X-Inactivation

Mary Frances Lyon, geneticist

In human genetics, X chromosome inactivation, also known as X inactivation, refers to a process in which an X chromosome is completely or largely silenced so that no more gene products are created from this chromosome. As early as 1949, a dense structure was discovered in the nucleus of female somatic cells (Barr corpuscles), which was identified as an inactivated X chromosome in 1960. The following year, geneticist Mary Frances Lyon hypothesized that in female cells, one of the two X chromosomes is permanently inactivated to prevent female cells from expressing twice as many X-linked genes as male cells (Lyon hypothesis). The X chromosome carries over 1000 genes and is present in males in only a single version.

Females carry two X chromosomes in each cell and would thus have double the gene dose compared to males. Random inactivation of either the paternal X chromosome (Xp) or maternal X chromosome (Xm) in females serves to dose compensate for X-linked genes between the two sexes, so that female cells have the same gene dose as male cells with only one X chromosome. By randomly inactivating one of the two X chromosomes, females represent a mosaic of two cell populations, cells with active Xm or active Xp. X inactivation occurs during early female embryonic development and is subject to a very complex molecular mechanism that has not been fully elucidated to date. For X inactivation to occur, a cell must be able to perform several tasks:

• Determination of the number of X chromosomes
• Differentiation of the X chromosomes
• Selection of the X chromosome to be inactivated
• Process of inactivation

An essential component in X inactivation is a region on the X chromosome called the X inactivation center (Xic) . Experimentally, it has been demonstrated that X inactivation occurs only when two (or more) Xic are present in the cell. The Xic contains the Xist (X inactivation specific transcript) gene, which codes for a non-coding RNA (Xist RNA). In early female embryonic development, Xist RNA is expressed in cells from only one of the two X chromosomes. Xist RNA remains in the nucleus where it coats the chromosome from which it is expressed, inducing inactivation of the entire chromosome.

X inactivation is a process that is usually always initiated once two or more X chromosomes are present in the cell, with the goal that only one active X chromosome remains in the cell. Therefore, inactivation of one of the two X chromosomes is also seen in males with genotype XXY(Klinefelter syndrome), and in females with genotype XXX (triple X syndrome= super-female syndromes), inactivation of two of the total three X chromosomes can be observed. However, about 15% of the genes on the inactivated X chromosome remain intact . Therefore, in these syndromes, despite the X inactivation of the supernumerary X chromosomes, various symptoms appear that can be attributed to the deviant dose of these genes.

In human genetics, X-inactivation plays a special role in the expression of X-linked inherited diseases. The following can be observed in X-linked recessive diseases:

• Usually only males are affected as they carry only one X chromosome.
• In very rare cases, an X-recessive disease can occur in a woman if she has inherited a mutant allele on both X chromosomes or if the X-inactivation is shifted in favor of the mutation-bearing X chromosome.
• Fathers cannot inherit the disease to sons. All daughters are heterozygous carriers (conductors).
• Offspring of a conductor inherit the mutation with a probability of 50%, girls with the mutation are thus again conductors, boys with the mutation contract the disease.

In carriers of an X-linked recessive disease, only about 50% of the cells express the mutant recessive allele due to random X inactivation. The other half of the cells expresses the functional allele, which often allows compensation for the inherited defect and thus usually results in no or milder phenotypic symptoms in women. Through cell-to-cell connections or via endocytosis, metabolites or enzymes are exchanged between cells, compensating for the defect in the mutant cells. This compensation is also calledmetabolic cooperation and can be observed in various diseases, such as Fabry disease (deficiency of alpha-galactosidase A), Hunter disease (deficiency of iduronate sulfatase), Lesch-Nyhan syndrome (hypoxanthine phosphoribosyltransferase (HPRT) deficiency).

1. Galupa R et al (2018) X-chromosome inactivation: A Crossroads Between Chromosome Architecture and Gene Regulation. Annu Rev Genet 52:535-566