X chromosome

X chromosome
Human X chromosome (after G-banding).
X chromosome in human male karyogram.
Features
Length (bp)	156,040,895
Number of genes	1,805
Type	Allosome
Centromere position	Submetacentric[1]
Identifiers
RefSeq	NC_000023
GenBank	CM000685

Ideogram of human X chromosome. Mbp means mega base pair. See locus for other notation.

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 (allosomes) in many animal species, including mammals (the other is the Y chromosome), and is found in both males and females. 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.^[2]

Humans

Function

The X chromosome in humans spans more than 153 million base pairs (the building material of DNA). It represents about 2000 out of 20,000 - 25,000 genes. Each person usually 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 (father's side), 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^[3] genes compared to the Y chromosome containing 78^[4] 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 of 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. 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.^[5]

Structure

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).^[6]

Role in diseases

Numerical abnormalities

Klinefelter syndrome:

• 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,^[7][8] 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.^[9] Their stature on average is taller than normal females. They are fertile and their children do not inherit the condition.^[10]
• 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 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

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

Role in mental abilities and intelligence

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.^[11][12] There has also been interest in the possibility that haploin sufficiency 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'.^[11][13]

Discovery

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. 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,^[14] which later became X chromosome after it was established that it was indeed a chromosome.^[15]

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 only take on a well defined shape 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.^[16]

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.^[14]

See also

• List of X-STR markers
• Sex linkage
• X-inactivation
• Y chromosome

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. "Table 2.3: Human chromosome groups". Human Molecular Genetics (2nd ed.). Garland Science. 1999.
2. Angier, Natalie (2007-05-01). "For Motherly X Chromosome, Gender Is Only the Beginning". New York Times. Retrieved 2007-05-01.
3. Macmillan Science Library (2001). "Genetics on X Chromosome".
4. Richard Harris (2003). "Scientists Decipher Y Chromosome".
5. 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. PMID 15772666.
6. Ross M, et al. (2005). "The DNA sequence of the human X chromosome". Nature 434 (7031): 325–37. doi:10.1038/nature03440. PMC 2665286. PMID 15772651.
7. Harold Chen, Ian Krantz, Mary L Windle, Margaret M McGovern, Paul D Petry, Bruce Buehler (2013-02-22). "Klinefelter Syndrome Pathophysiology". Medscape. Retrieved 2014-07-18.
8. Visootsak J, Graham JM (2006). "Klinefelter syndrome and other sex chromosomal aneuploidies". Orphanet J Rare Dis 1: 42. doi:10.1186/1750-1172-1-42. PMC 1634840. PMID 17062147.
9. Bender B, Puck M, Salbenblatt J, Robinson A. (1986). Smith S, ed. Cognitive development of children with sex chromosome abnormalities. San Diego: College Hill Press. pp. 175–201.
10. "Triple X syndrome". Genetics Home Reference. 2014-07-14. Retrieved 2014-07-18.
11. Skuse, David H. (2005-04-15). "X-linked genes and mental functioning". Human Molecular Genetics. 14 Spec No 1: R27–32. doi:10.1093/hmg/ddi112. ISSN 0964-6906. PMID 15809269.
12. Zhao, Min; Kong, Lei; Qu, Hong (2014-02-25). "A systems biology approach to identify intelligence quotient score-related genomic regions, and pathways relevant to potential therapeutic treatments". Scientific Reports 4. doi:10.1038/srep04176. ISSN 2045-2322. PMC 3933868. PMID 24566931.
13. Startin, Carla M.; Fiorentini, Chiara; de Haan, Michelle; Skuse, David H. (2015-01-01). "Variation in the X-linked EFHC2 gene is associated with social cognitive abilities in males". PLOS ONE 10 (6): e0131604. doi:10.1371/journal.pone.0131604. ISSN 1932-6203. PMC 4481314. PMID 26107779.
14. James Schwartz, In Pursuit of the Gene: From Darwin to DNA, pages 155-158, Harvard University Press, 2009 ISBN 0674034910
15. David Bainbridge, 'The X in Sex: How the X Chromosome Controls Our Lives, pages 3-5, Harvard University Press, 2003 ISBN 0674016211.
16. Bainbridge, pages 65-66