X chromosome

The X chromosome is one of the two sex-determining chromosomes (allosomes) in many organisms, 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, following its subsequent discovery.[5]

Human X chromosome
Human X chromosome (after G-banding)
X chromosome in human male karyogram
Features
Length (bp)156,040,895 bp
(GRCh38)[1]
No. of genes804 (CCDS)[2]
TypeAllosome
Centromere positionSubmetacentric[3]
(61.0 Mbp[4])
Complete gene lists
CCDSGene list
HGNCGene list
UniProtGene list
NCBIGene list
External map viewers
EnsemblChromosome X
EntrezChromosome X
NCBIChromosome X
UCSCChromosome X
Full DNA sequences
RefSeqNC_000023 (FASTA)
GenBankCM000685 (FASTA)

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 (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 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.[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]

Inheritance pattern
The number of possible ancestors on the X chromosome inheritance line at a given ancestral generation follows the Fibonacci sequence. (After Hutchison, L. "Growing the Family Tree: The Power of DNA in Reconstructing Family Relationships".[9])

Luke Hutchison noticed that a number of possible ancestors on the X chromosome inheritance line at a given ancestral generation follows the Fibonacci sequence.[9] A male individual has an X chromosome, which he received from his mother, and a Y chromosome, which he received from his father. The male counts as the "origin" of his own X chromosome (), and at his parents' generation, his X chromosome came from a single parent (). The male's mother received one X chromosome from her mother (the son's maternal grandmother), and one from her father (the son's maternal grandfather), so two grandparents contributed to the male descendant's X chromosome (). The maternal grandfather received his X chromosome from his mother, and the maternal grandmother received X chromosomes from both of her parents, so three great-grandparents contributed to the male descendant's X chromosome (). Five great-great-grandparents contributed to the male descendant's X chromosome (), etc. (Note that this assumes that all ancestors of a given descendant are independent, but if any genealogy is traced far enough back in time, ancestors begin to appear on multiple lines of the genealogy, until eventually, a population founder appears on all lines of the genealogy.)

Humans

Function
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 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 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.[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

Number of genes

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
CCDS804—— [2] 2016-09-08
HGNC825260606 [13] 2017-05-12
Ensembl841639871 [14] 2017-03-29
UniProt839—— [15] 2018-02-28
NCBI874494879 [16][17][18] 2017-05-19

Gene list

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

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).[19]

Role in disease

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,[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.

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).

X-linked recessive disorders

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

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

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

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]

Cytogenetic band
G-banding ideograms of human X chromosome
G-banding ideogram of human X chromosome in resolution 850 bphs. Band length in this diagram is proportional to base-pair length. This type of ideogram is generally used in genome browsers (e.g. Ensembl, UCSC Genome Browser).
G-banding patterns of human X chromosome in three different resolutions (400,[28] 550[29] and 850[4]). Band length in this diagram is based on the ideograms from ISCN (2013).[30] This type of ideogram represents actual relative band length observed under a microscope at the different moments during the mitotic process.[31]
G-bands of human X chromosome in resolution 850 bphs[4]
Chr. Arm[32] Band[33] ISCN
start[34]		 ISCN
stop[34]		 Basepair
start		 Basepair
stop		 Stain[35] Density
Xp 22.33032314,400,000 gneg
Xp 22.323235044,400,0016,100,000 gpos50
Xp 22.315048666,100,0019,600,000 gneg
Xp 22.286610349,600,00117,400,000 gpos50
Xp 22.131034134517,400,00119,200,000 gneg
Xp 22.121345144819,200,00121,900,000 gpos50
Xp 22.111448157721,900,00124,900,000 gneg
Xp 21.31577178424,900,00129,300,000 gpos100
Xp 21.21784186229,300,00131,500,000 gneg
Xp 21.11862212031,500,00137,800,000 gpos100
Xp 11.42120243037,800,00142,500,000 gneg
Xp 11.32430262442,500,00147,600,000 gpos75
Xp 11.232624294847,600,00150,100,000 gneg
Xp 11.222948312950,100,00154,800,000 gpos25
Xp 11.213129320654,800,00158,100,000 gneg
Xp 11.13206329758,100,00161,000,000 acen
Xq 11.13297349161,000,00163,800,000 acen
Xq 11.23491362063,800,00165,400,000 gneg
Xq 123620382765,400,00168,500,000 gpos50
Xq 13.13827413768,500,00173,000,000 gneg
Xq 13.24137429273,000,00174,700,000 gpos50
Xq 13.34292444774,700,00176,800,000 gneg
Xq 21.14447473276,800,00185,400,000 gpos100
Xq 21.24732480985,400,00187,000,000 gneg
Xq 21.314809510787,000,00192,700,000 gpos100
Xq 21.325107518492,700,00194,300,000 gneg
Xq 21.335184543094,300,00199,100,000 gpos75
Xq 22.15430570199,100,001103,300,000 gneg
Xq 22.257015843103,300,001104,500,000 gpos50
Xq 22.358436050104,500,001109,400,000 gneg
Xq 2360506322109,400,001117,400,000 gpos75
Xq 2463226619117,400,001121,800,000 gneg
Xq 2566197059121,800,001129,500,000 gpos100
Xq 26.170597253129,500,001131,300,000 gneg
Xq 26.272537395131,300,001134,500,000 gpos25
Xq 26.373957602134,500,001138,900,000 gneg
Xq 27.176027808138,900,001141,200,000 gpos75
Xq 27.278087886141,200,001143,000,000 gneg
Xq 27.378868145143,000,001148,000,000 gpos100
Xq 2881458610148,000,001156,040,895 gneg
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See also

References
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  2. "Search results - X[CHR] AND "Homo sapiens"[Organism] AND ("has ccds"[Properties] AND alive[prop]) - Gene". NCBI. CCDS Release 20 for Homo sapiens. 2016-09-08. Retrieved 2017-05-28.
  3. Tom Strachan; Andrew Read (2 April 2010). Human Molecular Genetics. Garland Science. p. 45. ISBN 978-1-136-84407-2.
  4. Genome Decoration Page, NCBI. Ideogram data for Homo sapience (850 bphs, Assembly GRCh38.p3). Last update 2014-06-03. Retrieved 2017-04-26.
  5. Angier, Natalie (2007-05-01). "For Motherly X Chromosome, Gender Is Only the Beginning". New York Times. Retrieved 2007-05-01.
  6. James Schwartz, In Pursuit of the Gene: From Darwin to DNA, pages 155-158, Harvard University Press, 2009 ISBN 0674034910
  7. David Bainbridge, 'The X in Sex: How the X Chromosome Controls Our Lives, pages 3-5, Harvard University Press, 2003 ISBN 0674016211.
  8. Bainbridge, pages 65-66
  9. Hutchison, Luke (September 2004). "Growing the Family Tree: The Power of DNA in Reconstructing Family Relationships" (PDF). Proceedings of the First Symposium on Bioinformatics and Biotechnology (BIOT-04). Retrieved 2016-09-03.
  10. 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.
  11. Veneti Z, Gkouskou KK, Eliopoulos AG (July 2017). "Polycomb Repressor Complex 2 in Genomic Instability and Cancer". Int J Mol Sci. 18 (8): 1657. doi:10.3390/ijms18081657. PMC 5578047. PMID 28758948.
  12. Pertea M, Salzberg SL (2010). "Between a chicken and a grape: estimating the number of human genes". Genome Biol. 11 (5): 206. doi:10.1186/gb-2010-11-5-206. PMC 2898077. PMID 20441615.
  13. "Statistics & Downloads for chromosome X". HUGO Gene Nomenclature Committee. 2017-05-12. Retrieved 2017-05-19.
  14. "Chromosome X: Chromosome summary - Homo sapiens". Ensembl Release 88. 2017-03-29. Retrieved 2017-05-19.
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  18. "Search results - X[CHR] AND "Homo sapiens"[Organism] AND ("genetype pseudo"[Properties] AND alive[prop]) - Gene". NCBI. 2017-05-19. Retrieved 2017-05-20.
  19. 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.
  20. 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.
  21. 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.
  22. 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.
  23. "Triple X syndrome". Genetics Home Reference. 2014-07-14. Retrieved 2014-07-18.
  24. Morgan, T. H. (1910). "Sex-limited inheritance in Drosophila". Science. 32 (812): 120–122. Bibcode:1910Sci....32..120M. doi:10.1126/science.32.812.120. PMID 17759620.
  25. 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.
  26. 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: 4176. doi:10.1038/srep04176. ISSN 2045-2322. PMC 3933868. PMID 24566931.
  27. 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.
  28. Genome Decoration Page, NCBI. Ideogram data for Homo sapience (400 bphs, Assembly GRCh38.p3). Last update 2014-03-04. Retrieved 2017-04-26.
  29. Genome Decoration Page, NCBI. Ideogram data for Homo sapience (550 bphs, Assembly GRCh38.p3). Last update 2015-08-11. Retrieved 2017-04-26.
  30. International Standing Committee on Human Cytogenetic Nomenclature (2013). ISCN 2013: An International System for Human Cytogenetic Nomenclature (2013). Karger Medical and Scientific Publishers. ISBN 978-3-318-02253-7.
  31. Sethakulvichai, W.; Manitpornsut, S.; Wiboonrat, M.; Lilakiatsakun, W.; Assawamakin, A.; Tongsima, S. (2012). Estimation of band level resolutions of human chromosome images. In Computer Science and Software Engineering (JCSSE), 2012 International Joint Conference on. pp. 276–282. doi:10.1109/JCSSE.2012.6261965. ISBN 978-1-4673-1921-8.
  32. "p": Short arm; "q": Long arm.
  33. For cytogenetic banding nomenclature, see article locus.
  34. These values (ISCN start/stop) are based on the length of bands/ideograms from the ISCN book, An International System for Human Cytogenetic Nomenclature (2013). Arbitrary unit.
  35. gpos: Region which is positively stained by G banding, generally AT-rich and gene poor; gneg: Region which is negatively stained by G banding, generally CG-rich and gene rich; acen Centromere. var: Variable region; stalk: Stalk.
  • National Institutes of Health. "X chromosome". Genetics Home Reference. Retrieved 2017-05-06.
  • "X chromosome". Human Genome Project Information Archive 1990–2003. Retrieved 2017-05-06.
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