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Lyonization and X-linked disorders?

Lyonization and X-linked disorders?


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Lyonization or X-chromosome inactivation is the conversion of all but one, X-chromosomes in Females into non-coding heterochromatin (i.e. deactivated) leading to the formation of one or more Barr bodies. The selection of the X-chromosome to be inactivated is different in different animals. In female Marsupials, the inactivation is always of the Paternal X-chromosome while in placental mammals, the selection is random. (Although the extent of lyonization is not completely random and varies directionally with age).

My question is

If the X-chromosome to be inactivated is randomly selected in placental mammals (including humans), then why don't the females heterozygous for a X-linked recessive disorder do not show the phenotype of the disease though the functional gene is equally likely (as compared to the defective) to be the one to be lyonized?

There are some evidences of genes escaping inactivation and managing to exhibit themselves but I don't think they can account for all the recessive x-linked disorders.


The simple answer is that which X chromosome is inactivated varies in different cell lineages, so typically a female will have cells exhibiting either wild-type or mutant phenotypes. It was Mary Lyon's observation of mosaicism in heterozygous mouse coat colour that gave the phenomenon its name. So in the case of a recessive disease there will be a phenotype, but in many cases the 50% of cells expressing the normal gene will provide sufficient functional cells to get by. From the Wikipedia article about Mary Lyon:

Her research has allowed us to understand the genetic control mechanisms of chromosome X, which explains the absence of symptoms in numerous healthy women that are carriers of diseases associated with this chromosome.

Edit - response to comments:

Plug, I et al. (2006) Bleeding in carriers of hemophilia. Blood 108: 52-56

Abstract:

A wide range of factor VIII and IX levels is observed in heterozygous carriers of hemophilia as well as in noncarriers. In female carriers, extreme lyonization may lead to low clotting factor levels. We studied the effect of heterozygous hemophilia carriership on the occurrence of bleeding symptoms. A postal survey was performed among most of the women who were tested for carriership of hemophilia in the Netherlands before 2001. The questionnaire included items on personal characteristics, characteristics of hemophilia in the affected family members, and carrier testing and history of bleeding problems such as bleeding after tooth extraction, bleeding after tonsillectomy, and other operations. Information on clotting factor levels was obtained from the hospital charts. Logistic regression was used to assess the relation of carrier status and clotting factor levels with the occurrence of hemorrhagic events. In 2004, 766 questionnaires were sent, and 546 women responded (80%). Of these, 274 were carriers of hemophilia A or B. The median clotting factor level of carriers was 0.60 IU/mL (range, 0.05-2.19 IU/mL) compared with 1.02 IU/mL (range, 0.45-3.28 IU/mL) in noncarriers. Clotting factor levels from 0.60 to 0.05 IU/mL were increasingly associated with prolonged bleeding from small wounds and prolonged bleeding after tooth extraction, tonsillectomy, and operations. Carriers of hemophilia bleed more than other women, especially after medical interventions. Our findings suggest that not only clotting factor levels at the extreme of the distribution, resembling mild hemophilia, but also mildly reduced clotting factor levels between 0.41 and 0.60 IU/mL are associated with bleeding.

Bimler, D & Kirkland, J (2009) Colour-space distortion in women who are heterozygous for colour deficiency. Vision Research 49: 536-543

from the Introduction:

About 15% of women are heterozygous for some form of colour vision deficiency (CVD). That is, they possess a genetic abnormality on one of their two X chromosomes, affecting the photopigments (opsins) which subserve colour vision. The retina of a heterozygous woman is a mosaic in which some cone cells express the aberrant gene while others express the normal copy, depending on which X chromosome is active (inactivation of one X chromosome occurs randomly in retinal stem-cells at some stage of fetal development). The normal cells are sufficient to provide full trichromatic vision.


Epigenetics of X Chromosome Inactivation

Tamar Dvash , Guoping Fan , in Handbook of Epigenetics , 2011

XCI Regulation During Development

XCI is a developmentally-regulated process that involves sequential acquisition of silencing markers on the X chromosome to be inactivated. Two different patterns of XCI exist: imprinted and random. The majority of XCI properties are shared between the two different patterns, yet some differences exist that reflect the nature and the degree of stability of inactivation. Most of the research concerning XCI in mammals has been conducted with the mouse model system. At the fertilization stage, the female mouse zygote has both X chromosomes active. The first inactivation during development occurs upon the first cleavage. This inactivation is imprinted and therefore only the paternal X chromosome is inactivated [4,5] . Later on, after the blastocyst has formed, cells from the inner cell mass (ICM) reactivate the inactive X [5,6] . At this stage the embryo has two types of XCI status the ICM cells have both active X chromosomes while the trophectoderm and the primitive endoderm still retain their imprinted paternal XCI since the first cleavage. Then, only upon differentiation will the ICM cells again inactivate one of their X chromosomes but this time stochastically, in contrast to the first cleavage event [5,6] . Since the ICM cells are the origin of the embryo proper, the second round of inactivation will result in random XCI in each cell and throughout development its progenies will maintain that particular Xi. The primordial germ cells (PGC) are an exception in this regard since these cells again reactivate their Xi later on in mouse development (E11.5–E13.5) and this status is maintained in the female germ cells [7] .

Both random and imprinted XCI are initiated by monoallelic Xist gene expression. This expression leads to a series of epigenetic modifications such as depletion of RNA polymerase II, transcription factors, and euchromatic markers (see Fig. 21.3 ). Imprinted XCI is temporary compared to the random XCI that remains stable from the moment of establishment throughout many cell divisions and across the entire lifespan. Therefore in order to establish stable random XCI, the mechanisms for CpG island methylation are employed [8] . This modification is considered to be more stable than histone modifications which are characteristic of imprinted XCI and early epigenetic events of random inactivation [9] . Although XCI occurs in a narrow time window during mouse development it is suggested that the kinetics of gene silencing varies. Existing evidence shows that genes located in the vicinity of the X chromosome inactivation center (XIC) are first silenced during differentiation [10] .

Another interesting phenomenon in XCI is the “escape” from inactivation although the majority of the genes on the Xi are subjected to complete silencing, some are able to express from both active and inactive X chromosomes. The exact mechanism for genes escaping XCI is not fully understood but a recent study using the transgene approach revealed that it is probably an intrinsic property of a specific locus. Random integration of BAC clones carrying normally silenced or escaped gene (Jarid1c) loci into the X chromosome of female ESC lines was able to recapitulate the endogenous expression pattern. The authors concluded that the DNA sequence itself is sufficient to determine whether a locus will be subjected to XCI [11] .


Lingering Lyonization:The Genetics of Asperger's Syndrome?

THE BASICS

As I pointed out in a previous post, female mammals deal with the problem of having two X chromosomes (left) to the male’s one by randomly inactivating one of them in each cell. The effect is sometimes called Lyonization after Mary Lyon, who discovered it. Lyonization explains why one of a pair of American identical twin sisters suffers from Duchenne Muscular Dystrophy (DMD, an X-linked genetic disease which has made her paraplegic) while the other is a successful athlete. Identical twins result when the fertilized egg has only divided a few times but then splits into two individuals, and X-inactivation occurs at the same stage. Cell lineages inherit their pattern of Lyonization from their predecessors, and so in this case it looks as if only one twin was unfortunate enough to inherit the cell lineages which expressed the DMD gene from one parental X chromosome, while the other inherited those expressed from the other parent’s unaffected X.

As I also pointed out in the previous post, a recent study found that compared to male, female identical twins vary more on measures of pro-social behaviour, peer problems, and verbal ability thanks to differential Lyonization. Deficits and deviations in precisely these traits are symptomatic of Asperger’s syndrome (AS), and one possible explanation of the strange genetics of the disorder (which demonstrably runs in families, but does not obey the rules of classical genetic inheritance like DMD does) might be found in lingering Lyonization.

What I mean by this is the known possibility that X-inactivation imprints placed on specific X genes in a woman’s body might be accidentally retained on the X chromosome she passed on to her children. If these inactivating imprints affected the very same genes implicated in AS, the striking sex ratio of the disorder’s incidence would be explained. AS affects approximately 10 to 20 times more males than females (depending on the exact diagnostic criteria). Because males have only a single X, they could be predicted to be much more vulnerable to lingering Lyonization than a woman’s daughters, who would always have a second, paternal X chromosome lacking such imprints to compensate and dilute the effect. However, the fact that 35% of women have a greater than 70:30 skew in their pattern of Lyonization and that 7% have more than a 90:10 skew in favour of one parent’s X, a much smaller number of females might also be predicted to be vulnerable. In other words, highly skewed Lyonization in a minority of females would inevitably resemble the single X situation found in males, and if the lingering Lyonization imprints were inactivating the critical genes in those cases, AS would result, but at a far lower incidence than in males—just as we find.

The same reasoning would explain the often-remarked variability of the symptoms in AS. Classically-heritable single-gene disorders like DMD usually have strikingly consistent symptoms because only one gene is affected, usually in the same way (in the case of DMD, this is Dystrophin, the longest gene in the human genome). But if imperfectly-erased Lyonization imprints on several genes were at issue in AS, the outcome in each case might be surprisingly different, and the combined effects highly variable—again, just as we find.

At present this is only speculation: we do not know the genetic causes of AS. But the model proposed here fits the general theory outlined in The Imprinted Brain. This is that increased paternal and/or reduced maternal and/or X-chromosome gene expression causes autistic disorders like AS. Given the fact that so many cognitive capacities seem to be inherited from the mother as my previous post pointed out, the likelihood must be that the latter alternative—reduced maternal and perhaps especially X-chromosome gene expression—is the likely culprit. Time will tell.


Contents

Someone with two X chromosomes (such as most human females) has only one Barr body per somatic cell, while someone with one X chromosome (such as most human males) has none.

Mammalian X-chromosome inactivation is initiated from the X inactivation centre or Xic, usually found near the centromere. [6] The center contains twelve genes, seven of which code for proteins, five for untranslated RNAs, of which only two are known to play an active role in the X inactivation process, Xist and Tsix. [6] The centre also appears to be important in chromosome counting: ensuring that random inactivation only takes place when two or more X-chromosomes are present. The provision of an extra artificial Xic in early embryogenesis can induce inactivation of the single X found in male cells. [6]

The roles of Xist and Tsix appear to be antagonistic. The loss of Tsix expression on the future inactive X chromosome results in an increase in levels of Xist around the Xic. Meanwhile, on the future active X Tsix levels are maintained thus the levels of Xist remain low. [7] This shift allows Xist to begin coating the future inactive chromosome, spreading out from the Xic. [2] In non-random inactivation this choice appears to be fixed and current evidence suggests that the maternally inherited gene may be imprinted. [4] Variations in Xi frequency have been reported with age, pregnancy, the use of oral contraceptives, fluctuations in menstrual cycle and neoplasia. [8]

It is thought that this constitutes the mechanism of choice, and allows downstream processes to establish the compact state of the Barr body. These changes include histone modifications, such as histone H3 methylation (i.e. H3K27me3 by PRC2 which is recruited by Xist) [9] and histone H2A ubiquitination, [10] as well as direct modification of the DNA itself, via the methylation of CpG sites. [11] These changes help inactivate gene expression on the inactive X-chromosome and to bring about its compaction to form the Barr body.

Reactivation of a Barr body is also possible, and has been seen in breast cancer patients. [12] One study showed that the frequency of Barr bodies in breast carcinoma were significantly lower than in healthy controls, indicating reactivation of these once inactivated X chromosomes. [12]

Links to full text articles are provided where access is free, in other cases only the abstract has been linked.


Lingering Lyonization:The Genetics of Asperger's Syndrome?

THE BASICS

As I pointed out in a previous post, female mammals deal with the problem of having two X chromosomes (left) to the male’s one by randomly inactivating one of them in each cell. The effect is sometimes called Lyonization after Mary Lyon, who discovered it. Lyonization explains why one of a pair of American identical twin sisters suffers from Duchenne Muscular Dystrophy (DMD, an X-linked genetic disease which has made her paraplegic) while the other is a successful athlete. Identical twins result when the fertilized egg has only divided a few times but then splits into two individuals, and X-inactivation occurs at the same stage. Cell lineages inherit their pattern of Lyonization from their predecessors, and so in this case it looks as if only one twin was unfortunate enough to inherit the cell lineages which expressed the DMD gene from one parental X chromosome, while the other inherited those expressed from the other parent’s unaffected X.

As I also pointed out in the previous post, a recent study found that compared to male, female identical twins vary more on measures of pro-social behaviour, peer problems, and verbal ability thanks to differential Lyonization. Deficits and deviations in precisely these traits are symptomatic of Asperger’s syndrome (AS), and one possible explanation of the strange genetics of the disorder (which demonstrably runs in families, but does not obey the rules of classical genetic inheritance like DMD does) might be found in lingering Lyonization.

What I mean by this is the known possibility that X-inactivation imprints placed on specific X genes in a woman’s body might be accidentally retained on the X chromosome she passed on to her children. If these inactivating imprints affected the very same genes implicated in AS, the striking sex ratio of the disorder’s incidence would be explained. AS affects approximately 10 to 20 times more males than females (depending on the exact diagnostic criteria). Because males have only a single X, they could be predicted to be much more vulnerable to lingering Lyonization than a woman’s daughters, who would always have a second, paternal X chromosome lacking such imprints to compensate and dilute the effect. However, the fact that 35% of women have a greater than 70:30 skew in their pattern of Lyonization and that 7% have more than a 90:10 skew in favour of one parent’s X, a much smaller number of females might also be predicted to be vulnerable. In other words, highly skewed Lyonization in a minority of females would inevitably resemble the single X situation found in males, and if the lingering Lyonization imprints were inactivating the critical genes in those cases, AS would result, but at a far lower incidence than in males—just as we find.

The same reasoning would explain the often-remarked variability of the symptoms in AS. Classically-heritable single-gene disorders like DMD usually have strikingly consistent symptoms because only one gene is affected, usually in the same way (in the case of DMD, this is Dystrophin, the longest gene in the human genome). But if imperfectly-erased Lyonization imprints on several genes were at issue in AS, the outcome in each case might be surprisingly different, and the combined effects highly variable—again, just as we find.

At present this is only speculation: we do not know the genetic causes of AS. But the model proposed here fits the general theory outlined in The Imprinted Brain. This is that increased paternal and/or reduced maternal and/or X-chromosome gene expression causes autistic disorders like AS. Given the fact that so many cognitive capacities seem to be inherited from the mother as my previous post pointed out, the likelihood must be that the latter alternative—reduced maternal and perhaps especially X-chromosome gene expression—is the likely culprit. Time will tell.


X chromosome inactivation ratios in female carriers of X-linked sideroblastic anemia

Aivado et al raise a number of questions concerning our recent paper on familial-skewed X chromosome inactivation as a predisposing factor for late-onset X-linked sideroblastic anemia (XLSA) in carrier females.1-1 We are pleased to provide them with technical details that could not be placed in a brief report and also to have the opportunity of discussing the pathophysiology of sideroblastic anemia.

Aivado et al correctly state that distinction between skewed and balanced lyonization depends on various arbitrary definitions as well as certain technical variables. They claim that we did not provide methods for calculation of cleavage ratios or their correction but do not consider that we had just one sentence available for describing clonal analysis of hematopoiesis. Therefore, we referred the reader to our previous methodological paper,1-2 which can provide technical and methodological details. It is a shame that our colleagues did not have the chance to read this article.

The decision to use a cleavage ratio equal to 3.0 as the cutoff between cases with balanced X chromosome inactivation and cases with excessive skewing was arbitrary by definition. More generally, any cutoff is arbitrarily established (eg, a hemoglobin level of 12 g/dL for distinguishing between healthy and anemic women): what counts is the rationale supporting the arbitrary decision. In the previously mentioned paper,1-2 we did perform a detailed analysis of the literature, which indicated that a value of 3.0 was the best cutoff. Our German and American colleagues recommend the use of an automated laser fluorescence sequencer or a similar device for enhanced resolution: we fully agree and have indeed started to use this technique in the last few months.

As regards case II-2 in our report, it is true that the ratio of 3.2 would translate into 76% of cells with an inactive wild-typeALAS2 allele [(3.2 × 100) / (1 + 3.2)]. Aivado et al find it difficult to explain the fact that sequence analysis of cDNA derived from her reticulocyte RNA showed only expression of the wild-type allele. They also argue that it is puzzling how 20% to 24% of cells with an active wild-type ALAS2 allele can account for the lack of anemia in women II-2, II-3, and III-2. What they do not account for is the pathophysiology of anemia in XLSA. We are glad to provide them with the interpretation of these findings that was included in the first version of our manuscript and eventually had to be omitted for reasons of space.

Despite the fact that our proband was not informative for clonal analysis of hematopoiesis, studies on the erythroid-specific 5-aminolevulinic acid synthase (ALAS2) structure and expression provided useful information. In fact, although she was heterozygous for the ALAS2 mutation, only the mutantALAS2 mRNA was expressed in her reticulocytes, as happened with her grandson, who is hemizygous and therefore carries only the mutant X chromosome. It should be noted that both the woman and her grandson were under pyridoxine treatment and no longer anemic at the time they were found to express the mutatedALAS2 allele. On the other hand, the remaining 3 heterozygous women in this family had normal hemoglobin levels and, despite unbalanced X chromosome inactivation, expressed the normalALAS2 in their reticulocytes. In the proband's daughters, red cell production is essentially sustained by erythroid cells carrying the nonmutant X chromosome as the active one. Even if such erythroid cells represent only about 20% to 24% of total immature red cells, they can clearly sustain a normal red cell production.1-3 Most erythroid precursors expressing the mutant ALAS2 are ring sideroblasts that die prematurely in the bone marrow, a mechanism responsible for anemia in hemizygous males and known as ineffective erythropoiesis. The few mature red cells deriving from erythroid precursors expressing the mutant gene account for the slightly increased red blood cell distribution width (RDW) values that are typically observed in heterozygous females. But the RNA content of reticulocytes expressing the mutant gene is only a small fraction of total reticulocyte RNA and may or may not be detected using the cDNA assay employed by us (which is semiquantitative). One experiment we did not carry out involved administration of pyridoxine to the nonanemic heterozygous women in order to see its effect on mutant ALAS2 expression in their reticulocytes. It is possible that under pyridoxine women II-2 and II-3 would also have expressed the mutant allele.

Finally, Aivado et al raise doubts about our conclusion that skewing was familial. They suggest that the moderately skewed X chromosome inactivation patterns (XCIPs) in the 3 females' leukocytes could also be the result of an age-related stochastic event. In our previous paper,1-2 we studied XCIPs in blood cells from healthy women belonging to 3 age groups: neonates (umbilical cord blood), women 25 to 32 years old (young women group), and women more than 75 years old (elderly women). The frequency of skewed X inactivation in polymorphonuclear cells (PMNs) increased with age: in fact, a cleavage ratio of at least 3.0 was found in 3 of 36 cord blood samples, 5 of 30 young women, and 14 of 31 elderly women. The inactivation patterns found in T lymphocytes were significantly related to those observed in PMNs in both young (P < .001) and elderly women (P < .01). Based on the above estimates, the probability that the 4 women in our family simply had age-related skewing would be 8 divided by 10 000 [(5 of 30) 4 ], while the probability that skewing was familial is 9992 divided by 10 000. Consequently our conclusion had a strong scientific basis.

Aivado et al suggest that a comparison of leukocyte XCIP with XCIP from other tissues is needed. To define the best control tissue for the interpretation of X chromosome inactivation patterns in hematopoietic cells, we previously analyzed X chromosome inactivation patterns in different peripheral blood cell populations and in hair bulbs from healthy women belonging to different age groups.1-2 When PMNs were compared with hair bulbs, 2(Fig3 ) no relationship was found with respect to the inactivation ratio (r = .31,P > .05). There was no difference between young and elderly women in this respect, a cleavage ratio of at least 3.0 in PMNs being associated with a similar value only in about 50% of hair bulb DNA from either young or elderly women.

In summary, findings of our study clearly indicate that the most likely explanation of the above findings is that the proband, despite a markedly congenitally unbalanced X chromosome inactivation in her hematopoietic cells, was able to produce normal amounts of red cells for the first 6 decades of her life, as her daughters and granddaughter do. In the seventh decade she developed acquired skewing, as do about one third of elderly women. She unfortunately further inactivated the parental X chromosome carrying the normal ALAS2 gene, and when nearly all red cell precursors expressed the mutant gene, she became severely anemic.


Contents

It was first noted that the X chromosome was special in 1890 by Hermann Henking in Leipzig. Henking was studying the testicles of Pyrrhocoris and noticed that one chromosome did not take part in meiosis. Chromosomes are so named because of their ability to take up staining (chroma in Greek means color). Although the X chromosome could be stained just as well as the others, Henking was unsure whether it was a different class of object and consequently named it X element, [6] which later became X chromosome after it was established that it was indeed a chromosome. [7]

The idea that the X chromosome was named after its similarity to the letter "X" is mistaken. All chromosomes normally appear as an amorphous blob under the microscope and take on a well defined shape only during mitosis. This shape is vaguely X-shaped for all chromosomes. It is entirely coincidental that the Y chromosome, during mitosis, has two very short branches which can look merged under the microscope and appear as the descender of a Y-shape. [8]

It was first suggested that the X chromosome was involved in sex determination by Clarence Erwin McClung in 1901. After comparing his work on locusts with Henking's and others, McClung noted that only half the sperm received an X chromosome. He called this chromosome an accessory chromosome, and insisted (correctly) that it was a proper chromosome, and theorized (incorrectly) that it was the male-determining chromosome. [6]

Function Edit

The X chromosome in humans spans more than 153 million base pairs (the building material of DNA). It represents about 800 protein-coding genes compared to the Y chromosome containing about 70 genes, out of 20,000–25,000 total genes in the human genome. Each person usually has one pair of sex chromosomes in each cell. Females typically have two X chromosomes, whereas males typically have one X and one Y chromosome. Both males and females retain one of their mother's X chromosomes, and females retain their second X chromosome from their father. Since the father retains his X chromosome from his mother, a human female has one X chromosome from her paternal grandmother (father's side), and one X chromosome from her mother. This inheritance pattern follows the Fibonacci numbers at a given ancestral depth.

Genetic disorders that are due to mutations in genes on the X chromosome are described as X linked. If X chromosome has a genetic disease gene, it always causes illness in male patients, since men have only one X chromosome and therefore only one copy of each gene. Females, instead, may stay healthy and only be carrier of genetic illness, since they have another X chromosome and possibility to have healthy gene copy. For example hemophilia and red-green colorblindness run in family this way.

The X chromosome carries hundreds of genes but few, if any, of these have anything to do directly with sex determination. Early in embryonic development in females, one of the two X chromosomes is permanently inactivated in nearly all somatic cells (cells other than egg and sperm cells). This phenomenon is called X-inactivation or Lyonization, and creates a Barr body. If X-inactivation in the somatic cell meant a complete de-functionalizing of one of the X-chromosomes, it would ensure that females, like males, had only one functional copy of the X chromosome in each somatic cell. This was previously assumed to be the case. However, recent research suggests that the Barr body may be more biologically active than was previously supposed. [10]

The partial inactivation of the X-chromosome is due to repressive heterochromatin that compacts the DNA and prevents the expression of most genes. Heterochromatin compaction is regulated by Polycomb Repressive Complex 2 (PRC2). [11]

Genes Edit

Number of genes Edit

The following are some of the gene count estimates of human X chromosome. Because researchers use different approaches to genome annotation their predictions of the number of genes on each chromosome varies (for technical details, see gene prediction). Among various projects, the collaborative consensus coding sequence project (CCDS) takes an extremely conservative strategy. So CCDS's gene number prediction represents a lower bound on the total number of human protein-coding genes. [12]

Estimated by Protein-coding genes Non-coding RNA genes Pseudogenes Source Release date
CCDS 804 [2] 2016-09-08
HGNC 825 260 606 [13] 2017-05-12
Ensembl 841 639 871 [14] 2017-03-29
UniProt 839 [15] 2018-02-28
NCBI 874 494 879 [16] [17] [18] 2017-05-19

Gene list Edit

The following is a partial list of genes on human chromosome X. For complete list, see the link in the infobox on the right.

    : encoding Alzheimer disease 16 protein : encoding protein AIC : encoding protein Apolipoprotein O : encoding protein Armadillo repeat containing X-linked 6 : encoding protein Brain-expressed X-linked protein 1 : encoding protein Brain-expressed X-linked protein 2 : encoding protein Brain expressed, X-linked 4 : encoding protein Coiled coil domain containing protein 120 : encoding protein Coiled-coil domain containing 22 : CD99 antigen-like protein 2 : encoding protein Chordin-like 1 encoding protein Charcot-Marie-Tooth neuropathy, X-linked 2 (recessive) encoding protein Charcot-Marie-Tooth neuropathy, X-linked 3 (dominant) : encoding protein Cancer/testis antigen family 45, member A5 : encoding protein hypothetical protein LOC79742 : Chromosome X open reading frame 40 : chromosome X open reading frame 49. encoding protein : encoding protein Chromosome X Open Reading Frame 66 : encoding protein Uncharacterized protein CXorf67 : encoding protein Dachshund homolog 2 : encoding protein EF-hand domain (C-terminal) containing 2 encoding protein ERCC excision repair 6 like, spindle assembly checkpoint helicase : Factor VIII intron 22 protein : encoding protein Family with sequence similarity 120C : Family with sequence similarity 122 member B : encoding protein Family with sequence similarity 122C : CAAX box protein 1 : Family with sequence similarity 50 member A : Fetal and adult testis-expressed transcript protein : encoding a long non-coding RNA FMR1 antisense RNA 1 : encoding protein FERM and PDZ domain containing 3 : encoding protein FUN14 domain containing 1 : FUN14 domain-containing protein 2 : encoding G antigen 12F protein : encoding G antigen 2A protein : encoding GATA1 transcription factor encoding protein G protein nucleolar 3 like : G-protein coupled receptor-associated sorting protein 2 : encoding protein GRIP1-associated protein 1 : encoding enzyme Haloacid dehalogenase-like hydrolase domain-containing protein 1A encoding protein LAS1-like protein : encoding protein Melanoma-associated antigen 2 encoding protein Melanoma antigen family A, 5 : encoding protein Melanoma antigen family A, 8 : encoding protein Melanoma-associated antigen D4 : encoding protein Magnesium transporter protein 1 : encoding protein Muscleblind-like protein 3 : encoding microRNA MicroRNA 222 : encoding microRNA MicroRNA 361 : encoding protein MicroRNA 660 : encoding protein Mortality factor 4-like protein 2 : encoding protein Motile sperm domain containing 1 : encoding protein Motile sperm domain containing 2 : encoding protein NF-kappa-B-repressing factor : encoding enzyme Nik-related protein kinase : encoding protein OTU deubiquitinase 5 : encoding protein PAS domain-containing protein 1 :encoding a protein of unestablished function : encoding a protein of unestablished function : encoding enzyme Choline-phosphate cytidylyltransferase B : encoding enzyme Peptidyl-prolyl cis-trans isomerase NIMA-interacting 4 : encoding protein Placenta-specific protein 1 : encoding protein Proteolipid protein 2 : encoding protein Replication protein A 30 kDa subunit : encoding protein Ribosomal protein S6 kinase, 90kDa, polypeptide 6 : encoding protein Ras-related GTP-binding protein B : encoding protein Splicing factor, arginine/serine-rich 17A : encoding protein SLIT and NTRK-like protein 2 : encoding protein Probable global transcription activator SNF2L1 : encoding enzyme Spermine synthase : encoding protein Translocon-associated protein subunit delta : encoding protein TATA-box binding protein associated factor 7-like : encoding protein Transcription elongation factor A protein-like 1 : encoding protein Transcription elongation factor A protein-like 4 : encoding protein THO complex subunit 2 : encoding protein Protein FAM156A : encoding protein Transmembrane protein 47 : encoding enzyme Trimethyllysine dioxygenase, mitochondrial encoding protein Tenomodulin (also referred to as tendin, myodulin, Tnmd and TeM) encoding protein Trafficking protein particle complex subunit 2 : encoding enzyme Three prime repair exonuclease 2 : encoding protein Trophinin : encoding protein Testis-specific Y-encoded-like protein 2 : encoding enzyme Ubiquitin carboxyl-terminal hydrolase 51 : encoding protein Protein YIPF6 : encoding protein ZC3H12B : encoding protein ZFP92 zinc finger protein : encoding protein Zinc finger MYM-type protein 3 : encoding protein Zinc finger protein 157 encoding protein Zinc finger protein 182 : encoding protein Zinc finger protein 275 : encoding protein Zinc finger protein 674

Structure Edit

It is theorized by Ross et al. 2005 and Ohno 1967 that the X chromosome is at least partially derived from the autosomal (non-sex-related) genome of other mammals, evidenced from interspecies genomic sequence alignments.

The X chromosome is notably larger and has a more active euchromatin region than its Y chromosome counterpart. Further comparison of the X and Y reveal regions of homology between the two. However, the corresponding region in the Y appears far shorter and lacks regions that are conserved in the X throughout primate species, implying a genetic degeneration for Y in that region. Because males have only one X chromosome, they are more likely to have an X chromosome-related disease.

It is estimated that about 10% of the genes encoded by the X chromosome are associated with a family of "CT" genes, so named because they encode for markers found in both tumor cells (in cancer patients) as well as in the human testis (in healthy patients). [19]

Role in disease Edit

Numerical abnormalities Edit

  • Klinefelter syndrome is caused by the presence of one or more extra copies of the X chromosome in a male's cells. Extra genetic material from the X chromosome interferes with male sexual development, preventing the testicles from functioning normally and reducing the levels of testosterone.
  • Males with Klinefelter syndrome typically have one extra copy of the X chromosome in each cell, for a total of two X chromosomes and one Y chromosome (47,XXY). It is less common for affected males to have two or three extra X chromosomes (48,XXXY or 49,XXXXY) or extra copies of both the X and Y chromosomes (48,XXYY) in each cell. The extra genetic material may lead to tall stature, learning and reading disabilities, and other medical problems. Each extra X chromosome lowers the child's IQ by about 15 points, [20][21] which means that the average IQ in Klinefelter syndrome is in general in the normal range, although below average. When additional X and/or Y chromosomes are present in 48,XXXY, 48,XXYY, or 49,XXXXY, developmental delays and cognitive difficulties can be more severe and mild intellectual disability may be present.
  • Klinefelter syndrome can also result from an extra X chromosome in only some of the body's cells. These cases are called mosaic 46,XY/47,XXY.

Triple X syndrome (also called 47,XXX or trisomy X):

  • This syndrome results from an extra copy of the X chromosome in each of a female's cells. Females with trisomy X have three X chromosomes, for a total of 47 chromosomes per cell. The average IQ of females with this syndrome is 90, while the average IQ of unaffected siblings is 100. [22] Their stature on average is taller than normal females. They are fertile and their children do not inherit the condition. [23]
  • Females with more than one extra copy of the X chromosome (48, XXXX syndrome or 49, XXXXX syndrome) have been identified, but these conditions are rare.
  • This results when each of a female's cells has one normal X chromosome and the other sex chromosome is missing or altered. The missing genetic material affects development and causes the features of the condition, including short stature and infertility.
  • About half of individuals with Turner syndrome have monosomy X (45,X), which means each cell in a woman's body has only one copy of the X chromosome instead of the usual two copies. Turner syndrome can also occur if one of the sex chromosomes is partially missing or rearranged rather than completely missing. Some women with Turner syndrome have a chromosomal change in only some of their cells. These cases are called Turner syndrome mosaics (45,X/46,XX).

X-linked recessive disorders Edit

Sex linkage was first discovered in insects, e.g., T. H. Morgan's 1910 discovery of the pattern of inheritance of the white eyes mutation in Drosophila melanogaster. [24] Such discoveries helped to explain x-linked disorders in humans, e.g., haemophilia A and B, adrenoleukodystrophy, and red-green color blindness.

Other disorders Edit

XX male syndrome is a rare disorder, where the SRY region of the Y chromosome has recombined to be located on one of the X chromosomes. As a result, the XX combination after fertilization has the same effect as a XY combination, resulting in a male. However, the other genes of the X chromosome cause feminization as well.

X-linked endothelial corneal dystrophy is an extremely rare disease of cornea associated with Xq25 region. Lisch epithelial corneal dystrophy is associated with Xp22.3.

Adrenoleukodystrophy, a rare and fatal disorder that is carried by the mother on the x-cell. It affects only boys between the ages of 5 and 10 and destroys the protective cell surrounding the nerves, myelin, in the brain. The female carrier hardly shows any symptoms because females have a copy of the x-cell. This disorder causes a once healthy boy to lose all abilities to walk, talk, see, hear, and even swallow. Within 2 years after diagnosis, most boys with Adrenoleukodystrophy die.

Role in mental abilities and intelligence Edit

The X-chromosome has played a crucial role in the development of sexually selected characteristics for over 300 million years. During that time it has accumulated a disproportionate number of genes concerned with mental functions. For reasons that are not yet understood, there is an excess proportion of genes on the X-chromosome that are associated with the development of intelligence, with no obvious links to other significant biological functions. [25] [26] In other words, a significant proportion of genes associated with intelligence is passed on to the male offspring from the maternal side and to the female offspring from either/both maternal and paternal side. There has also been interest in the possibility that haploinsufficiency for one or more X-linked genes has a specific impact on development of the Amygdala and its connections with cortical centres involved in social–cognition processing or the ‘social brain'. [25] [27] [ clarification needed ]


Inheritance Inheritance

Fragile X syndrome (FXS) is inherited in an X-linked dominant manner. A condition is X-linked if the responsible gene is located on the X chromosome . The inheritance is dominant if having only one changed ( mutated ) copy of the responsible gene is enough to cause symptoms of the condition. [4]

In women who carry an FMR1 gene premutation (approximately 55 to 200 CGG repeats), the repeats can expand to more than 200 repeats in their cells that develop into eggs. This means that women with a premutation (or a full mutation) have an increased risk to have a child with FXS. [4] [5] The size of the risk corresponds to the number of CGG repeats they have. [5] By contrast, men with premutations are not at risk for the repeats expanding to over 200 when passing the gene to offspring. However, men with a premutation will pass the premutation on to all of their daughters and none of their sons. [4] [5] This is because boys receive only a Y chromosome from their fathers. [4]


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