{{Short description|Cellular mechanism in B cells}} '''Somatic hypermutation''' (or '''SHM''') is a cellular mechanism by which the immune system adapts to the new foreign elements that confront it (e.g. microbes). A major component of the process of affinity maturation, SHM diversifies B cell receptors used to recognize foreign elements (antigens) and allows the immune system to adapt its response to new threats during the lifetime of an organism.<ref name="Janeway2005">{{cite book| author=Janeway, C.A.|author2=Travers, P.|author3=Walport, M.|author4=Shlomchik, M.J. |year=2005 |title=Immunobiology |edition=6th |publisher=Garland Science |isbn=978-0-8153-4101-7}}</ref> Somatic hypermutation involves a programmed process of mutation affecting the variable regions of immunoglobulin genes. Unlike germline mutation, SHM affects only an organism's individual immune cells, and the mutations are not transmitted to the organism's offspring.<ref name="Oprea1999">Oprea, M. (1999) [http://www.santafe.edu/~mihaela/thesis/version_short.html ''Antibody Repertoires and Pathogen Recognition:''] {{webarchive|url=https://web.archive.org/web/20080906130252/http://www.santafe.edu/~mihaela/thesis/version_short.html |date=2008-09-06 }} The Role of Germline Diversity and Somatic Hypermutation'' (Thesis) University of Leeds.''</ref> Because this mechanism is merely selective and not precisely targeted, somatic hypermutation has been strongly implicated in the development of B-cell lymphomas<ref name="Odegard2006">{{cite journal|year=2006|title=Targeting of somatic hypermutation|journal=Nat. Rev. Immunol.|volume=6|issue=8|pages=573–583|doi=10.1038/nri1896|pmid=16868548|author1=Odegard V.H.|author2=Schatz D.G.|s2cid=6477436}}</ref> and many other cancers.<ref name=":18">{{Cite journal|last1=Steele|first1=E.J.|last2=Lindley|first2=R.A.|year=2010|title=Somatic mutation patterns in non-lymphoid cancers resemble the strand biased somatic hypermutation spectra of antibody genes|url=http://researchrepository.murdoch.edu.au/id/eprint/4482/1/Somatic_mutation_patterns.pdf|journal=DNA Repair|volume=9|issue=6|pages=600–603|doi=10.1016/j.dnarep.2010.03.007|pmid=20418189}}</ref><ref name=":19">{{Cite journal|last1=Lindley|first1=R.A.|last2=Steele|first2=E.J.|year=2013|title=Critical analysis of strand-biased somatic mutation signatures in TP53 versus Ig genes, in genome -wide data and the etiology of cancer|url=https://www.hindawi.com/journals/isrn/2013/921418/|journal=ISRN Genomics|volume=2013 Article ID 921418|pages=18 pages}}</ref>
==Targeting==
thumb|400px|Simplistic overview of V(D)J recombination and somatic hypermutations at the immunoglobulin heavy chain variable region. Abbreviation of the regions: C = constant, D = diversity, J = joining, V = variable, L = light, H = heavy, FW = frame work, CDR = complementarity-determining regions, N = junctional diversity sequence.
When a B cell recognizes an antigen, it is stimulated to divide (or proliferate). During proliferation, the B-cell receptor locus undergoes an extremely high rate of somatic mutation that is at least 10<sup>5</sup>–10<sup>6</sup> fold greater than the normal rate of mutation across the genome.<ref name= "Oprea1999"/> Variation is mainly in the form of single-base substitutions, with insertions and deletions being less common. These mutations occur mostly at "hotspots" in the DNA, which are concentrated in hypervariable regions. These regions correspond to the complementarity-determining regions; the sites involved in antigen recognition on the immunoglobulin.<ref name="Li2004">{{cite journal| author=Li, Z.|author2=Wool, C.J.|author3=Iglesias-Ussel|author4=M.D., Ronai, D.|author5=Scharff, M.D. |year=2004 |title=The generation of antibody diversity through somatic hypermutation and class switch recombination |journal=Genes & Development |volume=18 |pages=1–11| doi=10.1101/gad.1161904| pmid=14724175| issue=1 | url=http://genesdev.cshlp.org/content/18/1/1.full|doi-access=free}}</ref> The "hotspots" of somatic hypermutation vary depending on the base that is being mutated. RGYW (i.e. A/G G C/T A/T) for a G, WRCY for a C, WA for an A and TW for a T.<ref name=":1">{{cite journal|last1=Dunn-Walters|first1=DK|last2=Dogan|first2=A|last3=Boursier|first3=L|last4=MacDonald|first4=CM|last5=Spencer|first5=J|title=Base-specific sequences that bias somatic hypermutation deduced by analysis of out of frame genes.|journal=J. Immunol.|date=1998|volume=160|pages=2360–64|doi=10.4049/jimmunol.160.5.2360 |s2cid=23647692 |doi-access=free}}</ref><ref name=":2">{{cite journal|last1=Spencer|first1=J|last2=Dunn-Walters|first2=DK|title=Hypermutation at A-T base pairs: The A nucleotide replacement spectrum is affected by adjacent nucleotides and there is no reverse complementarity of sequences around A and T nucleotides.|journal=J. Immunol.|date=2005|volume=175|issue=8|pages=5170–77|doi=10.4049/jimmunol.175.8.5170|pmid=16210621|doi-access=free}}</ref> The overall result of the hypermutation process is achieved by a balance between error-prone and high fidelity repair.<ref name="Liu2009">{{cite journal| author=Liu, M.|author2=Schatz, D.G. | year=2009 |title=Balancing AID and DNA repair during somatic hypermutation |volume=30 |pages=173–181 |url=http://www.cell.com/trends/immunology/abstract/S1471-4906%2809%2900042-8| doi=10.1016/j.it.2009.01.007| journal=Trends in Immunology| issue=4| pmid=19303358| url-access=subscription}}</ref> This directed hypermutation allows for the selection of B cells that express immunoglobulin receptors possessing an enhanced ability to recognize and bind a specific foreign antigen.<ref name="Janeway2005"/>
==Mechanisms== [[File:Cytosine chemical structure.svg|thumb|75px|Cytosine]] [[File:Uracil.svg|thumb|75px|Uracil]] The mechanism of SHM involves deamination of cytosine to uracil in DNA by the enzyme activation-induced cytidine deaminase, or AID.<ref name="Teng2007">{{cite journal |author1=Teng, G. |author2=Papavasiliou, F.N. |year=2007 |title=Immunoglobulin Somatic Hypermutation |journal=Annu. Rev. Genet. |volume=41 |pages=107–120 |doi=10.1146/annurev.genet.41.110306.130340 |pmid=17576170 }}</ref><ref name="Larson2004">{{cite journal|author1=Larson, E.D. |author2=Maizels, N. |year=2004 |title=Transcription-coupled mutagenesis by the DNA deaminase AID |journal=Genome Biol. |volume=5 |pages=211| doi=10.1186/gb-2004-5-3-211| pmid=15003109| issue=3| pmc=395756 | url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=15003109 | archive-url=https://archive.today/20130801121913/http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=15003109 | url-status=dead | archive-date=August 1, 2013 |doi-access=free }}</ref> A cytosine:guanine pair is thus directly mutated to a uracil:guanine mismatch. Uracil residues are not normally found in DNA, therefore, to maintain the integrity of the genome, most of these mutations must be repaired by high-fidelity base excision repair enzymes. The uracil bases are removed by the repair enzyme, uracil-DNA glycosylase,<ref name="Larson2004"/> followed by cleavage of the DNA backbone by apurinic endonuclease. Error-prone DNA polymerases are then recruited to fill in the gap and create mutations.<ref name="Teng2007"/><ref name="Bachl2006">{{cite journal| author=Bachl, J.|author2=Ertongur, I.|author3=Jungnickel, B. |year=2006 |title=Involvement of Rad18 in somatic hypermutation |journal=Proc. Natl. Acad. Sci. USA |volume=103 |pages=12081–86 | doi=10.1073/pnas.0605146103| issue=32 | pmid=16873544 | pmc=1567700|bibcode=2006PNAS..10312081B|doi-access=free}}</ref>
The synthesis of this new DNA involves error-prone DNA polymerases, which often introduce mutations at the position of the deaminated cytosine itself or neighboring base pairs. The introduction of mutations in the rapidly proliferating population of B cells ultimately culminates in the production of thousands of B cells, possessing slightly different receptors and varying specificity for the antigen, from which the B cell with highest affinities for the antigen can be selected. The B cells with the greatest affinity will then be selected to differentiate into plasma cells producing antibody and long-lived memory B cells contributing to enhanced immune responses upon reinfection.<ref name= "Oprea1999"/>
The hypermutation process also utilizes cells that auto-select against the 'signature' of an organism's own cells. It is hypothesized that failures of this auto-selection process may also lead to the development of an auto-immune response.<ref>{{Cite journal|last=Metzger|first=T.C.|title=Control of Central and Peripheral Tolerance by Aire|journal=Immunological Reviews|year=2011|volume=241 |issue=1|pages=89–103|doi=10.1111/j.1600-065X.2011.01008.x|pmid=21488892|pmc=3093413}}</ref>
=== Somatic gene conversion === Alternation of DNA by the AID enzyme can also lead to double-strand breaks, which is repaired by gene conversion between similar segments. This process is important for generating antibody diversity in birds because they have a very limited number of genes available for V(D)J recombination. The bird genomes have a large number of pseudogenic V segments which are effectively used by this additional recombination process.<ref name=Mallaby23>{{cite journal |last1=Mallaby |first1=Jessica |last2=Mwangi |first2=William |last3=Ng |first3=Joseph |last4=Stewart |first4=Alexander |last5=Dorey-Robinson |first5=Daniel |last6=Kipling |first6=David |last7=Hershberg |first7=Uri |last8=Fraternali |first8=Franca |last9=Nair |first9=Venugopal |last10=Dunn-Walters |first10=Deborah |title=Diversification of immunoglobulin genes by gene conversion in the domestic chicken ( Gallus gallus domesticus) |journal=Discovery Immunology |date=1 January 2023 |volume=2 |issue=1 |doi=10.1093/discim/kyad002|pmc=10917233 }}</ref>
Mammals such as cattle, sheep, and horses have a sufficiently large selection for V(D)J, but they also perform somatic gene conversion. Humans are not known to perform such gene conversion, except for one report of indirect evidence.<ref name=Mallaby23/>
==See also== * Affinity maturation * Anergy * Immune system * V(D)J recombination * Immunoglobulin class switching
==References== {{reflist|30em}}
==External links== * {{MeshName|Immunoglobulin+somatic+hypermutation}} {{Immune system}}
Category:Immune system Category:Antibodies