation and enrichment of the X chromosome with LINE1 mobile elements, allowed for more efficient spread and maintenance of an inactive state and has made the X‐chromosome inactivation process more complete and stable. During eutherian evolution, X‐chromosome inactivation mechanisms have tended to accumulate the taxon‐ and species‐specific differences.

Key Concepts:

  • X‐chromosome inactivation emerged as part of dosage compensation mechanism caused by differentiation of mammalian X and Y chromosomes.

  • X‐chromosome inactivation is unique for marsupial and eutherian mammals.

  • X‐chromosome inactivation has evolved from imprinted, incomplete, and unstable to random, complete, and efficiently maintained.

  • The long noncoding nuclear RNA controlling X‐chromosome inactivation, initially rsx in marsupials, has been replaced for xist in eutherians.

  • The noncoding nuclear RNA gene xist, responsible for initiation of inactivation in eutherians, emerged from a protein coding gene and a set of mobile elements.

  • Xist and the surrounding genes regulating its expression have formed the inactivation centre that regulate a random choice of one of the two X chromosomes to be transcriptionally silent.

  • Presumably, the main steps leading to complete and stable X‐chromosome inactivation are involvement of the xist‐dependent repressive histone modifications in gene rich clusters together with DNA methylation of the promoters and enrichment of X chromosome with the mobile elements LINE.

  • During eutherian evolution, X‐chromosome inactivation mechanisms mainly accumulated taxon‐ and species‐specific differences.

Keywords: mammals; X inactivation; xist; evolution

Figure 1.

The evolution of epigenetic mechanisms underlying the X‐chromosome inactivation in mammals (Chaumeil et al., ). Xi is inactive X chromosome. The divergence time of the taxa (Ma) is shown at the branches of the phylogenetic tree. Reproduced from Chaumeil et al., with permission PLoS.

Figure 2.

Comparison of the human and mouse XIC with its homologous region in chicken. Coloured boxes represent genes, arrows show their transcription direction. Homologous genes in different species are shown in the same colour. Lines connect same homologous genes in cognate loci of chicken, mouse and human. cdx4, chic1 and slc16a2 are conserved protein‐coding genes that flank both eutherian XIC and its homologous locus in chicken. cnbp2 is a protein‐coding gene, which was retrotransposed to XIC locus in eutherian lineage. tsx is a testis‐specific protein‐coding gene, which partially evolved from cognate chicken protein‐coding gene fip1l2. Note that in human Ψ TSX is not functional any more and represents a pseudogene. xist, enox (jpx) and ftx are genes of XIC produced nuclear RNA; they show homology to the cognate chicken protein‐coding genes lnx3, uspl and wave4, respectively. The remainder of chicken protein‐coding gene rasl11c is found in eutherian XIC between genes ftx and enox (jpx).

Figure 3.

Comparison of xist gene structure in vole, cow and human. Grey rectangles represent exons. (1–8), exon numbers. Green rectangles indicate parts of introns, which in xist of other species are exons. Lines connect homologous sequences. Coloured rectangle indicate arrays of tandem repeats, named A, B, C, D, E and F which are present in xist exons of all of the three species, and B*‐repeats which is specific for human. Yang species‐specific LINE and SINE (short interspersed nuclear elements) mobile elements are indicated by blue and red arrows, respectively.

Figure 4.

The origin of xist gene from the sequences of the protein‐coding gene lnx3 and various classes of mobile elements (Elisaphenko et al., ). Blue rectangles denote the exons that evolved from the gene lnx3; red rectangles, the exons originating from mobile elements; hatched blue and red rectangles, the exon sequences detectable in the genome but not contained in the xist transcript in the corresponding species. Consensus is a putative ancestral structure of the xist gene. Exon numbering is given for the human (Homo sapiens) and mouse (Mus musculus) xist genes: m1–m8 for mouse and h1–h8 for human. Reproduced from Elisaphenko et al., with permission from PLoS.

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Shevchenko, Alexander I, and Zakian, Suren M(Feb 2013) Evolution of X‐Chromosome Inactivation. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0020848.pub2]