X inactivation

X inactivation (also lyonisation) is the phenomenon where one of the two X chromosomes in female mammals is made irreversibly transcriptionally silent as a form of dosage compensation; i.e. so that the amount of X-chromosomal gene product is equal in males and females.

In placental mammals, including humans, the choice of which X chromosome is inactivated is random so that one cell (and all of its descendants within the organism) could express the maternal X chromosome while another could express the paternal X chromosome. In marsupials, however, the process is not random and it is always the paternal X chromosome which is inactivated.

In the two-to-four-cell stage of embryonic development, all mammals share inactivation of the paternally-derived X chromosome. The extraembryonic tissues, which give rise to the placenta, retain this genomic imprinting and thus always express the maternally-derived X chromosome. In the development of the early blastocyst, this is reversed in the inner cell body mass (which will give rise to the embryo), so that both X chromosomes are active, ready for one to be randomly inactivated. When the female is fully developed and producing gametes, X-inactivation is reversed so that all of her egg cells have active X chromosomes.

This phenomenon can be phenotypically observed in tortoiseshell cats. In these cats, coat colour is determined by two loci, a B locus for black coat colour and an O locus for orange coat colour. The O locus is an X-linked gene, where O is the dominant allele coding for orange fur and o is the recessive allele coding for no pigmentation. The B locus is epistatic to the O locus (or, if you like, the expression of the B locus to give black coat colour is dependent on the presence of a dominant O allele that is coding for pigmentation in the first place). If a female has the genotype XO/Xo, B/B, then she will express a combination of black and orange fur, depending on which of the X-linked genes is inactivated (i.e. if the dominant XO gene is inactivated, then the fur in this region will be orange; otherwise it will be black). This is the reason for random black-orange patterning of fur on some female tortoiseshell cats.

In any given cell, there is one active X chromosome (Xa) and one inactive X chromosome (Xi). However, if a female has the condition called trisomy X (three X chromosomes), then still only one will be Xa while two are Xi. This implies that the default fate for an X chromosome is inactivation, and X-activation is an active process. It is hypothesised that an autosomally-encoded 'blocking factor' binds to an X chromosome, at random, preventing it from inactivation. There is then no blocking factor remaining to protect the others, regardless of how many there are, from being inactivated. The blocking factor is thought to bind to a region on the X chromosome called the X inactivation centre (XIC); the sequence thought to be responsible for mediating the silencing of the X chromosome. Support for this hypothesis comes not only from the existence of two Xis in trisomy X, but also from the fact that two X chromosomes can remain active in cells where there are twice the usual number of autosomes (i.e. and twice the amount of blocking factor). It should be noted that the pseudoautosomal region, which is homologous between the X and Y chromosomes, always manages to escape X inactivation.

DNA on the inactive X chromosome, Xi, is packaged in heterochromatin, meaning that it is more condensed than DNA packaged in euchromatin, such as the Xa. The inactive X forms a discrete body within the nucleus called a Barr body. The Barr body is generally located on the periphery of the nucleus, is late replicating within the cell cycle, and, as it contains the Xi, contains heterochromatin modifications (such as histone deacetylation and DNA methylation).

Because X-inactivation is an epigenetic phenomenon, it should be considered distinct from mosaicism, which refers to different genotypes in different cells within an organism.