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<title>Somatic hypermutation</title>

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<span id="openzim-page-title" class="mw-page-title-main"><span class="mw-page-title-main">Somatic hypermutation</span></span>

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<p><b>Somatic hypermutation</b> (or <b>SHM</b>) is a <a href="Cell_(biology)" title="Cell (biology)">cellular</a> mechanism by which the <a href="Adaptive_immune_system" title="Adaptive immune system">immune system</a> adapts to the new foreign elements that confront it (e.g. <a href="Microbes" class="mw-redirect" title="Microbes">microbes</a>). A major component of the process of <a href="Affinity_maturation" title="Affinity maturation">affinity maturation</a>, SHM diversifies <a href="B_cell" title="B cell">B cell</a> receptors used to recognize foreign elements (<a href="Antigen" title="Antigen">antigens</a>) and allows the immune system to adapt its response to new threats during the lifetime of an organism.<sup id="cite_ref-Janeway2005_1-0" class="reference"><a href="#cite_note-Janeway2005-1"><span class="cite-bracket">[</span>1<span class="cite-bracket">]</span></a></sup> Somatic hypermutation involves a programmed process of <a href="Mutation" title="Mutation">mutation</a> affecting the variable regions of <a href="Immunoglobulin" class="mw-redirect" title="Immunoglobulin">immunoglobulin</a> genes. Unlike <a href="Germline_mutation" title="Germline mutation">germline mutation</a>, SHM affects only an organism's individual <a href="Lymphocytes" class="mw-redirect" title="Lymphocytes">immune cells</a>, and the mutations are not transmitted to the organism's <a href="Offspring" title="Offspring">offspring</a>.<sup id="cite_ref-Oprea1999_2-0" class="reference"><a href="#cite_note-Oprea1999-2"><span class="cite-bracket">[</span>2<span class="cite-bracket">]</span></a></sup> Because this mechanism is merely selective and not precisely targeted, somatic hypermutation has been strongly implicated in the development of <a href="B-cell_lymphoma" title="B-cell lymphoma">B-cell lymphomas</a><sup id="cite_ref-Odegard2006_3-0" class="reference"><a href="#cite_note-Odegard2006-3"><span class="cite-bracket">[</span>3<span class="cite-bracket">]</span></a></sup> and many other cancers.<sup id="cite_ref-:18_4-0" class="reference"><a href="#cite_note-:18-4"><span class="cite-bracket">[</span>4<span class="cite-bracket">]</span></a></sup><sup id="cite_ref-:19_5-0" class="reference"><a href="#cite_note-:19-5"><span class="cite-bracket">[</span>5<span class="cite-bracket">]</span></a></sup>

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<div class="mw-heading mw-heading2"><h2 id="Targeting">Targeting</h2></div>

<p>When a B cell recognizes an antigen, it is stimulated to divide (or <a href="Cell_growth" title="Cell growth">proliferate</a>). During proliferation, the <a href="B-cell_receptor" title="B-cell receptor">B-cell receptor</a> <a href="Locus_(genetics)" title="Locus (genetics)">locus</a> undergoes an extremely high rate of <a href="Somatic_(biology)" title="Somatic (biology)">somatic</a> mutation that is at least <a href="Metric_prefix" title="Metric prefix">10<sup>5</sup>–10<sup>6</sup></a> fold greater than the normal rate of mutation across the genome.<sup id="cite_ref-Oprea1999_2-1" class="reference"><a href="#cite_note-Oprea1999-2"><span class="cite-bracket">[</span>2<span class="cite-bracket">]</span></a></sup> Variation is mainly in the form of <a href="Point_mutation" title="Point mutation">single-base substitutions</a>, with insertions and deletions being less common. These mutations occur mostly at "hotspots" in the <a href="DNA" title="DNA">DNA</a>, which are concentrated in <a href="Hypervariable_region" title="Hypervariable region">hypervariable regions</a>. These regions correspond to the <a href="Complementarity-determining_region" title="Complementarity-determining region">complementarity-determining regions</a>; the sites involved in antigen recognition on the immunoglobulin.<sup id="cite_ref-Li2004_6-0" class="reference"><a href="#cite_note-Li2004-6"><span class="cite-bracket">[</span>6<span class="cite-bracket">]</span></a></sup> 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.<sup id="cite_ref-:1_7-0" class="reference"><a href="#cite_note-:1-7"><span class="cite-bracket">[</span>7<span class="cite-bracket">]</span></a></sup><sup id="cite_ref-:2_8-0" class="reference"><a href="#cite_note-:2-8"><span class="cite-bracket">[</span>8<span class="cite-bracket">]</span></a></sup> The overall result of the hypermutation process is achieved by a balance between error-prone and high fidelity repair.<sup id="cite_ref-Liu2009_9-0" class="reference"><a href="#cite_note-Liu2009-9"><span class="cite-bracket">[</span>9<span class="cite-bracket">]</span></a></sup> 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 <a href="Antigen" title="Antigen">antigen</a>.<sup id="cite_ref-Janeway2005_1-1" class="reference"><a href="#cite_note-Janeway2005-1"><span class="cite-bracket">[</span>1<span class="cite-bracket">]</span></a></sup>

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<div class="mw-heading mw-heading2"><h2 id="Mechanisms">Mechanisms</h2></div>

<p>The mechanism of SHM involves <a href="Deamination" title="Deamination">deamination</a> of <a href="Cytosine" title="Cytosine">cytosine</a> to <a href="Uracil" title="Uracil">uracil</a> in DNA by the enzyme <a href="Activation-induced_cytidine_deaminase" title="Activation-induced cytidine deaminase">activation-induced cytidine deaminase</a>, or AID.<sup id="cite_ref-Teng2007_10-0" class="reference"><a href="#cite_note-Teng2007-10"><span class="cite-bracket">[</span>10<span class="cite-bracket">]</span></a></sup><sup id="cite_ref-Larson2004_11-0" class="reference"><a href="#cite_note-Larson2004-11"><span class="cite-bracket">[</span>11<span class="cite-bracket">]</span></a></sup> A cytosine:<a href="Guanine" title="Guanine">guanine</a> 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 <a href="Base_excision_repair" title="Base excision repair">base excision repair</a> <a href="Enzyme" title="Enzyme">enzymes</a>. The uracil bases are removed by the repair enzyme, <a href="Uracil-DNA_glycosylase" title="Uracil-DNA glycosylase">uracil-DNA glycosylase</a>,<sup id="cite_ref-Larson2004_11-1" class="reference"><a href="#cite_note-Larson2004-11"><span class="cite-bracket">[</span>11<span class="cite-bracket">]</span></a></sup> 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.<sup id="cite_ref-Teng2007_10-1" class="reference"><a href="#cite_note-Teng2007-10"><span class="cite-bracket">[</span>10<span class="cite-bracket">]</span></a></sup><sup id="cite_ref-Bachl2006_12-0" class="reference"><a href="#cite_note-Bachl2006-12"><span class="cite-bracket">[</span>12<span class="cite-bracket">]</span></a></sup>

</p><p>The synthesis of this new DNA involves error-prone <a href="DNA_polymerase" title="DNA polymerase">DNA polymerases</a>, which often introduce mutations at the position of the deaminated cytosine itself or neighboring <a href="Base_pair" title="Base pair">base pairs</a>. 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 <a href="Affinity_(pharmacology)" class="mw-redirect" title="Affinity (pharmacology)">affinities</a> for the antigen can be selected. The B cells with the greatest affinity will then be selected to differentiate into <a href="Plasma_cell" title="Plasma cell">plasma cells</a> producing <a href="Antibody" title="Antibody">antibody</a> and long-lived <a href="Memory_B_cell" title="Memory B cell">memory B cells</a> contributing to enhanced immune responses upon reinfection.<sup id="cite_ref-Oprea1999_2-2" class="reference"><a href="#cite_note-Oprea1999-2"><span class="cite-bracket">[</span>2<span class="cite-bracket">]</span></a></sup>

</p><p>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 <a href="Auto-immune" class="mw-redirect" title="Auto-immune">auto-immune</a> response.<sup id="cite_ref-13" class="reference"><a href="#cite_note-13"><span class="cite-bracket">[</span>13<span class="cite-bracket">]</span></a></sup>

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<div class="mw-heading mw-heading3"><h3 id="Somatic_gene_conversion">Somatic gene conversion</h3></div>

<p>In birds which have a very limited number of genes available to V(D)J recombination, <a href="Gene_conversion" title="Gene conversion">gene conversion</a> between pseudogenic V segments and the currently-active V segment occur with SMH, thereby introducing extra diversity. Mammals such as cattle, sheep, and horses have a sufficiently large selection for V(D)J, but they also perform somatic gene conversion. This kind of gene conversion is also started by the AID enzyme, leading to a double-strand break, which is then repaired by using other V or pseudogenic-V segments as templates. Humans are not known to perform such gene conversion, except for one report of indirect evidence.<sup id="cite_ref-14" class="reference"><a href="#cite_note-14"><span class="cite-bracket">[</span>14<span class="cite-bracket">]</span></a></sup>

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<ul><li><a href="Affinity_maturation" title="Affinity maturation">Affinity maturation</a></li>

<li><a href="Anergy" class="mw-redirect" title="Anergy">Anergy</a></li>

<li><a href="Immune_system" title="Immune system">Immune system</a></li>

<li><a href="V(D)J_recombination" title="V(D)J recombination">V(D)J recombination</a></li>

<li><a href="Immunoglobulin_class_switching" title="Immunoglobulin class switching">Immunoglobulin class switching</a></li></ul>

<div class="mw-heading mw-heading2"><h2 id="References">References</h2></div>

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<li id="cite_note-Bachl2006-12"><span class="mw-cite-backlink"><b><a href="#cite_ref-Bachl2006_12-0">^</a></b></span> <span class="reference-text"><cite id="CITEREFBachl,_J.Ertongur,_I.Jungnickel,_B.2006" class="citation journal cs1">Bachl, J.; Ertongur, I.; Jungnickel, B. (2006). <a rel="nofollow" class="external text" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1567700">"Involvement of Rad18 in somatic hypermutation"</a>. <i>Proc. Natl. Acad. Sci. USA</i>. <b>103</b> (32): <span class="nowrap">12081–</span>86. <a href="Bibcode_(identifier)" class="mw-redirect" title="Bibcode (identifier)">Bibcode</a>:<a rel="nofollow" class="external text" href="https://ui.adsabs.harvard.edu/abs/2006PNAS..10312081B">2006PNAS..10312081B</a>. <a href="Doi_(identifier)" class="mw-redirect" title="Doi (identifier)">doi</a>:<span class="id-lock-free" title="Freely accessible"><a rel="nofollow" class="external text" href="https://doi.org/10.1073%2Fpnas.0605146103">10.1073/pnas.0605146103</a></span>. <a href="PMC_(identifier)" class="mw-redirect" title="PMC (identifier)">PMC</a> <span class="id-lock-free" title="Freely accessible"><a rel="nofollow" class="external text" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1567700">1567700</a></span>. <a href="PMID_(identifier)" class="mw-redirect" title="PMID (identifier)">PMID</a> <a rel="nofollow" class="external text" href="https://pubmed.ncbi.nlm.nih.gov/16873544">16873544</a>.</cite></span>

</li>

<li id="cite_note-13"><span class="mw-cite-backlink"><b><a href="#cite_ref-13">^</a></b></span> <span class="reference-text"><cite id="CITEREFMetzger2011" class="citation journal cs1">Metzger, T.C. (2011). <a rel="nofollow" class="external text" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3093413">"Control of Central and Peripheral Tolerance by Aire"</a>. <i>Immunological Reviews</i>. <b>241</b> (1): <span class="nowrap">89–</span>103. <a href="Doi_(identifier)" class="mw-redirect" title="Doi (identifier)">doi</a>:<a rel="nofollow" class="external text" href="https://doi.org/10.1111%2Fj.1600-065X.2011.01008.x">10.1111/j.1600-065X.2011.01008.x</a>. <a href="PMC_(identifier)" class="mw-redirect" title="PMC (identifier)">PMC</a> <span class="id-lock-free" title="Freely accessible"><a rel="nofollow" class="external text" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3093413">3093413</a></span>. <a href="PMID_(identifier)" class="mw-redirect" title="PMID (identifier)">PMID</a> <a rel="nofollow" class="external text" href="https://pubmed.ncbi.nlm.nih.gov/21488892">21488892</a>.</cite></span>

</li>

<li id="cite_note-14"><span class="mw-cite-backlink"><b><a href="#cite_ref-14">^</a></b></span> <span class="reference-text"><cite id="CITEREFMallabyMwangiNgStewart2023" class="citation journal cs1">Mallaby, Jessica; Mwangi, William; Ng, Joseph; Stewart, Alexander; Dorey-Robinson, Daniel; Kipling, David; Hershberg, Uri; Fraternali, Franca; Nair, Venugopal; Dunn-Walters, Deborah (1 January 2023). <a rel="nofollow" class="external text" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10917233">"Diversification of immunoglobulin genes by gene conversion in the domestic chicken ( Gallus gallus domesticus)"</a>. <i>Discovery Immunology</i>. <b>2</b> (1). <a href="Doi_(identifier)" class="mw-redirect" title="Doi (identifier)">doi</a>:<a rel="nofollow" class="external text" href="https://doi.org/10.1093%2Fdiscim%2Fkyad002">10.1093/discim/kyad002</a>. <a href="PMC_(identifier)" class="mw-redirect" title="PMC (identifier)">PMC</a> <span class="id-lock-free" title="Freely accessible"><a rel="nofollow" class="external text" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10917233">10917233</a></span>.</cite></span>

</li>

</ol></div>

<div class="mw-heading mw-heading2"><h2 id="External_links">External links</h2></div>

<ul><li><a rel="nofollow" class="external text" href="https://meshb.nlm.nih.gov/record/ui?name=Immunoglobulin+somatic+hypermutation">Immunoglobulin+somatic+hypermutation</a> at the U.S. National Library of Medicine <a href="Medical_Subject_Headings" title="Medical Subject Headings">Medical Subject Headings</a> (MeSH)</li></ul>

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</style><div id="Lymphocytic_adaptive_immune_system_and_complement123" style="font-size:114%;margin:0 4em"><a href="Lymphocyte" title="Lymphocyte">Lymphocytic</a> <a href="Adaptive_immune_system" title="Adaptive immune system">adaptive immune system</a> and <a href="Complement_system" title="Complement system">complement</a></div></th></tr><tr><th scope="row" class="navbox-group" style="width:1%">Lymphoid</th><td class="navbox-list-with-group navbox-list navbox-odd hlist" style="width:100%;padding:0"><div style="padding:0 0.25em"></div><table class="nowraplinks navbox-subgroup" style="border-spacing:0"><tbody><tr><th scope="row" class="navbox-group" style="width:1%">Antigens</th><td class="navbox-list-with-group navbox-list navbox-odd" style="width:100%;padding:0"><div style="padding:0 0.25em">

<ul><li><a href="Antigen" title="Antigen">Antigen</a>

<ul><li><a href="Superantigen" title="Superantigen">Superantigen</a></li>

<li><a href="Allergen" title="Allergen">Allergen</a></li>

<li><a href="Antigenic_variation" title="Antigenic variation">Antigenic variation</a></li></ul></li>

<li><a href="Hapten" title="Hapten">Hapten</a></li></ul>

<ul><li><a href="Epitope" title="Epitope">Epitope</a>

<ul><li><a href="Linear_epitope" title="Linear epitope">Linear</a></li>

<li><a href="Conformational_epitope" title="Conformational epitope">Conformational</a></li></ul></li>

<li><a href="Mimotope" title="Mimotope">Mimotope</a></li></ul>

<ul><li><a href="Antigen_presentation" title="Antigen presentation">Antigen presentation</a>/<a href="Antigen-presenting_cell" title="Antigen-presenting cell">professional APCs</a>: <a href="Dendritic_cell" title="Dendritic cell">Dendritic cell</a></li>

<li><a href="Macrophage" title="Macrophage">Macrophage</a></li>

<li><a href="Immunogen" title="Immunogen">Immunogen</a></li></ul>

</div></td></tr><tr><th scope="row" class="navbox-group" style="width:1%">Antibodies</th><td class="navbox-list-with-group navbox-list navbox-even" style="width:100%;padding:0"><div style="padding:0 0.25em">

<ul><li><a href="Antibody" title="Antibody">Antibody</a>

<ul><li><a href="Monoclonal_antibody" title="Monoclonal antibody">Monoclonal antibodies</a></li>

<li><a href="Polyclonal_antibodies" title="Polyclonal antibodies">Polyclonal antibodies</a></li>

<li><a href="Autoantibody" title="Autoantibody">Autoantibody</a></li>

<li><a href="Microantibody" title="Microantibody">Microantibody</a></li></ul></li>

<li><a href="Polyclonal_B_cell_response" title="Polyclonal B cell response">Polyclonal B cell response</a></li>

<li><a href="Allotype_(immunology)" title="Allotype (immunology)">Allotype</a></li>

<li><a href="Isotype_(immunology)" title="Isotype (immunology)">Isotype</a></li>

<li><a href="Idiotype" title="Idiotype">Idiotype</a></li></ul>

<ul><li><a href="Immune_complex" title="Immune complex">Immune complex</a></li>

<li><a href="Paratope" title="Paratope">Paratope</a></li></ul>

</div></td></tr><tr><th scope="row" class="navbox-group" style="width:1%">Immunity vs.<br> tolerance</th><td class="navbox-list-with-group navbox-list navbox-odd" style="width:100%;padding:0"><div style="padding:0 0.25em">

<ul><li>Action: <a href="Immunity_(medical)" class="mw-redirect" title="Immunity (medical)">Immunity</a></li>

<li><a href="Autoimmunity" title="Autoimmunity">Autoimmunity</a></li>

<li><a href="Alloimmunity" title="Alloimmunity">Alloimmunity</a></li>

<li><a href="Allergy" title="Allergy">Allergy</a></li>

<li><a href="Hypersensitivity" title="Hypersensitivity">Hypersensitivity</a></li>

<li><a href="Inflammation" title="Inflammation">Inflammation</a></li>

<li><a href="Cross-reactivity" title="Cross-reactivity">Cross-reactivity</a></li>

<li><a href="Co-stimulation" title="Co-stimulation">Co-stimulation</a></li></ul>

<ul><li>Inaction: <a href="Immune_tolerance" title="Immune tolerance">Tolerance</a>

<ul><li><a href="Central_tolerance" title="Central tolerance">Central</a></li>

<li><a href="Peripheral_tolerance" title="Peripheral tolerance">Peripheral</a></li>

<li><a href="Clonal_anergy" title="Clonal anergy">Clonal anergy</a></li>

<li><a href="Clonal_deletion" title="Clonal deletion">Clonal deletion</a></li>

<li><a href="T-cell_depletion" title="T-cell depletion">T-cell depletion</a></li>

<li><a href="Immune_tolerance_in_pregnancy" title="Immune tolerance in pregnancy">Tolerance in pregnancy</a></li></ul></li>

<li><a href="Immunodeficiency" title="Immunodeficiency">Immunodeficiency</a></li>

<li><a href="Immune_privilege" title="Immune privilege">Immune privilege</a></li></ul>

</div></td></tr><tr><th scope="row" class="navbox-group" style="width:1%"><a href="Immunogenetics" title="Immunogenetics">Immunogenetics</a></th><td class="navbox-list-with-group navbox-list navbox-even" style="width:100%;padding:0"><div style="padding:0 0.25em">

<ul><li><a href="Affinity_maturation" title="Affinity maturation">Affinity maturation</a>

<ul>

<li><a href="Clonal_selection" title="Clonal selection">Clonal selection</a></li></ul></li>

<li><a href="V(D)J_recombination" title="V(D)J recombination">V(D)J recombination</a></li>

<li><a href="Junctional_diversity" title="Junctional diversity">Junctional diversity</a></li>

<li><a href="Immunoglobulin_class_switching" title="Immunoglobulin class switching">Immunoglobulin class switching</a></li>

</div></td></tr></tbody></table><div></div></td></tr><tr><th scope="row" class="navbox-group" style="width:1%"><a href="Lymphocyte" title="Lymphocyte">Lymphocytes</a></th><td class="navbox-list-with-group navbox-list navbox-odd hlist" style="width:100%;padding:0"><div style="padding:0 0.25em">

<ul><li><a href="Cell-mediated_immunity" title="Cell-mediated immunity">Cellular</a>

<li><a href="Humoral_immunity" title="Humoral immunity">Humoral</a>

</div></td></tr><tr><th scope="row" class="navbox-group" style="width:1%">Substances</th><td class="navbox-list-with-group navbox-list navbox-even hlist" style="width:100%;padding:0"><div style="padding:0 0.25em">

<ul><li><a href="Cytokine" title="Cytokine">Cytokines</a></li>

<li><a href="Opsonin" title="Opsonin">Opsonin</a></li>

<li><a href="Cytolysin" title="Cytolysin">Cytolysin</a></li></ul>

</div></td></tr></tbody></table></div></div><div><div class="zim-footer">

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