Editing X-inactivation (section)

=== Expression of X-linked disorders in heterozygous females ===
The effect of female X heterozygosity is apparent in some localized traits, such as the unique coat pattern of a [[calico cat]]. It can be more difficult, however, to fully understand the expression of un-localized traits in these females, such as the expression of disease.

Since males only have one copy of the X chromosome, all expressed X-chromosomal [[gene]]s (or [[allele]]s, in the case of multiple variant forms for a given gene in the population) are located on that copy of the chromosome. Females, however, will primarily express the genes or alleles located on the X-chromosomal copy that remains active. Considering the situation for one gene or multiple genes causing individual differences in a particular [[Phenotypic trait|phenotype]] (i.e., causing variation observed in the population for that phenotype), in homozygous females it does not particularly matter which copy of the chromosome is inactivated, as the alleles on both copies are the same. However, in females that are heterozygous at the causal genes, the inactivation of one copy of the chromosome over the other can have a direct impact on their phenotypic value. Because of this phenomenon, there is an observed increase in phenotypic variation in females that are heterozygous at the involved gene or genes than in females that are homozygous at that gene or those genes.<ref>{{cite journal | vauthors = Ma L, Hoffman G, Keinan A | title = X-inactivation informs variance-based testing for X-linked association of a quantitative trait | journal = BMC Genomics | volume = 16 | pages = 241 | date = March 2015 | issue = 1 | pmid = 25880738 | pmc = 4381508 | doi = 10.1186/s12864-015-1463-y | doi-access = free }}</ref> There are many different ways in which the phenotypic variation can play out. In many cases, heterozygous females may be asymptomatic or only present minor symptoms of a given disorder, such as with [[Adrenoleukodystrophy|X-linked adrenoleukodystrophy.]]<ref>{{cite journal | vauthors = Habekost CT, Pereira FS, Vargas CR, Coelho DM, Torrez V, Oses JP, Portela LV, Schestatsky P, Felix VT, Matte U, Torman VL, Jardim LB | title = Progression rate of myelopathy in X-linked adrenoleukodystrophy heterozygotes | journal = Metabolic Brain Disease | volume = 30 | issue = 5 | pages = 1279–84 | date = October 2015 | pmid = 25920484 | doi = 10.1007/s11011-015-9672-2 | s2cid = 11375978 }}</ref>

The differentiation of phenotype in heterozygous females is furthered by the presence of X-inactivation skewing. Typically, each X-chromosome is silenced in half of the cells, but this process is skewed when preferential inactivation of a chromosome occurs. It is thought that skewing happens either by chance or by a physical characteristic of a chromosome that may cause it to be silenced more or less often, such as an unfavorable mutation.<ref name=":0">{{cite journal | vauthors = Belmont JW | title = Genetic control of X inactivation and processes leading to X-inactivation skewing | journal = American Journal of Human Genetics | volume = 58 | issue = 6 | pages = 1101–8 | date = June 1996 | pmid = 8651285 | pmc = 1915050 }}</ref><ref name=":1">{{cite journal | vauthors = Holle JR, Marsh RA, Holdcroft AM, Davies SM, Wang L, Zhang K, Jordan MB | title = Hemophagocytic lymphohistiocytosis in a female patient due to a heterozygous XIAP mutation and skewed X chromosome inactivation | journal = Pediatric Blood & Cancer | volume = 62 | issue = 7 | pages = 1288–90 | date = July 2015 | pmid = 25801017 | doi = 10.1002/pbc.25483 | s2cid = 5516967 }}</ref>

On average, each X chromosome is inactivated in half of the cells, although 5-20% of women display X-inactivation skewing.<ref name=":0" /> In cases where skewing is present, a broad range of symptom expression can occur, resulting in expression varying from minor to severe depending on the skewing proportion. An extreme case of this was seen where monozygotic female twins had extreme variance in expression of [[Menkes disease]] (an X-linked disorder) resulting in the death of one twin while the other remained asymptomatic.<ref>{{cite journal | vauthors = Burgemeister AL, Zirn B, Oeffner F, Kaler SG, Lemm G, Rossier E, Büttel HM | title = Menkes disease with discordant phenotype in female monozygotic twins | journal = American Journal of Medical Genetics. Part A | volume = 167A | issue = 11 | pages = 2826–9 | date = November 2015 | pmid = 26239182 | pmc = 6475897 | doi = 10.1002/ajmg.a.37276 }}</ref>

It is thought that X-inactivation skewing could be caused by issues in the mechanism that causes inactivation, or by issues in the chromosome itself.<ref name=":0" /><ref name=":1" /> However, the link between phenotype and skewing is still being questioned, and should be examined on a case-by-case basis. A study looking at both symptomatic and asymptomatic females who were heterozygous for [[Duchenne muscular dystrophy|Duchenne]] and Becker muscular dystrophies (DMD) found no apparent link between transcript expression and skewed X-Inactivation. The study suggests that both mechanisms are independently regulated, and there are other unknown factors at play.<ref name="pmid22894145">{{cite journal | vauthors = Brioschi S, Gualandi F, Scotton C, Armaroli A, Bovolenta M, Falzarano MS, Sabatelli P, Selvatici R, D'Amico A, Pane M, Ricci G, Siciliano G, Tedeschi S, Pini A, Vercelli L, De Grandis D, Mercuri E, Bertini E, Merlini L, Mongini T, Ferlini A | title = Genetic characterization in symptomatic female DMD carriers: lack of relationship between X-inactivation, transcriptional DMD allele balancing and phenotype | journal = BMC Medical Genetics | volume = 13 | pages = 73 | date = August 2012 | pmid = 22894145 | pmc = 3459813 | doi = 10.1186/1471-2350-13-73 | doi-access = free }}</ref>