X-chromosome

The sex chromosome associated with female characteristics in mammals, occurring paired in the female and single in the male.

A sex chromosome that in humans and many other species is present in both male and female. The male somatic cell consists of one X chromosome and one Y chromosome; the female somatic cell carries two X chromosomes. All female gametes carry the X chromosome, whereas half of the male gametes possess the X chromosome and the other half the Y chromosome.

The X chromosome occupies an exceptional place in the mammalian genome. Together with the Y chromosome, the X chromosome differentiates the sexes. Males have one X chromosome and a Y chromosome and females have two X chromosomes. Because of this fundamental genetic difference, diseases caused by genes located on the X chromosome affect males and females differently and thus present unusual inheritance patterns. Furthermore, equal dosage of expression from genes on the X chromosome is restored between males and females by a special process called X inactivation, in which genes on one of the female X chromosomes are shut down.

Role of the X Chromosome in Sex Differentiation

The so-called sex chromosomes differentiate the sexes: females are XX and males XY, which is the basis for the development of a fetus into a girl or a boy (Figure 1). All other chromosomes (called autosomes) are present in two copies in both males and females. It is the presence of a Y chromosome that determines the male sex of a baby, because the Y carries a gene that induces undifferentiated gonads to turn into testes in the fetus. The number of X chromosomes does not change the sex of a baby. Indeed, people with a single X chromosome and no Y chromosome are females with Turner syndrome, a rare genetic disorder characterized by short stature and infertility. Conversely, people who have two X chromosomes and a Y chromosome are males with Klinefelter's syndrome, which includes tall stature and infertility.

Sex Chromosome Evolution

Present-day sex chromosomes look very different from each other: The X chromosome comprises about 5 percent of the human genome, and contains about 2,000 genes, while the Y chromosome is quite small and contains only about 50 genes (Figure 1). This striking difference in size and gene content between the sex chromosomes makes it hard to believe that they are actually ancient partners in a pair of chromosomes that originally were very similar. Once sex became determined by a genetic signal from the Y, the sex chromosomes largely stopped recombining in germ cells. Degeneration of Y genes ensued, together with accumulation of genes that are advantageous to males on the Y chromosome, such as genes involved in testicular function and in male fertility. Similar genes appear to have accumulated on the X chromosome, so that the X chromosome also plays an important role in sperm production. The X chromosome may also have a prominent role in brain function and intelligence. A strong argument in favor of this intriguing but still controversial theory is that mental disability is more common in males.

The X Chromosome and Diseases

Some diseases affect males but not females in a family. Such diseases, called X-linked recessives, are often caused by mutations in genes located on the X chromosome, called X-linked genes. An X-linked disease is transmitted from the mother, not from the father, to an affected male, and an affected male will transmit a copy of the mutant gene to all his daughters. A famous example of an X-linked disease is hemophilia A. The blood of hemophiliac males fails to coagulate properly, leading to thinning of the blood and unstoppable bleeding after injury. This disease was recognized in the royal family of Queen Victoria, where examination of the huge pedigree readily confirmed recessive X-linked inheritance. Only males were affected, having inherited an X chromosome with a copy of a mutated gene from their healthy mothers, who were carriers of the disease. The mutated gene in hemophilia A was identified as factor VIII, a gene that encodes a protein essential for proper clotting of the blood. Males with a mutated gene cannot compensate since they have only one X chromosome, whereas female carriers have one normal gene that can compensate for the diseased gene. This typical recessive X-linked inheritance has been described for a variety of genes.

Dominant X-linked mutations, in which female carriers with just one mutated copy of the gene are affected, are rare. One example of such a disease is vitamin D-resistant rickets, in which people develop skeletal deformities. Generally, the disease is less severe in females than in males, because of X inactivation (see below). A famous X-linked disorder with inheritance that cannot be classified as either recessive or dominant is fragile X mental retardation. The fragile X chromosome bears its name because it displays a site susceptible to chromosome breakage. The mutated gene at the site contains a triplet repeat expansion, in which a series of three consecutive bases are copied multiple times. This causes the gene to be turned off by secondary changes in its structure. Affected males have severe mental retardation and female carriers can also be affected.

X Inactivation

X inactivation consists of the silencing of genes on one of the X chromo somes in the female fetus. This silencing, which results in the absence of protein products from the inactivated genes, restores equal X-linked gene expression between the sexes. So, in the end, females have only one active X chromosome, like males (Figure 1). In the case of individuals with an abnormal number of X chromosomes, such as three X chromosomes, only one X will remain active.

One may wonder then why females do not express deleterious recessive X-linked mutations like males. This is because X inactivation is random, and a female is a mosaic of cells with either her paternal X active or her maternal X active (Figure 1). Thanks to this randomness, female carriers usually have plenty of cells with the normal gene remaining functional. Sometimes, there is even cell selection in carrier females, leading to skewed X inactivation in favor of the normal gene remaining functional. One intriguing feature of X inactivation is that it does not affect all X-linked genes. About 20 percent of genes "escape" X inactivation in humans. With a higher expression level in females than in males, such genes could perhaps play a role in female-specific functions. In males, some of these unusual genes have retained a functionally similar gene on the Y, as remnants of the ancient partnership of the sex chromosomes.

X inactivation was discovered in 1961 by Mary Lyon, a British scientist who studied mice. Thus, another name for this phenomenon is "Lyonization." The physiologic or normal regulation of expression of many genes is at the level of the individual gene. In contrast, X inactivation regulates a whole chromosome that comprises a huge number of genes. Special mechanisms of regulation evolved to initiate X inactivation through the action of a master gene on the X. Once one of the two X chromosomes (maternal or paternal) is randomly chosen to become inactivated in a given fetal cell, it will be faithfully maintained in this state in the progeny of the cell. The stability of the inactivation is mediated by a series of complex molecular changes called epigenetic modifications. X inactivation is lost in only one type of cells, the female germ cells, where both X chromosomes are functional for transmission to the next generation. Thus, X inactivation involves special mechanisms of initiation, maintenance, and reactivation. Much work still needs to be done to fully understand the fascinating roles of the X chromosome and its regulation.

Bibliography

Miller, Orlando J., and Eeva Therman. Human Chromosomes. New York: Springer-Verlag, 2001.

Nussbaum, Robert L., Rod R. McInnes, and Huntington F. Willard. Thompson & Thompson Genetics in Medicine. Philadelphia, PA: Saunders, 2001.

Wang, Jeremy P., et al. "An Abundance of X-linked Genes Expressed in Spermatogonia." Nature Genetics 27, no. 4 (2001): 422-426.

—Christine M. Disteche

Sex chromosome present in both sexes. In males who have one X chromosome and one Y chromosome, the alleles carried on the X chromosomes are always expressed whether they are dominant or recessive.

Scheme of the X chromatid

Nucleus of a female amniotic fluid cell. Top: Both X-chromosome territories are detected by FISH. Shown is a single optical section made with a confocal microscope. Bottom: Same nucleus stained with DAPI and recorded with a CCD camera. The Barr body is indicated by the arrow, it identifies the inactive X (Xi).

The X chromosome is one of the two sex-determining chromosomes in many animal species, including mammals (the other is the Y chromosome). It is a part of the XY sex-determination system and X0 sex-determination system. The X chromosome was named for its unique properties by early researchers, which resulted in the naming of its counterpart Y chromosome, for the next letter in the alphabet, after it was discovered later.^[1]

Contents 1 In humans 1.1 Function 1.2 Structure 2 Role in diseases 2.1 Numerical abnormalities 2.2 Other disorders 3 See also 4 References

In humans

Function

The sex chromosomes X X are one of the 23 homologous pairs of chromosomes in a female. The X chromosome spans more than 153 million base pairs (the building material of DNA) and represents about 5% of the total DNA in women's cells, 2.5% in men's.

Each person normally has one pair of sex chromosomes in each cell. Females have two X chromosomes, whereas males 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, and one X chromosome from her mother.

Identifying genes on each chromosome is an active area of genetic research. Because researchers use different approaches to predict the number of genes on each chromosome, the estimated number of genes varies. The X chromosome contains about 2000^[2] genes compared to the Y chromosome containing 78^[3] genes, out of the estimated 20,000 to 25,000 total genes in the human genome. Genetic disorders that are due to mutations in genes on the X chromosome are described as X linked.

The X chromosome carries a couple thousand 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 randomly and 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. X-inactivation ensures that females, like males, have one functional copy of the X chromosome in each body cell. It was previously assumed that only one copy is actively used. However, recent research suggests that the Barr body may be more biologically active than was previously supposed.^[4]

Structure

The X-chromosome is a remarkably gene-poor region. It is composed primarily of repeated segments of DNA that do not code for proteins or any known function. Only 1.7% of the chromosome encodes for any functional proteins at all - lowest density of genes to date - and the genes themselves are very short compared to the length of the average human gene. 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). These CT genes found on the X-chromosome are estimated to account for about 90% of all the CT genes encoded within the human genome. Due to their relative abundance, it is, thus, hypothesized that these genes (and thus the X-chromosome) confer evolutionary fitness to human males.^[5]

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.

Role in diseases

Numerical abnormalities

Klinefelter's syndrome:

• Klinefelter's 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's 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 mental retardation and other medical problems.
• Klinefelter's 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 their normal siblings is 100 [1]. Their stature on average is taller than for normal females. They are fertile and their children do not inherit the condition. [2]

• 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.

Turner syndrome:

• 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 characteristic 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).

Other disorders

Further information: X-linked recessive and X-linked dominant

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.

Megalocornea 1 is associated with Xq21.3-q22

See also

• Sex linkage
• List of DXS markers

References

• Earlier versions of this article contain material from the National Library of Medicine (http://www.nlm.nih.gov/copyright.html) , a part of the National Institutes of Health (USA,) which, as a US government publication, is in the public domain.

1. ^ Angier, Natalie (2007-05-01). "For Motherly X Chromosome, Gender Is Only the Beginning". New York Times. http://www.nytimes.com/2007/05/01/science/01angi.html. Retrieved 2007-05-01. 
2. ^ Macmillan Science Library (2001). "Genetics on X Chromosome". http://www.bookrags.com/X_chromosome#br_2. 
3. ^ Richard Harris (2003). "Scientists Decipher Y Chromosome". http://www.npr.org/templates/story/story.php?storyId=1303260. 
4. ^ Carrel L, Willard H (2005). "X-inactivation profile reveals extensive variability in X-linked gene expression in females". Nature 434 (7031): 400–4. doi:10.1038/nature03479. 
5. ^ Ross M et al. (2005). "The DNA sequence of the human X chromosome". Nature 434 (7031): 325–37. doi:10.1038/nature03440. http://www.nature.com/nature/journal/v434/n7031/full/nature03440.html. 

v • d • e Human chromosomes Autosome 1 · 2 · 3 · 4 · 5 · 6 · 7 · 8 · 9 · 10 · 11 · 12 · 13 · 14 · 15 · 16 · 17 · 18 · 19 · 20 · 21 · 22 Sex chromosome X · Y · Pseudoautosomal region

This entry is from Wikipedia, the leading user-contributed encyclopedia. It may not have been reviewed by professional editors (see full disclaimer)