Dual enigma of somatic hypermutation of immunoglobulin variable genes: targeting and mechanism

Abstract

The immunoglobulin loci are uniquely unstable regions of the genome which undergo as much mutation and selection in a matter of days as a species can undergo in generations of evolution. We have studied the mutational pattern and targeting of this unusual hypermutation process over the past 16 years. The pattern of somatic mutations in rearranged variable (V) genes differs from the pattern of meiotic mutations, indicating that a different mechanism generates hypermutation than generates spontaneous mutation. Hypermutations begin on the 5' end of rearranged V genes downstream of the transcription initiation site and continue through the V exon and into the 3'-flanking region before tapering off. Mutations are located randomly throughout the DNA sequence and exhibit strand bias. The targeting of mutations to the region in and around the rearranged V gene appears to require interactions between the promoter and downstream intronic DNA sequences. The same mechanism that initiates hypermutation around V genes may also produce double-strand breaks that catalyze homologous recombination between rearranged V genes on two chromosomal alleles. With this data we have built a model of hypermutation which predicts that V-region DNA is destabilized at the nuclear matrix during transcription and undergoes strand breaks.

Increased Transcription Levels Induce Higher Mutation Rates in a Hypermutating Cell Line

“…A correlation between the mutation frequency and the transcription level in the Ig loci has been reported by Fukita et al (15,16). We used here a previously described green fluorescent protein (GFP) 3 -based assay (17,18) to directly investigate the linkage of transcription levels and mutation rate in the hypermutating pre-B cell line 18-81 (19). A GFP transgene containing a premature stop codon, which renders the GFP gene nonfunctional, was stably transfected into cell line 18-81.…”

“…Ϫ4 mutations/base pair/generation, a rate that is some million-fold higher than the spontaneous mutation rate in the rest of the genome (2,3). The hypermutable segment in the Ig genes encompasses an ϳ2-kb stretch of DNA that includes the rearranged V(D)J segment and thus defines Ag receptor specificity (4 -6).…”

Analysis of Mutational Lineage Trees from Sites of Primary and Secondary Ig Gene Diversification in Rabbits and Chickens

“…I n humans and mice, primary diversification of Ig genes occurs throughout life by gene rearrangement in progenitor B cells in the bone marrow (1)(2)(3)(4), and secondary diversification occurs in the course of affinity maturation of the cells' Ag receptors, via somatic hypermutation of receptor genes and Ag-driven selection of the resulting mutants (5)(6)(7)(8)(9)(10). However, this is not the rule in all species.…”

B‐cell clonal diversification and gut‐lymph node trafficking in ulcerative colitis revealed using lineage tree analysis

“…SHM of immunoglobulin (Ig) variable region (IgV) genes is million-fold faster than normal somatic mutation, and uses different mechanisms [19][20][21]; it depends on transcription, activationinduced cytidine deaminase and DNA mismatch repair, and is mechanistically related to class switch recombination [22]. It is as yet unknown how SHM is triggered, although germinal center initiation and its structural organization [23][24][25] are known to require both cognate and co-stimulatory interactions with T cells [26,27], and are assumed to involve B cells that are already participating in the response.…”

“…It is as yet unknown how SHM is triggered, although germinal center initiation and its structural organization [23][24][25] are known to require both cognate and co-stimulatory interactions with T cells [26,27], and are assumed to involve B cells that are already participating in the response. SHM may be triggered, and possibly be also maintained in germinal center B cells, by immune complexes formed by IgG antibodies bound to the antigen [15,19,28,29]. It is particularly not clear how the processes of SHM and selection interact dynamically and temporally to shape the memory B-cell repertoire, on which the system depends for fast antigen elimination in subsequent encounters [30][31][32][33], although several models have been suggested based on imaging studies [34][35][36].…”