Bioinformatics Genetics Genetics Mutation

HyperMutations

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Somatic hypermutation is also known as SHM that is a cellular mechanism by which the immune system adjusts to the new foreign elements that confront it (e.g. microbes), as seen during class switching. A major component of the process of affinity maturation, SHM changes 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.

Somatic hypermutation includes a programmed process of mutation affecting the variable regions of immunoglobulin genes. Unlike germ-line mutation, SHM affects only an organism’s individual immune cells, and these mutations are not transmitted to the organism’s offspring. Mis-targeted somatic hypermutation is a likely mechanism in the development of B-cell lymphomas and many other cancers.

Hypermutation is a process in which point mutations gathered in the antibody V-regions of both the heavy and light chains, at rates that are about 106-fold higher than the background mutation rates observed in other genes. This accumulation of mutations at the V-region genes happens at the centroblast stage of B-cell differentiation in the germinal centers of secondary lymphoid organs. Whereas the overall goal of this process is to produce high-affinity antibodies, in the absence of selection, SHM does not distinguish between favorable and unfavorable mutations and can produce antibodies with 

  • higher affinity for antigen
  • lower affinity for antigen
  • no change in affinity for antigen

Somatic hypermutation can also lead to nonfunctional antibodies, such as antibodies that cannot fold correctly, or antibody genes that harbor premature stop codons. Whereas SHM of the antibody V-region does not always produce a higher-affinity antibody, the selection process for antigen binding that occurs in the light zone of the germinal center selects for B-cells that produce the highest-affinity antibodies. 

Somatic hypermutation is a key mechanism in producing antibody diversity. The details of the mechanisms and regulation of somatic hypermutation are unknown. In the human, somatic hypermutation occurs in the presence of antigen, unlike in sheep where antigen-independent somatic hypermutation occurs. The germinal centers of peripheral lymphoid tissues are the sites where somatic hypermutation, positive selection and differentiation of B cells with high-affinity receptors occur. 

There are many features characteristic of the hypermutation process: 

  • mutations are mainly point mutations, with very rare deletions or insertions of mostly single nucleotides
  • there is one strand of the double helix which is preferentially targeted
  • foreign DNA in the context of an immunoglobulin transgene is somatically mutated, suggesting that the targeted sequence itself does not initiate the mutation process
  • hotspots of mutation are observed at different positions in different sequences suggesting that the process is influenced by the primary DNA sequence
  • the 5′ boundary of mutations is within the leader intron
  • while there is no defined 3′ end-point of the mutation tract, mutation does not extend into the C region

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