Editing Centromere

{{short description|Specialized DNA sequence of a chromosome that links a pair of sister chromatids}}
{{distinguish|Centisome|Centrosome}}
[[Image:Chromosome.svg|thumb|In this diagram of a duplicated chromosome, (2) identifies the centromere—the region that joins the two [[sister chromatids]], or each half of the chromosome. In prophase of mitosis, specialized regions on centromeres called [[kinetochore]]s attach chromosomes to spindle fibers.]]

The '''centromere''' links a pair of sister [[chromatid]]s together during cell division. This constricted region of chromosome connects the sister chromatids, creating a short arm (p) and a long arm (q) on the chromatids. During [[mitosis]], [[Spindle apparatus|spindle fibers]] attach to the centromere via the [[kinetochore]].

The physical role of the centromere is to act as the site of assembly of the [[kinetochores]] – a highly complex multiprotein structure that is responsible for the actual events of [[chromosome segregation]] – i.e. binding [[microtubules]] and signaling to the cell cycle machinery when all chromosomes have adopted correct attachments to the [[Spindle apparatus|spindle]], so that it is safe for [[cell division]] to proceed to completion and for cells to enter [[anaphase]].

There are, broadly speaking, two types of centromeres. "Point centromeres" bind to specific [[protein]]s that recognize particular [[DNA]] [[Nucleic acid sequence|sequences]] with high efficiency. Any piece of DNA with the point centromere DNA sequence on it will typically form a centromere if present in the appropriate species. The best characterized point centromeres are those of the budding yeast, ''[[Saccharomyces cerevisiae]]''. "Regional centromeres" is the term coined to describe most centromeres, which typically form on regions of preferred DNA sequence, but which can form on other DNA sequences as well. The signal for formation of a regional centromere appears to be [[Epigenetics|epigenetic]]. Most organisms, ranging from the fission yeast ''[[Schizosaccharomyces pombe]]'' to humans, have regional centromeres.

Regarding mitotic chromosome structure, centromeres represent a constricted region of the chromosome (often referred to as the primary constriction) where two identical [[sister chromatids]] are most closely in contact. When cells enter mitosis, the sister chromatids (the two copies of each chromosomal DNA molecule resulting from [[DNA replication]] in chromatin form) are linked along their length by the action of the [[cohesin]] complex. It is now believed that this complex is mostly released from chromosome arms during prophase, so that by the time the chromosomes line up at the mid-plane of the mitotic spindle (also known as the metaphase plate), the last place where they are linked with one another is in the chromatin in and around the centromere.

== Position ==
[[File:Centromere Placement.svg|thumb|'''Classifications of Chromosomes'''<br />
{| class="wikitable sortable" style="text-align: left;"
|-
| '''I''' || Telocentric || Centromere placement very close to the top, p arms barely visible if visible at all.
|-
| '''II''' || Acrocentric || q arms are still much longer than the p arms, but the p arms are longer than those in telocentric.
|-
| '''III''' || Submetacentric || p and q arms are very close in length but not equal.
|-
| '''IV''' || Metacentric || p and q arms are equal in length.
|-
|}
'''A''': Short arm (p arm)<br />'''B''': Centromere<br />'''C''': Long arm (q arm)<br />'''D''': Sister Chromatids
]]
<!-- Subsections of this section are linked in [[Lund's Amphibious Rat]]-->
In humans, centromere positions define the chromosomal [[karyotype]], in which each chromosome has two arms, ''p'' (the shorter of the two) and ''q'' (the longer). The short arm 'p' is reportedly named for the French word "petit" meaning 'small'.<ref>{{cite web|url= http://thednaexchange.com/2011/05/02/p-q-solved-being-the-true-story-of-how-the-chromosome-got-its-name/|title= p + q = Solved, Being the True Story of How the Chromosome Got Its Name|date = 2011-05-03}}</ref> The position of the centromere relative to any particular linear chromosome is used to classify chromosomes as  metacentric, submetacentric, acrocentric, telocentric, or holocentric.<ref>{{Citation| work = Nikolay's Genetics Lessons|title=What different types of chromosomes exist?|date=2013-10-12|url=https://www.youtube.com/watch?v=0bfpOhbKEAk| archive-url=https://ghostarchive.org/varchive/youtube/20211211/0bfpOhbKEAk| archive-date=2021-12-11 | url-status=live|access-date=2017-05-28 | publisher = YouTube }}{{cbignore}}</ref><ref name="Levan A. 1964">{{cite journal | vauthors = Levan A, Fredga K, Sandberg AA | title = Nomenclature for centromeric position on chromosomes. | journal = Hereditas | date = December 1964 | volume = 52 | issue = 2 | pages = 201–220 | doi = 10.1111/j.1601-5223.1964.tb01953.x | doi-access =  }}</ref>

{| class="wikitable " style="font-size:95%;"
|+ Categorization of chromosomes according to the relative arms length<ref name="Levan A. 1964"/>
|-
! Centromere position
! Arms length ratio
! Sign
! Description
|-
|'''Medial ''sensu stricto'' '''
|1.0 – 1.6
|'''M'''
|'''[[#Metacentric|Metacentric]]'''
|-
|'''Medial region'''
|1.7
|'''m'''
|'''[[#Metacentric|Metacentric]]'''
|-
|'''Submedial'''
|3.0
|'''sm'''
|'''[[Submetacentric]]'''
|-
|'''Subterminal'''
|3.1 – 6.9
|'''st'''
|'''[[telocentric|Subtelocentric]]'''
|-
|'''Terminal region'''
|7.0
|'''t'''
|'''[[Acrocentric]]'''
|-
|'''Terminal ''sensu stricto'' '''
|'''''∞'''''
|'''T'''
|'''[[Telocentric]]'''
|-
|'''Notes'''
|'''''–'''''
|'''[[#Metacentric|Metacentric]]''': '''M'''+'''m'''
|'''[[Telocentric|Atelocentric]]''': '''M'''+'''m'''+'''sm'''+'''st'''+'''t'''
|-
|}

=== Metacentric ===
Metacentric means that the centromere is positioned midway between the chromosome ends, resulting in the arms being approximately equal in length. When the centromeres are metacentric, the chromosomes appear to be "x-shaped."

=== Submetacentric ===
Submetacentric means that the centromere is positioned below the middle, with one chromosome arm shorter than the other, often resulting in an L shape.

=== Acrocentric ===
An acrocentric chromosome's centromere is situated so that one of the chromosome arms is much shorter than the other. The "acro-" in acrocentric refers to the Greek word for "peak." The [[human genome]] has six acrocentric chromosomes, including five autosomal chromosomes ([[Chromosome 13 (human)|13]], [[Chromosome 14 (human)|14]], [[Chromosome 15 (human)|15]], [[Chromosome 21 (human)|21]], [[Chromosome 22 (human)|22]]) and the [[Y chromosome]].

Short acrocentric p-arms contain little genetic material and can be translocated without significant harm, as in a balanced [[Robertsonian translocation]]. In addition to some protein coding genes, human acrocentric p-arms also contain [[Nucleolus organizer region]]s (NORs), from which [[ribosomal RNA]] is transcribed. However, a proportion of acrocentric p-arms in cell lines and tissues from normal human donors do not contain detectable NORs.<ref>{{cite journal | vauthors = van Sluis M, van Vuuren C, Mangan H, McStay B | title = NORs on human acrocentric chromosome p-arms are active by default and can associate with nucleoli independently of rDNA | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 117 | issue = 19 | pages = 10368–10377 | date = May 2020 | pmid = 32332163 | pmc = 7229746 | doi = 10.1073/pnas.2001812117 | bibcode = 2020PNAS..11710368V | doi-access = free }}</ref> The [[Horse|domestic horse]] genome includes one metacentric chromosome that is [[Homologous chromosome|homologous]] to two acrocentric chromosomes in the [[Conspecificity|conspecific]] but undomesticated [[Przewalski's horse]]. This may reflect either fixation of a balanced Robertsonian translocation in domestic horses or, conversely, fixation of the fission of one metacentric chromosome into two acrocentric chromosomes in Przewalski's horses. A similar situation exists between the human and great ape genomes, with a reduction of two acrocentric chromosomes in the great apes to one metacentric chromosome in humans (see [[Karyotype#Aneuploidy|aneuploidy]] and the [[human chromosome 2]]).

Many diseases from the result of unbalanced translocations more frequently involve acrocentric chromosomes than other non-acrocentric chromosomes. Acrocentric chromosomes are usually located in and around the [[nucleolus]]. As a result, these chromosomes tend to be less densely packed than chromosomes in the nuclear periphery. Consistently, chromosomal regions that are less densely packed are also more prone to chromosomal translocations in cancers.

=== Telocentric ===
Telocentric chromosomes have a centromere at one end of the chromosome and therefore exhibit only one arm at the cytological (microscopic) level. They are not present in humans but can form through cellular chromosomal errors. Telocentric chromosomes occur naturally in many species, such as the [[house mouse]], in which all chromosomes except the Y are telocentric.

=== Subtelocentric ===
Subtelocentric chromosomes' centromeres are located between the middle and the end of the chromosomes, but reside closer to the end of the chromosomes.

==Centromere types==

=== Acentric ===
An acentric chromosome is fragment of a chromosome that lacks a centromere. Since centromeres are the attachment point for spindle fibers in cell division, acentric fragments are not evenly distributed to daughter cells during cell division. As a result, a daughter cell will lack the acentric fragment and deleterious consequences could occur.

Chromosome-breaking events can also generate acentric chromosomes or acentric fragments.   

===Dicentric===

A [[dicentric chromosome]] is an abnormal chromosome with two centromeres, which can be unstable through cell divisions. It can form through translocation between or fusion of two chromosome segments, each with a centromere. Some rearrangements produce both dicentric chromosomes and acentric fragments which can not attach to spindles at mitosis.<ref name=":01">{{Cite book|title = Thompson & Thompson Genetics in Medicine| vauthors = Nussbaum R, McInnes R, Willard H, Hamosh A |first4 = Ada|publisher = Saunders|year = 2007|isbn = 978-1-4160-3080-5|location = Philadelphia(PA)|pages = 72}}</ref> The formation of dicentric chromosomes has been attributed to genetic processes, such as [[Robertsonian translocation]]<ref name=":0">{{cite book|title=Thompson & Thompson Genetics in Medicine | edition = 7th |pages=62}}</ref> and [[Chromosomal inversion|paracentric inversion.]]<ref name=":5">{{cite book|title = Genetics From Genes to Genomes | edition = 4th | vauthors = Hartwell L, Hood L, Goldberg M, Reynolds A, Lee S |publisher = McGraw-Hill|year = 2011|isbn = 9780073525266|location = New York}}</ref> Dicentric chromosomes can have a variety of fates, including mitotic stability.<ref name=":1">{{cite journal | vauthors = Lynch SA, Ashcroft KA, Zwolinski S, Clarke C, Burn J | title = Kabuki syndrome-like features in monozygotic twin boys with a pseudodicentric chromosome 13 | journal = Journal of Medical Genetics | volume = 32 | issue = 3 | pages = 227–230 | date = March 1995 | pmid = 7783176 | pmc = 1050324 | doi = 10.1136/jmg.32.3.227 }}</ref> In some cases, their stability comes from inactivation of one of the two centromeres to make a functionally monocentric chromosome capable of normal transmission to daughter cells during cell division.<ref>{{cite journal | url=https://doi.org/10.1007/s10577-012-9302-3 | doi=10.1007/s10577-012-9302-3 | title=Dicentric chromosomes: Unique models to study centromere function and inactivation | date=2012 | last1=Stimpson | first1=Kaitlin M. | last2=Matheny | first2=Justyne E. | last3=Sullivan | first3=Beth A. | journal=Chromosome Research | volume=20 | issue=5 | pages=595–605 | pmc=3557915 }}</ref>

For example, human [[chromosome 2]], which is believed to be the result of a Robertsonian translocation at some point in the evolution between the great apes and ''Homo'', has a second, vestigial, centromere near the middle of its long arm.<ref>{{cite journal
|author=Avarello
|title=Evidence for an ancestral alphoid domain on the long arm of human chromosome 2
|journal=Human Genetics
|year=1992
|pages=247–9
|volume=89
|pmid=1587535  |doi=10.1007/BF00217134
|last2=Pedicini
|first2=A
|last3=Caiulo
|first3=A
|last4=Zuffardi
|first4=O
|last5=Fraccaro
|first5=M
|issue=2
|s2cid=1441285
|display-authors=1
}}</ref>

===Monocentric===

The [[monocentric]] chromosome is a chromosome that has only one centromere in a chromosome and forms a narrow constriction.

Monocentric centromeres are the most common structure on highly repetitive DNA in plants and animals.<ref>{{cite journal | vauthors = Barra V, Fachinetti D | title = The dark side of centromeres: types, causes and consequences of structural abnormalities implicating centromeric DNA | journal = Nature Communications | volume = 9 | issue = 1 | pages = 4340 | date = October 2018 | pmid = 30337534 | pmc = 6194107 | doi = 10.1038/s41467-018-06545-y | bibcode = 2018NatCo...9.4340B }}</ref>

=== Holocentric ===
{{Main|Holocentric chromosome}}
Unlike monocentric chromosomes, holocentric chromosomes have no distinct primary constriction when viewed at mitosis. Instead, spindle fibers attach along almost the entire (Greek: holo-) length of the chromosome. In holocentric chromosomes centromeric proteins, such as [[CENPA]] (CenH3) are spread over the whole chromosome.<ref name="mono">{{cite journal | vauthors = Neumann P, Navrátilová A, Schroeder-Reiter E, Koblížková A, Steinbauerová V, Chocholová E, Novák P, Wanner G, Macas J | display-authors = 6 | title = Stretching the rules: monocentric chromosomes with multiple centromere domains | journal = PLOS Genetics | volume = 8 | issue = 6 | pages = e1002777 | year = 2012 | pmid = 22737088 | pmc = 3380829 | doi = 10.1371/journal.pgen.1002777 | doi-access = free }}</ref> The nematode, [[Caenorhabditis elegans]], is a well-known example of an organism with holocentric chromosomes,<ref>{{cite journal | vauthors = Dernburg AF | title = Here, there, and everywhere: kinetochore function on holocentric chromosomes | journal = The Journal of Cell Biology | volume = 153 | issue = 6 | pages = F33–F38 | date = June 2001 | pmid = 11402076 | pmc = 2192025 | doi = 10.1083/jcb.153.6.F33 }}</ref> but this type of centromere can be found in various species, plants, and animals, across eukaryotes. Holocentromeres are actually composed of multiple distributed centromere units that form a line-like structure along the chromosomes during mitosis.<ref>{{cite journal | vauthors = Marques A, Ribeiro T, Neumann P, Macas J, Novák P, Schubert V, Pellino M, Fuchs J, Ma W, Kuhlmann M, Brandt R, Vanzela AL, Beseda T, Šimková H, Pedrosa-Harand A, Houben A | display-authors = 6 | title = Holocentromeres in Rhynchospora are associated with genome-wide centromere-specific repeat arrays interspersed among euchromatin | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 112 | issue = 44 | pages = 13633–13638 | date = November 2015 | pmid = 26489653 | pmc = 4640781 | doi = 10.1073/pnas.1512255112 | bibcode = 2015PNAS..11213633M | doi-access = free }}</ref> Alternative or nonconventional strategies are deployed at meiosis to achieve the homologous chromosome pairing and segregation needed to produce viable gametes or gametophytes for sexual reproduction.

Different types of holocentromeres exist in different species, namely with or without centromeric repetitive DNA sequences and with or without [[CENPA|CenH3]]. Holocentricity has evolved at least 13 times independently in various green algae, protozoans, invertebrates, and different plant families.<ref>{{cite journal | vauthors = Melters DP, Paliulis LV, Korf IF, Chan SW | title = Holocentric chromosomes: convergent evolution, meiotic adaptations, and genomic analysis | journal = Chromosome Research | volume = 20 | issue = 5 | pages = 579–593 | date = July 2012 | pmid = 22766638 | doi = 10.1007/s10577-012-9292-1 | s2cid = 3351527 | doi-access = free }}</ref> Contrary to monocentric species where acentric fragments usually become lost during cell division, the breakage of holocentric chromosomes creates fragments with normal spindle fiber attachment sites.<ref>{{Cite journal | author1 = Hughes-Schrader S| author-link1 =Sally Hughes-Schrader| author2 =Ris H |date=August 1941 |title=The diffuse spindle attachment of coccids, verified by the mitotic behavior of induced chromosome fragments |url=https://onlinelibrary.wiley.com/doi/10.1002/jez.1400870306 |journal=Journal of Experimental Zoology |language=en |volume=87 |issue=3 |pages=429–456 |doi=10.1002/jez.1400870306 |issn=0022-104X|url-access=subscription }}</ref> Because of this, organisms with holocentric chromosomes can more rapidly evolve karyotype variation, able to heal fragmented chromosomes through subsequent addition of telomere caps at the sites of breakage.<ref>{{cite journal | vauthors = Jankowska M, Fuchs J, Klocke E, Fojtová M, Polanská P, Fajkus J, Schubert V, Houben A | display-authors = 6 | title = Holokinetic centromeres and efficient telomere healing enable rapid karyotype evolution | journal = Chromosoma | volume = 124 | issue = 4 | pages = 519–528 | date = December 2015 | pmid = 26062516 | doi = 10.1007/s00412-015-0524-y | s2cid = 2530401 }}</ref>

===Polycentric===
{{Main|Polycentric chromosome}}
Polycentric chromosomes have several kinetochore clusters, i.e. centromes. The term overlaps partially with "holocentric", but "polycentric" is clearly preferred when discussing defectively formed monocentric chromosomes. There is some actual ambiguity as well, as there is no clear line dividing up the transition from kinetochores covering the whole chromosome to distinct clusters. In other words, the difference between "the whole chromosome is a centrome" and "the chromosome has no centrome" is hazy and usage varies. Beyond "polycentricity" being used more about defects, there is no clear preference in other topics such as evolutionary origin or kinetochore distribution and detailed structure (e.g. as seen in [[Fluorescent tag|tagging]] or [[Sequence assembly|genome assembly]] analysis).<ref>{{cite journal | vauthors = Godward MB | date= April 1954 |title=The 'Diffuse' Centromere or Polycentric Chromosomes in Spirogyra |journal=Annals of Botany |volume=18 |issue=2 |pages=143–144 |doi=10.1093/oxfordjournals.aob.a083387 }}</ref><ref name="holocentric_micro">{{cite journal |last1=Kuo |first1=YT |last2=Camara |first2=AS |last3=Schubert |first3=V |title=Holocentromeres can consist of merely a few megabase-sized satellite arrays |journal=Nature Communications |date=2023-06-13 |volume=14 |doi=10.1038/s41467-023-38922-7 |url=https://www.nature.com/articles/s41467-023-38922-7|pmc=10264360 }}</ref><ref name="holocentric_evo">{{cite journal |last1=Senaratne |first1=Aruni P. |last2=Cortes-Silva |first2=Nuria |last3=Drinnenberg |first3=Ines A. |title=Evolution of holocentric chromosomes: Drivers, diversity, and deterrents |journal=Seminars in Cell & Developmental Biology |date=July 2022 |volume=127 |pages=90–99 |doi=10.1016/j.semcdb.2022.01.003 |url=https://www.sciencedirect.com/science/article/pii/S1084952122000052 |access-date=2024-09-11}}</ref><ref name="polycentric_2">{{cite journal |last1=Ma B, Wang H, Liu J, Chen L, Xia X, Wei W, Yang Z, Yuan J, Luo Y, He N. |title=The gap-free genome of mulberry elucidates the architecture and evolution of polycentric chromosomes |journal=Horticulture Research |date=2023-05-31 |volume=10 |issue=7 |doi=10.1093/hr/uhad111 |url=https://pubmed.ncbi.nlm.nih.gov/37786730/ |access-date=2024-09-11|pmc=10541557 }}</ref>

Even clearly distinct clusters of kinetochore proteins do not necessarily produce more than one constriction: "Metapolycentric" chromosomes feature one elongated constriction of the chromosome, joining a longer segment which is still visibly shorter than the chromatids.<ref name="centromere_composition">{{cite journal |last1=Ishii |first1=Midori |last2=Akiyoshi |first2=Bungo |title=Plasticity in centromere organization and kinetochore composition: Lessons from diversity |journal=Current Opinion in Cell Biology |date=February 2022 |volume=74 |issue=Cell Nucleus 2022 |pages=47–54 |doi=10.1016/j.ceb.2021.12.007 |url=https://www.sciencedirect.com/science/article/pii/S0955067422000011#fig3 |access-date=2024-09-11|hdl=20.500.11820/4aab4486-f439-4d7e-863a-b08e0da52a6b |hdl-access=free }}</ref> Metapolycentric chromosomes may be a step in the emergence and suppression of centromere drive, a type of [[meiotic drive]] that disrupts parity by monocentric centromeres growing additional kinetochore proteins to gain an advantage during meiosis.<ref name="centromere_drive">{{cite journal |last1=Zedek |first1=Frantisek |last2=Bures |first2=Petr |title=Absence of positive selection on CenH3 in Luzula suggests that holokinetic chromosomes may suppress centromere drive |journal=Annals of Botany |date=December 2016 |volume=118 |pages=1347–1352 |doi=10.1093/aob/mcw186 |url=https://www.researchgate.net/publication/306091873_Absence_of_positive_selection_on_CenH3_in_Luzula_suggests_that_holokinetic_chromosomes_may_suppress_centromere_drive#read |access-date=2024-09-11|pmc=5155603 }}</ref>

=== Human chromosomes ===
[[File:Human karyotype with bands and sub-bands.png|thumb|Human [[karyotype|karyogram]], with each row vertically aligned at centromere level, and with annotated [[Locus (genetics)|bands and sub-bands]]. It is a graphical representation of the idealized human [[diploid]] karyotype. It shows dark and white regions on [[G banding]]. It shows both the female (XX) and male (XY) versions of the [[sex chromosome]]. {{further|Karyotype}}]]
{| class="wikitable sortable" style="text-align: center;"
|+ Table of human chromosomes with data on centromeres and sizes.
|-
! Chromosome !! Centromere <br /> position ([[Base pair|Mbp]]) !! Category !! Chromosome <br /> Size (Mbp) !! Centromere <br /> size (Mbp)
|-
| [[Chromosome 1 (human)|1]] || 125.0 || metacentric || 247.2 || 7.4
|-
| [[Chromosome 2 (human)|2]] || 93.3 || submetacentric || 242.8 || 6.3
|-
| [[Chromosome 3 (human)|3]] || 91.0 || metacentric || 199.4 || 6.0
|-
| [[Chromosome 4 (human)|4]] || 50.4 || submetacentric || 191.3 || —
|-
| [[Chromosome 5 (human)|5]] || 48.4 || submetacentric || 180.8 || —
|-
| [[Chromosome 6 (human)|6]] || 61.0 || submetacentric || 170.9 || —
|-
| [[Chromosome 7 (human)|7]] || 59.9 || submetacentric || 158.8 || —
|-
| [[Chromosome 8 (human)|8]] || 45.6 || submetacentric || 146.3 || —
|-
| [[Chromosome 9 (human)|9]] || 49.0 || submetacentric || 140.4 || —
|-
| [[Chromosome 10 (human)|10]] || 40.2 || submetacentric || 135.4 || —
|-
| [[Chromosome 11 (human)|11]] || 53.7 || submetacentric || 134.5 || —
|-
| [[Chromosome 12 (human)|12]] || 35.8 || submetacentric || 132.3 || —
|-
| [[Chromosome 13 (human)|13]] || 17.9 || acrocentric || 114.1 || —
|-
| [[Chromosome 14 (human)|14]] || 17.6 || acrocentric || 106.3 || —
|-
| [[Chromosome 15 (human)|15]] || 19.0 || acrocentric || 100.3 || —
|-
| [[Chromosome 16 (human)|16]] || 36.6 || metacentric || 88.8 || —
|-
| [[Chromosome 17 (human)|17]] || 24.0 || submetacentric || 78.7 || —
|-
| [[Chromosome 18 (human)|18]] || 17.2 || submetacentric || 76.1 || —
|-
| [[Chromosome 19 (human)|19]] || 26.5 || metacentric || 63.8 || —
|-
| [[Chromosome 20 (human)|20]] || 27.5 || metacentric || 62.4 || —
|-
| [[Chromosome 21 (human)|21]] || 13.2 || acrocentric || 46.9 || —
|-
| [[Chromosome 22 (human)|22]] || 14.7 || acrocentric || 49.5 || —
|-
| [[X chromosome|X]] || 60.6 || submetacentric || 154.9 || —
|-
| [[Y chromosome|Y]] || 12.5 || acrocentric || 57.7 || —
|-
|}
Based on the micrographic characteristics of size, position of the centromere and sometimes the presence of a [[chromosomal satellite]], the human chromosomes are classified into the following groups:<ref>{{cite journal|author=Erwinsyah, R., Riandi, & Nurjhani, M.|year=2017|title=Relevance of human chromosome analysis activities against mutation concept in genetics course. IOP Conference Series.|journal=Materials Science and Engineering|doi=10.1088/1757-899x/180/1/012285|s2cid=90739754 |doi-access=free}}</ref>
{|class=wikitable
! Group
! Chromosomes
! Features
|-
| Group A
| Chromosome 1–3
| Large, metacentric and submetacentric
|-
| Group B
| Chromosome 4–5
| Large, submetacentric
|-
| Group C
| Chromosome 6–12, X
| Medium-sized, submetacentric
|-
| Group D
| Chromosome 13–15
| Medium-sized, acrocentric, with [[satellite chromosome|satellite]]
|-
| Group E
| Chromosome 16–18
| Small, metacentric and submetacentric
|-
| Group F
| Chromosome 19–20
| Very small, metacentric
|-
| Group G
| Chromosome 21–22, Y
| Very small, acrocentric, with [[satellite chromosome|satellite]]
|}

== Sequence ==
There are two types of centromeres.<ref>{{cite journal | vauthors = Pluta AF, Mackay AM, Ainsztein AM, Goldberg IG, Earnshaw WC | title = The centromere: hub of chromosomal activities | journal = Science | volume = 270 | issue = 5242 | pages = 1591–1594 | date = December 1995 | pmid = 7502067 | doi = 10.1126/science.270.5242.1591 | s2cid = 44632550 | bibcode = 1995Sci...270.1591P }}</ref> In regional centromeres, [[DNA]] sequences contribute to but do not define function. Regional centromeres contain large amounts of DNA and are often packaged into [[heterochromatin]]. In most [[eukaryotes]], the centromere's DNA sequence consists of large arrays of repetitive DNA (e.g. [[satellite DNA]]) where the sequence within individual repeat elements is similar but not identical. In humans, the primary centromeric repeat unit is called α-satellite (or alphoid), although a number of other sequence types are found in this region.<ref name="Mehta2010">{{cite journal | vauthors = Mehta GD, Agarwal MP, Ghosh SK | title = Centromere identity: a challenge to be faced | journal = Molecular Genetics and Genomics | volume = 284 | issue = 2 | pages = 75–94 | date = August 2010 | pmid = 20585957 | doi = 10.1007/s00438-010-0553-4 | s2cid = 24881938 }}</ref> Centromere satellites are hypothesized to evolve by a process called layered expansion. They evolve rapidly between species, and analyses in wild mice show that satellite copy number and heterogeneity relates to population origins and subspecies.<ref name="Arora et al">{{cite journal | vauthors = Arora UP, Charlebois C, Lawal RA, Dumont BL | title = Population and subspecies diversity at mouse centromere satellites | journal = BMC Genomics | volume = 22 | issue = 1 | pages = 279 | date = April 2021 | pmid = 33865332 | pmc = 8052823 | doi = 10.1186/s12864-021-07591-5 | doi-access = free }}</ref> Additionally, satellite sequences may be affected by inbreeding.<ref name="Arora et al" />

Point centromeres are smaller and more compact. DNA sequences are both necessary and sufficient to specify centromere identity and function in organisms with point centromeres. In budding yeasts, the centromere region is relatively small (about 125 bp DNA) and contains two highly conserved DNA sequences that serve as binding sites for essential [[kinetochore]] proteins.<ref name="Mehta2010"/>

== Inheritance ==
Since centromeric DNA sequence is not the key determinant of centromeric identity in [[metazoans]], it is thought that [[epigenetic inheritance]] plays a major role in specifying the centromere.<ref>{{cite journal | vauthors = Dalal Y | title = Epigenetic specification of centromeres | journal = Biochemistry and Cell Biology | volume = 87 | issue = 1 | pages = 273–282 | date = February 2009 | pmid = 19234541 | doi = 10.1139/O08-135 }}</ref> The daughter chromosomes will assemble centromeres in the same place as the parent chromosome, independent of sequence. It has been proposed that histone H3 variant [[CENPA|CENP-A]] (Centromere Protein A) is the epigenetic mark of the centromere.<ref>{{cite journal | vauthors = Bernad R, Sánchez P, Losada A | title = Epigenetic specification of centromeres by CENP-A | journal = Experimental Cell Research | volume = 315 | issue = 19 | pages = 3233–3241 | date = November 2009 | pmid = 19660450 | doi = 10.1016/j.yexcr.2009.07.023 }}</ref> The question arises whether there must be still some original way in which the centromere is specified, even if it is subsequently propagated epigenetically. If the centromere is inherited epigenetically from one generation to the next, the problem is pushed back to the origin of the first metazoans.

On the other hand, thanks to comparisons of the centromeres in the X chromosomes, epigenetic and structural variations have been seen in these regions. In addition, a recent assembly of the human genome has detected a possible mechanism of how pericentromeric and centromeric structures evolve, through a layered expansion model for αSat sequences. This model proposes that different αSat sequence repeats emerge periodically and expand within an active vector, displacing old sequences, and becoming the site of kinetochore assembly. The αSat can originate from the same, or from different vectors. As this process is repeated over time, the layers that flank the active centromere shrink and deteriorate. This process raises questions about the relationship between this dynamic evolutionary process and the position of the centromere.<ref>{{Cite journal |last1=Altemose |first1=Nicolas |last2=Logsdon |first2=Glennis A. |last3=Bzikadze |first3=Andrey V. |last4=Sidhwani |first4=Pragya |last5=Langley |first5=Sasha A. |last6=Caldas |first6=Gina V. |last7=Hoyt |first7=Savannah J. |last8=Uralsky |first8=Lev |last9=Ryabov |first9=Fedor D. |last10=Shew |first10=Colin J. |last11=Sauria |first11=Michael E. G. |last12=Borchers |first12=Matthew |last13=Gershman |first13=Ariel |last14=Mikheenko |first14=Alla |last15=Shepelev |first15=Valery A. |date=April 2022 |title=Complete genomic and epigenetic maps of human centromeres |journal=Science |language=en |volume=376 |issue=6588 |pages=eabl4178 |doi=10.1126/science.abl4178 |issn=0036-8075 |pmc=9233505 |pmid=35357911}}</ref>

== Structure ==
The centromeric DNA is normally in a [[heterochromatin]] state, which is essential for the recruitment of the [[cohesin]] complex that mediates sister chromatid cohesion after DNA replication as well as coordinating sister chromatid separation during anaphase. In this chromatin, the normal [[histone]] H3 is replaced with a centromere-specific variant, CENP-A in humans.<ref>{{cite journal | vauthors = Chueh AC, Wong LH, Wong N, Choo KH | title = Variable and hierarchical size distribution of L1-retroelement-enriched CENP-A clusters within a functional human neocentromere | journal = Human Molecular Genetics | volume = 14 | issue = 1 | pages = 85–93 | date = January 2005 | pmid = 15537667 | doi = 10.1093/hmg/ddi008 | doi-access = free }}</ref> The presence of CENP-A is believed to be important for the assembly of the kinetochore on the centromere. CENP-C has been shown to localise almost exclusively to these regions of CENP-A associated chromatin. In human cells, the histones are found to be most enriched for [[H4K20me]]3 and [[H3K9me3]]<ref name="Rosenfeld_2009">{{cite journal | vauthors = Rosenfeld JA, Wang Z, Schones DE, Zhao K, DeSalle R, Zhang MQ | title = Determination of enriched histone modifications in non-genic portions of the human genome | journal = BMC Genomics | volume = 10 | pages = 143 | date = March 2009 | pmid = 19335899 | pmc = 2667539 | doi = 10.1186/1471-2164-10-143 | doi-access = free }}</ref> which are known heterochromatic modifications. In  Drosophila, Islands of retroelements are major components of the centromeres.<ref>{{cite journal | vauthors = Chang CH, Chavan A, Palladino J, Wei X, Martins NM, Santinello B, Chen CC, Erceg J, Beliveau BJ, Wu CT, Larracuente AM, Mellone BG | display-authors = 6 | title = Islands of retroelements are major components of Drosophila centromeres | journal = PLOS Biology | volume = 17 | issue = 5 | pages = e3000241 | date = May 2019 | pmid = 31086362 | pmc = 6516634 | doi = 10.1371/journal.pbio.3000241 | doi-access = free }}</ref>

In the yeast ''[[Schizosaccharomyces pombe]]'' (and probably in other eukaryotes), the formation of centromeric heterochromatin is connected to [[RNAi]].<ref>{{cite journal | vauthors = Volpe TA, Kidner C, Hall IM, Teng G, Grewal SI, Martienssen RA | title = Regulation of heterochromatic silencing and histone H3 lysine-9 methylation by RNAi | journal = Science | volume = 297 | issue = 5588 | pages = 1833–1837 | date = September 2002 | pmid = 12193640 | doi = 10.1126/science.1074973 | s2cid = 2613813 | bibcode = 2002Sci...297.1833V | doi-access = free }}</ref> In nematodes such as ''[[Caenorhabditis elegans]]'', some plants, and the insect orders Lepidoptera and Hemiptera, chromosomes are "holocentric", indicating that there is not a primary site of microtubule attachments or a primary constriction, and a "diffuse" kinetochore assembles along the entire length of the chromosome.

== Centromeric aberrations ==
In rare cases, [[neocentromere]]s can form at new sites on a chromosome as a result of a repositioning of the centromere. This phenomenon is most well known from human clinical studies and there are currently over 90 known human neocentromeres identified on 20 different chromosomes.<ref>{{cite journal | vauthors = Marshall OJ, Chueh AC, Wong LH, Choo KH | title = Neocentromeres: new insights into centromere structure, disease development, and karyotype evolution | journal = American Journal of Human Genetics | volume = 82 | issue = 2 | pages = 261–282 | date = February 2008 | pmid = 18252209 | pmc = 2427194 | doi = 10.1016/j.ajhg.2007.11.009 }}</ref><ref>{{cite journal | vauthors = Warburton PE | title = Chromosomal dynamics of human neocentromere formation | journal = Chromosome Research | volume = 12 | issue = 6 | pages = 617–626 | year = 2004 | pmid = 15289667 | doi = 10.1023/B:CHRO.0000036585.44138.4b | s2cid = 29472338 }}</ref> The formation of a neocentromere must be coupled with the inactivation of the previous centromere, since chromosomes with two functional centromeres ([[Dicentric chromosome]]) will result in chromosome breakage during mitosis. In some unusual cases human neocentromeres have been observed to form spontaneously on fragmented chromosomes. Some of these new positions were originally euchromatic and lack alpha [[satellite DNA]] altogether. [[Neocentromere]]s lack the repetitive structure seen in normal centromeres which suggest that centromere formation is mainly controlled [[Epigenetics|epigenetically]].<ref name="Rocchi 59–67">{{cite journal | vauthors = Rocchi M, Archidiacono N, Schempp W, Capozzi O, Stanyon R | title = Centromere repositioning in mammals | journal = Heredity | volume = 108 | issue = 1 | pages = 59–67 | date = January 2012 | pmid = 22045381 | pmc = 3238114 | doi = 10.1038/hdy.2011.101 }}</ref><ref>{{cite journal | vauthors = Tolomeo D, Capozzi O, Stanyon RR, Archidiacono N, D'Addabbo P, Catacchio CR, Purgato S, Perini G, Schempp W, Huddleston J, Malig M, Eichler EE, Rocchi M | display-authors = 6 | title = Epigenetic origin of evolutionary novel centromeres | journal = Scientific Reports | volume = 7 | issue = 1 | pages = 41980 | date = February 2017 | pmid = 28155877 | pmc = 5290474 | doi = 10.1038/srep41980 | bibcode = 2017NatSR...741980T }}</ref> Over time a neocentromere can accumulate repetitive elements and mature into what is known as an evolutionary new centromere. There are several well known examples in primate chromosomes where the centromere position is different from the human centromere of the same chromosome and is thought to be evolutionary new centromeres.<ref name="Rocchi 59–67"/> Centromere repositioning and the formation of evolutionary new centromeres has been suggested to be a mechanism of [[speciation]].<ref>{{cite journal | vauthors = Brown JD, O'Neill RJ | title = Chromosomes, conflict, and epigenetics: chromosomal speciation revisited | journal = Annual Review of Genomics and Human Genetics | volume = 11 | issue = 1 | pages = 291–316 | date = September 2010 | pmid = 20438362 | doi = 10.1146/annurev-genom-082509-141554 }}</ref>

Centromere proteins are also the autoantigenic target for some [[anti-nuclear antibodies]], such as [[anti-centromere antibodies]].

== Dysfunction and disease ==
It has been known that centromere misregulation contributes to mis-segregation of chromosomes, which is strongly related to cancer and miscarriage. Notably, overexpression of many centromere genes have been linked to cancer malignant phenotypes. Overexpression of these centromere genes can increase genomic instability in cancers. Elevated genomic instability on one hand relates to malignant phenotypes; on the other hand, it makes the tumor cells more vulnerable to specific adjuvant therapies such as certain chemotherapies and radiotherapy.<ref>{{cite journal | vauthors = Zhang W, Mao JH, Zhu W, Jain AK, Liu K, Brown JB, Karpen GH | title = Centromere and kinetochore gene misexpression predicts cancer patient survival and response to radiotherapy and chemotherapy | journal = Nature Communications | volume = 7 | pages = 12619 | date = August 2016 | pmid = 27577169 | pmc = 5013662 | doi = 10.1038/ncomms12619 | bibcode = 2016NatCo...712619Z }}</ref> Instability of centromere repetitive DNA was recently shown in cancer and aging.<ref>{{cite journal | vauthors = Giunta S, Funabiki H | title = Integrity of the human centromere DNA repeats is protected by CENP-A, CENP-C, and CENP-T | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 114 | issue = 8 | pages = 1928–1933 | date = February 2017 | pmid = 28167779 | pmc = 5338446 | doi = 10.1073/pnas.1615133114 | bibcode = 2017PNAS..114.1928G | doi-access = free }}</ref>

==Repair of centromeric DNA==

When [[DNA damage (naturally occurring)|DNA breaks]] occur at centromeres in the [[G1 phase]] of the [[cell cycle]], the cells are able to recruit the [[homologous recombination]]al repair machinery to the damaged site, even in the absence of a [[sister chromatids|sister chromatid]].<ref name = "Yilmaz_2021">{{cite journal | vauthors = Yilmaz D, Furst A, Meaburn K, Lezaja A, Wen Y, Altmeyer M, Reina-San-Martin B, Soutoglou E | title = Activation of homologous recombination in G1 preserves centromeric integrity | journal = Nature | volume = 600 | issue = 7890 | pages = 748–753 | date = December 2021 | pmid = 34853474 | doi = 10.1038/s41586-021-04200-z | bibcode = 2021Natur.600..748Y | s2cid = 244800481 }}</ref> It appears that homologous recombinational repair can occur at centromeric breaks throughout the cell cycle in order to prevent the activation of inaccurate mutagenic DNA repair pathways and to preserve centromeric integrity.<ref name = "Yilmaz_2021" />

== Etymology and pronunciation ==
The word ''centromere'' ({{IPAc-en|ˈ|s|ɛ|n|t|r|ə|ˌ|m|ɪər}}<ref>{{MerriamWebsterDictionary|Centromere}}</ref><ref>{{Dictionary.com|Centromere}}</ref>) uses [[classical compound|combining forms]] of ''[[wikt:centro-#Prefix|centro-]] and [[wikt:-mere#Suffix|-mere]]'', yielding "central part", describing the centromere's location at the center of the chromosome.

== See also ==
* [[Telomere]]
* [[Chromatid]]
* [[Diploid]]
* [[Monopolin]]

== References ==
{{reflist}}

=== Further reading ===
{{refbegin}}
* {{cite journal | vauthors = Mehta GD, Agarwal MP, Ghosh SK | title = Centromere identity: a challenge to be faced | journal = Molecular Genetics and Genomics | volume = 284 | issue = 2 | pages = 75–94 | date = August 2010 | pmid = 20585957 | doi = 10.1007/s00438-010-0553-4 | s2cid = 24881938 }}
* {{cite book | vauthors = Lodish H, Berk A, Kaiser CA, Kaiser C, Krieger M, Scott MP, Bretscher A, Ploegh H, Matsudaira |year=2008 |title=Molecular Cell Biology |edition=6th |publisher=W.H. Freeman |location=New York |isbn=978-0-7167-7601-7}}
* {{cite journal | vauthors = Nagaki K, Cheng Z, Ouyang S, Talbert PB, Kim M, Jones KM, Henikoff S, Buell CR, Jiang J | display-authors = 6 | title = Sequencing of a rice centromere uncovers active genes | journal = Nature Genetics | volume = 36 | issue = 2 | pages = 138–145 | date = February 2004 | pmid = 14716315 | doi = 10.1038/ng1289 | doi-access = free }}
{{refend}}

== External links ==
* {{cite press release |date=January 13, 2004 |title=Rice Centromere, Supposedly Quiet Genetic Domain, Surprises |website=[[ScienceDaily]] |url=https://www.sciencedaily.com/releases/2004/01/040111212949.htm}}

{{Commons category|Centromere}}
{{Chromo}}
{{Autoantigens}}

[[Category:Chromosomes]]
[[Category:DNA replication]]