[citation needed] X-chromosome inactivation occurs in females to provide dosage compensation between the sexes.
At approximately the time of embryonic implantation, one of the two X chromosomes in each cell of the female embryo is randomly selected for inactivation.
Cells then undergo transcriptional and epigenetic changes to ensure this inactivation is permanent (such as methylation and being modified into Barr bodies).
The X-chromosome controlling element (Xce) gene in mice has been found to influence genetically mediated skewing.
It is difficult to identify primary nonrandom inactivation in humans, as early cell selection occurs in the embryo.
[citation needed] Skewed X-inactivation in mice is controlled by the Xce gene on the X chromosome.
The strength differences between the four alleles are likely due to variations in the number of binding sites for a crucial actor in inactivation.
Heterozygotes, will experience greater levels of skewing due to the differing inactivation likelihood of the two alleles.
The first is that genomic differences in the Xce alleles alter the sequence of the long non-coding RNA that is an integral part of X chromosome inactivation.
The second is that Xce acts as a binding site for dosage factors that will affect XIST gene and Tsix expression (long non-coding RNAs involved in X chromosome inactivation).
[2] Skewed inactivation patterns can also emerge due to mutations that change the quantity of guanine on the Xist promoter.
The mechanism has not been fully elucidated at this time, although research does point towards decreased promoter activity as a result of the mutation being a major part of the process.
In wildtype women, recessive diseases on the X chromosome are often unexpressed due to the roughly even inactivation process, which prevents mutated alleles from becoming heavily expressed.
Skewed X-inactivation has also been found to correlate with a higher rate of ovarian cancer, although the mechanism behind this is unknown.
Other researchers have contended that such a mutation would lead to higher rates of cancer among wild type females, as approximately half the cells would not express the gene due to random inactivation.
Asymptomatic carriers and patients with very mild symptoms have been described, who can show skewed X-inactivation that favors the inactivation of the mutated allele.
Asymptomatic carriers can pass on the mutated allele to their daughters, who can show full symptoms if skewing does not occur.
Skewing levels were found in 64% of informative patients, as compared to only 8% of the control group, also indicating a strong correlation and possible cause.
[14] Higher levels of skewed X chromosome inactivation have been correlated with cases of autism in women.
Since women are mosaic models when it comes to gene expression, they tend to mask X-linked mutations by using the other X to compensate.
Some symptoms of the disease are altered blood glucose levels, ketoacidosis, growth retardation, or liver distention.
Assays that detect the methylation level of the highly polymorphic CAG trinucleotide at the 5' end of the androgen receptor gene are often used in skewed X-inactivation studies.
At the turn of the 21st century, ratio detection moved to more direct methods by using mRNA or protein levels, and whole exome sequencing.
mRNA sequencing is then used on these regions to focus on the X chromosome and find single nucleotide polymorphisms (SNP) that are associated with the disease.
These levels of expression may give greater insight to the fundamental cause of the diseases seen from skewed X-inactivation.