Somatic hypermutation (or SHM) is a cellular mechanism by which the

immune system The immune system is a network of biological systems that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to bacteria, as well as Tumor immunology, cancer cells, Parasitic worm, parasitic ...

adapts to the new foreign elements that confront it (e.g.

microbes A microorganism, or microbe, is an organism of microscopic size, which may exist in its single-celled form or as a colony of cells. The possible existence of unseen microbial life was suspected from antiquity, with an early attestation in ...

). A major component of the process of

affinity maturation In immunology, affinity maturation is the process by which TFH cell-activated B cells produce antibodies with increased affinity for antigen during the course of an immune response. With repeated exposures to the same antigen, a host will produce ...

, SHM diversifies

B cell B cells, also known as B lymphocytes, are a type of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or inserted into the plasm ...

receptors used to recognize foreign elements (

antigen In immunology, an antigen (Ag) is a molecule, moiety, foreign particulate matter, or an allergen, such as pollen, that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. ...

s) and allows the immune system to adapt its response to new threats during the lifetime of an organism. Somatic hypermutation involves a programmed process of

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, ...

affecting the variable regions of

immunoglobulin An antibody (Ab) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as pathogenic bacteria, bacteria and viruses, includin ...

genes. Unlike

germline mutation A germline mutation, or germinal mutation, is any detectable variation within germ cells (cells that, when fully developed, become sperm and Egg cell, ova). Mutations in these cells are the only mutations that can be passed on to offspring, when e ...

, SHM affects only an organism's individual

immune cells White blood cells (scientific name leukocytes), also called immune cells or immunocytes, are cells of the immune system that are involved in protecting the body against both infectious disease and foreign entities. White blood cells are genera ...

, and the mutations are not transmitted to the organism's

offspring In biology, offspring are the young creation of living organisms, produced either by sexual reproduction, sexual or asexual reproduction. Collective offspring may be known as a brood or progeny. This can refer to a set of simultaneous offspring ...

.Oprea, M. (1999
''Antibody Repertoires and Pathogen Recognition:''
The Role of Germline Diversity and Somatic Hypermutation'' (Thesis) University of Leeds.'' Because this mechanism is merely selective and not precisely targeted, somatic hypermutation has been strongly implicated in the development of B-cell lymphomas and many other cancers.

Targeting

When a B cell recognizes an antigen, it is stimulated to divide (or proliferate). During proliferation, the

B-cell receptor The B-cell receptor (BCR) is a transmembrane protein on the surface of a B cell. A B-cell receptor is composed of a membrane-bound immunoglobulin molecule and a signal transduction moiety. The former forms a type 1 Transmembrane protein, transmemb ...

locus undergoes an extremely high rate of somatic mutation that is at least 10⁵–10⁶ fold greater than the normal rate of mutation across the genome. 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 Deoxyribonucleic acid (; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of al ...

, which are concentrated in hypervariable regions. These regions correspond to the complementarity-determining regions; the sites involved in antigen recognition on the immunoglobulin. 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. The overall result of the hypermutation process is achieved by a balance between error-prone and high fidelity repair. 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

Mechanisms

The mechanism of SHM involves

deamination Deamination is the removal of an amino group from a molecule. Enzymes that catalysis, catalyse this reaction are called deaminases. In the human body, deamination takes place primarily in the liver; however, it can also occur in the kidney. In s ...

cytosine Cytosine () (symbol C or Cyt) is one of the four nucleotide bases found in DNA and RNA, along with adenine, guanine, and thymine ( uracil in RNA). It is a pyrimidine derivative, with a heterocyclic aromatic ring and two substituents attac ...

uracil Uracil () (nucleoside#List of nucleosides and corresponding nucleobases, symbol U or Ura) is one of the four nucleotide bases in the nucleic acid RNA. The others are adenine (A), cytosine (C), and guanine (G). In RNA, uracil binds to adenine via ...

in DNA by the enzyme activation-induced cytidine deaminase, or AID. A cytosine:

guanine Guanine () (symbol G or Gua) is one of the four main nucleotide bases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine ( uracil in RNA). In DNA, guanine is paired with cytosine. The guanine nucleoside ...

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

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

s. The uracil bases are removed by the repair enzyme, uracil-DNA glycosylase, 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. The synthesis of this new DNA involves error-prone

DNA polymerase A DNA polymerase is a member of a family of enzymes that catalyze the synthesis of DNA molecules from nucleoside triphosphates, the molecular precursors of DNA. These enzymes are essential for DNA replication and usually work in groups to create t ...

s, which often introduce mutations at the position of the deaminated cytosine itself or neighboring

base pair A base pair (bp) is a fundamental unit of double-stranded nucleic acids consisting of two nucleobases bound to each other by hydrogen bonds. They form the building blocks of the DNA double helix and contribute to the folded structure of both DNA ...

s. 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 cell Plasma cells, also called plasma B cells or effector B cells, are white blood cells that originate in the lymphoid organs as B cells and secrete large quantities of proteins called antibodies in response to being presented specific substances ca ...

s producing

antibody An antibody (Ab) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as pathogenic bacteria, bacteria and viruses, includin ...

and long-lived

memory B cell In immunology, a memory B cell (MBC) is a type of B lymphocyte that forms part of the adaptive immune system. These cells develop within germinal centers of the secondary lymphoid organs. Memory B cells circulate in the blood stream in a quie ...

s contributing to enhanced immune responses upon reinfection. 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.

Somatic gene conversion

In birds which have a very limited number of genes available to V(D)J recombination,

gene conversion Gene conversion is the process by which one DNA sequence replaces a homologous sequence such that the sequences become identical after the conversion. Gene conversion can be either allelic, meaning that one allele of the same gene replaces another ...

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.

References

External links

* {{Immune system Immune system Antibodies

Targeting

Mechanisms

Somatic gene conversion

See also

References

External links