Admin: 1 версия импортирована

2025-11-13T17:59:56Z

1 версия импортирована

← Предыдущая версия		Версия от 17:59, 13 ноября 2025
(нет различий)

ru>GreenC bot: Move 1 url. Wayback Medic 2.5 per WP:URLREQ#nih.gov

2025-07-15T21:21:58Z

Move 1 url. Wayback Medic 2.5 per WP:URLREQ#nih.gov

Новая страница

{{Short description|Process by which one of the two alleles for a gene is expressed while the other is silenced}}
'''Allelic exclusion''' is a process by which only one [[allele]] of a [[gene]] is expressed while the other allele is silenced.<ref>{{cite book| vauthors = Korochkin LI, Grossman A | chapter =The Phenomenon of Allelic Exclusion|date=1981| title =Gene Interactions in Development| series =Monographs on Theoretical and Applied Genetics|volume=4|pages=108–124|place=Berlin, Heidelberg|publisher=Springer Berlin Heidelberg|doi=10.1007/978-3-642-81477-8_4|isbn=978-3-642-81479-2 }}</ref> This phenomenon is most notable for playing a role in the development of [[B cell|B lymphocytes]], where allelic exclusion allows for each mature B lymphocyte to express only one type of [[Antibody|immunoglobulin]]. This subsequently results in each B lymphocyte being able to recognize only one antigen.<ref name="Levin-Klein_2014">{{cite journal | vauthors = Levin-Klein R, Bergman Y | title = Epigenetic regulation of monoallelic rearrangement (allelic exclusion) of antigen receptor genes | journal = Frontiers in Immunology | volume = 5 | pages = 625 | date = December 2014 | pmid = 25538709 | pmc = 4257082 | doi = 10.3389/fimmu.2014.00625 | doi-access = free }}</ref> This is significant as the co-expression of both alleles in B lymphocytes is associated with [[autoimmunity]] and the production of [[Autoantibody|autoantibodies]].<ref>{{cite journal | vauthors = Pelanda R | title = Dual immunoglobulin light chain B cells: Trojan horses of autoimmunity? | journal = Current Opinion in Immunology | volume = 27 | pages = 53–9 | date = April 2014 | pmid = 24549093 | pmc = 3972342 | doi = 10.1016/j.coi.2014.01.012 }}</ref>

Many regulatory processes can lead to allelic exclusion. In one instance, one allele of the gene can become transcriptionally silent, resulting in the transcription and expression of only the other allele.<ref name="Levin-Klein_2014" /> This could be caused in part by decreased [[methylation]] of the expressed allele.<ref>{{cite book | vauthors = Schroeder HW, Imboden JB, Torres RM | chapter = Chapter 4: Antigen Receptor Genes, Gene Products, and Coreceptors|date=2019-01-01 |title =Clinical Immunology | edition = Fifth |pages=55–77.e1| veditors = Rich R, Fleisher TA, Shearer WT, Schroeder HW |place=London|publisher=Elsevier|language=en|doi=10.1016/b978-0-7020-6896-6.00004-1|isbn=978-0-7020-6896-6 }}</ref> Conversely, allelic exclusion can also be regulated through asynchronous [[V(D)J recombination|allelic rearrangement]].<ref>{{cite journal | vauthors = Jackson A, Kondilis HD, Khor B, Sleckman BP, Krangel MS | title = Regulation of T cell receptor beta allelic exclusion at a level beyond accessibility | journal = Nature Immunology | volume = 6 | issue = 2 | pages = 189–97 | date = February 2005 | pmid = 15640803 | doi = 10.1038/ni1157 | s2cid = 24687496 }}</ref> In this case, both alleles are transcribed but only one becomes a functional protein.<ref name="Levin-Klein_2014" />

== In B-lymphocytes ==

Allelic exclusion has been observed most often in genes for cell surface receptors and has been extensively studied in immune cells such as B lymphocytes. Allelic exclusion of immunoglobulin (Ig) heavy chain and light chain genes in B cells forms the genetic basis for the presence of only a single type of antigen receptor on a given B lymphocyte, which is central in explaining the ‘one B cell — one antibody’ rule.<ref>{{cite book| vauthors = Burnet FM | doi = 10.5962/bhl.title.8281|title=The clonal selection theory of acquired immunity|date=1959|publisher=Vanderbilt University Press|location=Nashville, Temessee| url = https://www.biodiversitylibrary.org/bibliography/8281}}</ref> The variable domain of the B-cell antigen receptor is encoded by the V, (D), and J gene segments, the recombination of which gives rise to Ig gene allelic exclusion. V(D)J recombination occurs imprecisely, so that while transcripts from both alleles are expressed, only one is able to give rise to a functional surface antigen receptor. If no successful rearrangement occurs on either chromosome, the cell dies.

=== Models ===

==== Stochastic ====
In the stochastic model, while the Ig rearrangement is proposed to be very efficient, the probability of functional allelic rearrangement is assumed to be very low as compared to the probability of non-functional rearrangement.<ref name="Vettermann_2010">{{cite journal | vauthors = Vettermann C, Schlissel MS | title = Allelic exclusion of immunoglobulin genes: models and mechanisms | journal = Immunological Reviews | volume = 237 | issue = 1 | pages = 22–42 | date = September 2010 | pmid = 20727027 | doi = 10.1111/j.1600-065x.2010.00935.x | pmc = 2928156 }}</ref> As a result, successful recombination of more than one functional Ig allele in one B cell statistically occurs very infrequently.<ref>{{cite journal | vauthors = Coleclough C, Perry RP, Karjalainen K, Weigert M | title = Aberrant rearrangements contribute significantly to the allelic exclusion of immunoglobulin gene expression | journal = Nature | volume = 290 | issue = 5805 | pages = 372–8 | date = April 1981 | pmid = 6783959 | doi = 10.1038/290372a0 | bibcode = 1981Natur.290..372C | s2cid = 2267279 }}</ref>

==== Asynchronous recombination ====
In the asynchronous recombination models, the recombination process is controlled by timing of [[recombination-activating gene]] (RAG) recombinase and accessibility of each Ig allele within the [[chromatin]] structure.<ref name="Vettermann_2010" />

# Asynchronous Probabilistic Recombination Model: This probabilistic model relies on the mechanisms which control chromatin accessibility. The limited accessibility of Ig alleles due to chromatin structure leads to low efficiency of recombination therefore, the probability of biallelic rearrangement is negligible.<ref name="Vettermann_2010" />
# Asynchronous Instructive Recombination Model: The instructive model is based on the difference in timing of allele replication, wherein the alleles undergo recombination sequentially. In this model the second allele undergoes rearrangement only if the first rearrangement was unsuccessful.<ref name="Vettermann_2010" /><ref>{{cite report| vauthors = Matthias P | date=2001-11-23|title=Faculty Opinions recommendation of Asynchronous replication and allelic exclusion in the immune system.|doi = 10.3410/f.1002314.23155 |website=Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature| doi-access=free}}</ref>

==== Classic feedback inhibition ====
The feedback inhibition model is similar to the asynchronous recombination mode, but it emphasizes the mechanisms that maintain the rearrangement asynchrony. This model suggests that a recombination which gives rise to a functional B cell surface receptor will cause a series of signals which suppress further recombination.<ref name="NCI_Thesaurus">{{cite web | title = Immunoglobulin Heavy Chain Variable, Diversity, and Joining Region Gene Rearrangement | url = https://evsexplore.semantics.cancer.gov/evsexplore/concept/ncit/C124221 | work = National Cancer Institute Thesaurus }}</ref> Without these signals, allelic rearrangement will carry on. The classic feedback model is empirically corroborated by observed recombination ratios.<ref name="NCI_Thesaurus" />

== In Igκ and Igλ light chain genes ==
The allelic exclusion of light chain genes Igκ and Igλ is a process that is controlled by the monoallelic initiation of [[V(D)J recombination]]. While little is known about the mechanism leading to the allelic exclusion of Igλ genes, the Igκ locus is generally inactivated by RAG-mediated deletion of the exon Cκ. The V(D)J recombination step is a random and non-specific process that occurs one allele at a time where segments V, (D) and J are rearranged to encode the variable region, resulting in a fraction of functional genes with a productive V(D)J region.<ref>{{cite journal | vauthors = Mostoslavsky R, Alt FW, Rajewsky K | title = The lingering enigma of the allelic exclusion mechanism | journal = Cell | volume = 118 | issue = 5 | pages = 539–44 | date = September 2004 | pmid = 15339659 | doi = 10.1016/j.cell.2004.08.023 | doi-access = free }}</ref> Allelic exclusion is then enforced via feedback inhibition where the functional Ig gene inhibits V(D)J rearrangement of the second allele. While this feedback mechanism is mainly achieved through inhibition of the juxtaposition of V and D-J segments, the down-regulation of transcription and suppression of RAG accessibility also plays a role.<ref>{{cite journal | vauthors = Brady BL, Steinel NC, Bassing CH | title = Antigen receptor allelic exclusion: an update and reappraisal | journal = Journal of Immunology | volume = 185 | issue = 7 | pages = 3801–8 | date = October 2010 | pmid = 20858891 | doi = 10.4049/jimmunol.1001158 | pmc = 3008371 | doi-access = free }}</ref>

== In sensory neurons ==
[[Vomeronasal organ#Sensory neurons|Vomeronasal sensory neurons]] are found in the [[vomeronasal organ]] at the [[nasal septum]] base and their specialty is in [[pheromone]] detection.<ref name="Capello_2009">{{cite journal | vauthors = Capello L, Roppolo D, Jungo VP, Feinstein P, Rodriguez I | title = A common gene exclusion mechanism used by two chemosensory systems | journal = The European Journal of Neuroscience | volume = 29 | issue = 4 | pages = 671–8 | date = February 2009 | pmid = 19200072 | pmc = 3709462 | doi = 10.1111/j.1460-9568.2009.06630.x }}</ref><ref name="Monahan_2015">{{cite journal | vauthors = Monahan K, Lomvardas S | title = Monoallelic expression of olfactory receptors | journal = Annual Review of Cell and Developmental Biology | volume = 31 | issue = 1 | pages = 721–40 | date = 2015-11-13 | pmid = 26359778 | pmc = 4882762 | doi = 10.1146/annurev-cellbio-100814-125308 }}</ref><ref name="Serizawa_2003">{{cite journal | vauthors = Serizawa S, Miyamichi K, Nakatani H, Suzuki M, Saito M, Yoshihara Y, Sakano H | title = Negative feedback regulation ensures the one receptor-one olfactory neuron rule in mouse | journal = Science | volume = 302 | issue = 5653 | pages = 2088–94 | date = December 2003 | pmid = 14593185 | doi = 10.1126/science.1089122 | bibcode = 2003Sci...302.2088S | s2cid = 26055164 | doi-access = free }}</ref><ref name="Lewcock_2004">{{cite journal | vauthors = Lewcock JW, Reed RR | title = A feedback mechanism regulates monoallelic odorant receptor expression | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 4 | pages = 1069–74 | date = January 2004 | pmid = 14732684 | pmc = 327152 | doi = 10.1073/pnas.0307986100 | bibcode = 2004PNAS..101.1069L | doi-access = free }}</ref><ref name="Shykind_2004">{{cite journal | vauthors = Shykind BM, Rohani SC, O'Donnell S, Nemes A, Mendelsohn M, Sun Y, Axel R, Barnea G | display-authors = 6 | title = Gene switching and the stability of odorant receptor gene choice | journal = Cell | volume = 117 | issue = 6 | pages = 801–15 | date = June 2004 | pmid = 15186780 | doi = 10.1016/j.cell.2004.05.015 | doi-access = free }}</ref><ref name="Serizawa_2000">{{cite journal | vauthors = Serizawa S, Ishii T, Nakatani H, Tsuboi A, Nagawa F, Asano M, Sudo K, Sakagami J, Sakano H, Ijiri T, Matsuda Y, Suzuki M, Yamamori T, Iwakura Y, Sakano H | display-authors = 6 | title = Mutually exclusive expression of odorant receptor transgenes | journal = Nature Neuroscience | volume = 3 | issue = 7 | pages = 687–93 | date = July 2000 | pmid = 10862701 | doi = 10.1038/76641 | s2cid = 1019250 }}</ref> A [[vomeronasal receptor]], V1R, exhibits allelic exclusion. When a V1R receptor [[gene]] is [[Gene expression|expressed]], an [[Olfactory receptor|odorant receptor]] gives [[negative feedback]] that prevents [[Transcription (biology)|transcription]] of other V1R receptor genes.<ref name="Capello_2009" /><ref name="Monahan_2015" /><ref name="Serizawa_2003" /><ref name="Lewcock_2004" /> In mice vomeronasal sensory neurons, an odorant receptor [[Coding region|coding sequence]]'s [[Exogeny|exogenous]] transcription from a V1R [[Promoter (genetics)|promoter]] can stop [[Endogeny (biology)|endogenous]] V1R genes from being transcribed.<ref name="Capello_2009" /><ref name="Monahan_2015" /><ref name="Serizawa_2003" /><ref name="Lewcock_2004" /> They<ref name="Capello_2009" /> also obtained data supporting [[Monoallelic gene expression|monoallelic expression]] of ''V1rb2<sup>mv</sup>'' and ''V1rb2<sup>vg</sup>'' alleles and monogenic expression of the ''V1rb2'' locus.<ref name="Capello_2009" />

Monoallelic expression was also found in [[Mouse|mice]] [[olfactory receptor]] genes in [[Olfactory receptor neuron|olfactory sensory neurons]].<ref name="Monahan_2015" /><ref name="Serizawa_2003" /><ref name="Lewcock_2004" /> An [[Upstream and downstream (DNA)|upstream]] [[Cis-regulatory element|cis-acting]] [[DNA]] region controls an olfactory receptor gene cluster's activation and resulted in monogenic expression of one olfactory receptor gene.<ref name="Monahan_2015" /><ref name="Serizawa_2003" /><ref name="Lewcock_2004" /> The expressed coding region's disruption or deletion resulted in expression of a second olfactory receptor gene.<ref name="Serizawa_2003" /> Based on this, they<ref name="Serizawa_2003" /> hypothesized that in order to enforce the "one receptor-one neuron rule” (Serizawa et al, 2003<ref name="Serizawa_2003" />), one olfactory receptor gene's [[Stochastic|random]] activation and the expressed gene product's [[negative feedback]] are necessary.<ref name="Monahan_2015" /><ref name="Serizawa_2003" /><ref name="Lewcock_2004" />

== Recent research ==
Intracellular [[GATA3]] expression is a crucial component of [[T-cell receptor|T cell receptor]] beta (TCR𝛽) allelic exclusion in [[mammal]]ian [[Cell (biology)|cells]].<ref name="Monahan_2015" /><ref name="Serizawa_2003" /><ref name="Lewcock_2004" /><ref name="Hosoya_2010">{{cite journal | vauthors = Hosoya T, Maillard I, Engel JD | title = From the cradle to the grave: activities of GATA-3 throughout T-cell development and differentiation | journal = Immunological Reviews | volume = 238 | issue = 1 | pages = 110–25 | date = November 2010 | pmid = 20969588 | pmc = 2965564 | doi = 10.1111/j.1600-065X.2010.00954.x }}</ref><ref name="Ho_2009">{{cite journal | vauthors = Ho IC, Tai TS, Pai SY | title = GATA3 and the T-cell lineage: essential functions before and after T-helper-2-cell differentiation | journal = Nature Reviews. Immunology | volume = 9 | issue = 2 | pages = 125–35 | date = February 2009 | pmid = 19151747 | pmc = 2998182 | doi = 10.1038/nri2476 }}</ref> GATA3 [[Transgene|transgenic]] overexpression by a 2.5- to 5-fold increase partly due to ''Gata3'' transcriptional activation from [[Monoallelic gene expression|monoallelic]] to biallelic primarily resulted in both [[allele]]s of TCR𝛽 [[Genetic recombination|recombining]].<ref name="Monahan_2015" /> Intracellular GATA3 expression can divide [[Wild type|wild-type]] immature [[thymocyte]] cell populations.<ref name="Monahan_2015" /><ref name="Serizawa_2003" /><ref name="Lewcock_2004" /><ref name="Hosoya_2010" /><ref name="Ho_2009" /> Although cells regardless of GATA3 expression level yielded functional TCR𝛽 sequences, there was nearly sole recombination of one ''Tcrb'' locus in lowly expressed GATA3 cells and constant recombination of both alleles in highly expressed GATA3 cells.<ref name="Monahan_2015" />

V𝛽 [[Recombination signal sequences]] (RSSs) with poor qualities suppressed one allele's expression of two TCR𝛽 genes.<ref name="Wu_2020">{{cite journal | vauthors = Wu GS, Bassing CH | title = Inefficient V(D)J recombination underlies monogenic T cell receptor β expression | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 117 | issue = 31 | pages = 18172–18174 | date = August 2020 | pmid = 32690689 | pmc = 7414081 | doi = 10.1073/pnas.2010077117 | bibcode = 2020PNAS..11718172W | doi-access = free }}</ref><ref name="Wu_2020b">{{cite journal | vauthors = Wu GS, Yang-Iott KS, Klink MA, Hayer KE, Lee KD, Bassing CH | title = Poor quality Vβ recombination signal sequences stochastically enforce TCRβ allelic exclusion | journal = The Journal of Experimental Medicine | volume = 217 | issue = 9 | date = September 2020 | pmid = 32526772 | doi = 10.1084/jem.20200412 | pmc = 7478721 | doi-access = free }}</ref> These poor quality V𝛽 RSSs decreased the chances of upstream V𝛽 and V31 recombination on the same allele, which in turn enabled functional TCR𝛽 genes’ monoallelic assembly and expression.<ref name="Wu_2020" /><ref name="Wu_2020b" /> However, poor quality V𝛽 RSSs were unlikely to result in monogenic TCR𝛽 expression alone and might have involved other [[Epigenetics|epigenetic]] processes.<ref name="Wu_2020" /><ref name="Wu_2020b" /> RSSs is involved in mammalian TCR𝛽 genes’ monogenic assembly and expression and may also be involved in other mammalian TCR-related genes.<ref name="Wu_2020" /> Low quality V𝛽 [[recombinase]] targets randomly constrain two functional rearrangements’ production which imposes TCR𝛽 allelic exclusion.<ref name="Wu_2020b" />

== References ==
{{Reflist}}

== Further reading ==
{{refbegin}}
* {{cite book | title = Cellular and Molecular Immunology | edition = 5th | vauthors = Abbas AK, Lichtman AH | publisher = Saunders | location = Philadelphia | date = 2003 }}
{{refend}}

[[Category:Genetics]]

Allelic exclusion - История изменений

Admin: 1 версия импортирована

ru>GreenC bot: Move 1 url. Wayback Medic 2.5 per WP:URLREQ#nih.gov