Somatic hypermutation of VHS107 genes is not associated with gene conversion among family members

Activation-induced deaminase (AID) is a protein indispensable for the diversification of immunoglobulin (Ig) genes by somatic hypermutation (SHM), class switch recombination (CSR), and gene conversion. To date, the precise role of AID in these processes has not been determined. Here we demonstrate that purified, tetrameric AID can deaminate cytidine residues in DNA, but not in RNA. Furthermore, we show that AID will bind and deaminate only single-stranded DNA, which implies a direct, functional link between hypermutation and transcription. Finally, AID does not target mutational hotspots, thus mutational targeting to specific residues must be attributed to different factors.

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Control of gene conversion and somatic hypermutation by immunoglobulin promoter and enhancer sequences

Journal of Experimental Medicine ◽

10.1084/jem.20061835 ◽

2006 ◽

Vol 203 (13) ◽

pp. 2919-2928 ◽

Cited By ~ 42

Author(s):

Shu Yuan Yang ◽

Sebastian D. Fugmann ◽

David G. Schatz

Keyword(s):

Rna Polymerase Ii ◽

Gene Conversion ◽

Transcriptional Control ◽

Somatic Hypermutation ◽

Cytidine Deaminase ◽

Cis Acting ◽

Gene Diversification ◽

Combined Action ◽

High Level ◽

Enhancer Sequences

It is thought that gene conversion (GCV) and somatic hypermutation (SHM) of immunoglobulin (Ig) genes occur in two steps: the generation of uracils in DNA by activation-induced cytidine deaminase, followed by their subsequent repair by various DNA repair pathways to generate sequence-diversified products. It is not known how either of the two steps is targeted specifically to Ig loci. Because of the tight link between transcription and SHM, we have investigated the role of endogenous Ig light chain (IgL) transcriptional control elements in GCV/SHM in the chicken B cell line DT40. Promoter substitution experiments led to identification of a strong RNA polymerase II promoter incapable of supporting efficient GCV/SHM. This surprising finding indicates that high levels of transcription are not sufficient for robust GCV/SHM in Ig loci. Deletion of the IgL enhancer in a context in which high-level transcription was not compromised showed that the enhancer is not necessary for GCV/SHM. Our results indicate that cis-acting elements are important for Ig gene diversification, and we propose that targeting specificity is achieved through the combined action of several Ig locus elements that include the promoter.

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Ablation of XRCC2/3 transforms immunoglobulin V gene conversion into somatic hypermutation

Nature ◽

10.1038/35091100 ◽

2001 ◽

Vol 412 (6850) ◽

pp. 921-926 ◽

Cited By ~ 167

Author(s):

Julian E. Sale ◽

Daniella M. Calandrini ◽

Minoru Takata ◽

Shunichi Takeda ◽

Michael S. Neuberger

Keyword(s):

Gene Conversion ◽

Somatic Hypermutation ◽

V Gene

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Molecular evolution of the small subunit of ribulose bisphosphate carboxylase: nucleotide substitution and gene conversion.

Genetics ◽

10.1093/genetics/123.4.845 ◽

1989 ◽

Vol 123 (4) ◽

pp. 845-863 ◽

Cited By ~ 2

Author(s):

R B Meagher ◽

S Berry-Lowe ◽

K Rice

Keyword(s):

Gene Conversion ◽

Gene Tree ◽

Family Members ◽

Small Subunit ◽

Ribulose Bisphosphate Carboxylase ◽

Nucleotide Substitutions ◽

Sequence Comparisons ◽

Bisphosphate Carboxylase ◽

Cyanobacterial Species ◽

Related Plant

Abstract The nucleotide sequences encoding the mature portion of 31 ribulose 1.5-bisphosphate carboxylase small subunit (SSU) genes from 17 genera of plants, green algae and cyanobacteria were examined. Among the 465 pairwise sequence comparisons, SSU multigene family members within the same species were more similar to each other in nonsynonymous or replacement nucleotide substitutions (RNS) than they were to SSU sequences in any other organism. The concerted evolution of independent SSU gene lineages within closely related plant species suggests that homogenization of RNS positions has occurred at least once in the life of each genus. The rate of expected RNS among mature SSU sequences was calculated to be 1.25 X 10(-9)/site/yr for the first 70 million years (MY) of divergence with a significant slowing to 0.13 X 10(-9)/site/yr for the next 1,400 MY. The data suggest that mature SSU sequences do not accumulate more than 20% differences in the RNS positions without compensatory changes in other components of this enzyme system. During the first 70 MY of divergence between species, the rate of expected synonymous or silent nucleotide substitutions (SNS) is approximately 6.6 X 10(-9)/site/yr. This is five times the RNS rate and is similar to the silent rate observed in animals. In striking contrast, SNS and RNS do not show this correlation among SSU gene family members within a species. A mechanism involving gene conversion within the exons followed by selection for biased gene conversion products with conservation of RNS positions and divergence of SNS positions is discussed. A SSU gene tree based on corrected RNS for 31 SSU sequences is presented and agrees well with a species tree based on morphological and cytogenetic traits for the 17 genera examined. SSU gene comparisons may be useful in predicting phylogenetic relationships and in some cases divergence times of various plant, algal and cyanobacterial species.

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