Somatic mutation, or
somatic hypermutation (
SHM) is a
diversity generating, regulated
cellular mechanism displayed by the
adaptive immune response.
▼
activation B cells :
activation-induced (cytidine) deaminase :
affinity maturation :
AID :
antibody diversification :
antibody production :
base excision repair :
BCR :
BER :
C to U :
class-switch recombination :
CSR :
deoxycytidine,
deoxyuracil :
deletions :
DNA polymerase :
GC :
gene-conversion :
hypermutation :
immunoglobulins :
indels :
insertions :
memory B cells :
plasma cells :
secondary antibody diversification :
single nucleotide polymorphism :
somatic hypermutation,
somatic mutation :
SNP :
transmission :
uracil-DNA glycosylase :
V region ▼
AID-generated
somatic hypermutations affect the
variable (V) regions of genes encoding immunoglobulins. Somatic (hyper)mutation affects only individual cells of the immune system, so the programmed mutations that it generates are transmitted only within the particular cell line (somatic) and are not transmitted to the organism's offspring.
Following
activation of
naïve B cells and during the subsequent
antigen-stimulated
proliferation of
B cells, the gene locus for the
Ig-
BCR experiences a
highly accelerated rate of somatic mutation (increased by a factor of 10^5 to 10^6). That is, mutation rate is roughly 1 per 1,000 for each V gene base pair per cell division
compared to 1 per 1,000,000 for each base pair per cell division for 'regular' DNA. This acceleration is attributable to the enzyme
activation-induced (cytidine) deaminase (
AID), which extracts the amino group from a
deoxycytidine base in
DNA, converting deoxycytidine to
deoxyuracil. Deoxycytidine is a
nucleoside formed through attachment of the nucleobase
cytosine to a
deoxyribose ring via a β-N1-glycosidic bond, and deamination of
cytosine generates
uracil []im
C to U[].
AID is currently considered the
master regulator of
secondary antibody diversification because it is involved in the initiation of three distinct
immunoglobulin diversification processes:
somatic hypermutation (SHM),
class-switch recombination (
CSR), and
gene-conversion (
GC).
AID-catalyzed deamination of deoxycytidine creates a
single nucleotide polymorphism (
SNP) in the DNA strand by generating a
uracil:
guanine mismatch. The nucleobases that normally occur in
DNA are
adenine paired with
thymine, and
cytosine paired with
guanine.
Uracil is normally found only in
RNA, where it is paired with
adenine.
A high-fidelity
DNA repair enzyme,
uracil-DNA glycosylase (UNG2), excises the alien
uracil nucleobase, then error-prone
DNA polymerases complete the
base-excision repair process. During this base-excision repair, incorrect nucleobases may be substituted at or adjacent to the original
C to U mutation site.
Mispairing mutations are susceptible to
indels -
insertions and
deletions. Such mutation vulnerable areas in the genome are termed 'hotspots', and they have played a significant role in
biological evolution.
When the
B cell proliferates,
AID-generated
somatic hypermutations are
transcribed and
translated into thousands of slightly different
immunoglobulins coded by the hypermutated V regions. Ultimately, those B cells that express
Ig-
antibodies (
BCRs) with greatest affinity for encountered antigen will differentiate into
memory B cells plus
plasma cells that produce affinity-specified
antibodies against the
cognate, stimulating
antigen.
Affinity maturation ensures that repeated encounter with the same antigen will induce production of antibody with greater affinity.
Tables
Fc receptors
Immune Cytokines
ImmunoglobulinsLabels: AID-enzyme, class-switch recombination, gene conversion, immunoglobulins, secondary antibody diversification, somatic hypermutation
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