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Prospective estimation of recombination signal efficiency and identification of functional cryptic signals in the genome by statistical modeling.

ABSTRACT: The recombination signals (RS) that guide V(D)J recombination are phylogenetically conserved but retain a surprising degree of sequence variability, especially in the nonamer and spacer. To characterize RS variability, we computed the position-wise information, a measure correlated with sequence conservation, for each nucleotide position in an RS alignment and demonstrate that most position-wise information is present in the RS heptamers and nonamers. We have previously demonstrated significant correlations between RS positions and here show that statistical models of the correlation structure that underlies RS variability efficiently identify physiologic and cryptic RS and accurately predict the recombination efficiencies of natural and synthetic RS. In scans of mouse and human genomes, these models identify a highly conserved family of repetitive DNA as an unexpected source of frequent, cryptic RS that rearrange both in extrachromosomal substrates and in their genomic context.

SUBMITTER: Cowell LG

PROVIDER: S-EPMC2193808 | biostudies-literature | 2003 Jan

REPOSITORIES: biostudies-literature

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Prospective estimation of recombination signal efficiency and identification of functional cryptic signals in the genome by statistical modeling.

Cowell Lindsay G LG Davila Marco M Yang Kaiyong K Kepler Thomas B TB Kelsoe Garnett G

The Journal of experimental medicine 20030101 2

The recombination signals (RS) that guide V(D)J recombination are phylogenetically conserved but retain a surprising degree of sequence variability, especially in the nonamer and spacer. To characterize RS variability, we computed the position-wise information, a measure correlated with sequence conservation, for each nucleotide position in an RS alignment and demonstrate that most position-wise information is present in the RS heptamers and nonamers. We have previously demonstrated significant ...[more]

PMID: 12538660

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Project description:BackgroundThe cleavage of recombination signals (RS) at the boundaries of immunoglobulin V, D, and J gene segments initiates the somatic generation of the antigen receptor genes expressed by B lymphocytes. RS contain a conserved heptamer and nonamer motif separated by non-conserved spacers of 12 or 23 nucleotides. Under physiologic conditions, V(D)J recombination follows the "12/23 rule" to assemble functional antigen-receptor genes, i.e., cleavage and recombination occur only between RS with dissimilar spacer types. Functional, cryptic RS (cRS) have been identified in VH gene segments; these VH cRS were hypothesized to facilitate self-tolerance by mediating VH --> VHDJH replacements. At the Igkappa locus, however, secondary, de novo rearrangements can delete autoreactive VkappaJkappa joins. Thus, under the hypothesis that V-embedded cRS are conserved to facilitate self-tolerance by mediating V-replacement rearrangements, there would be little selection for Vkappa cRS. Recent studies have demonstrated that VH cRS cleavage is only modestly more efficient than V(D)J recombination in violation of the 12/23 rule and first occurs in pro-B cells unable to interact with exogenous antigens. These results are inconsistent with a model of cRS cleavage during autoreactivity-induced VH gene replacement.ResultsTo test the hypothesis that cRS are absent from Vkappa gene segments, a corollary of the hypothesis that the need for tolerizing VH replacements is responsible for the selection pressure to maintain VH cRS, we searched for cRS in mouse Vkappa gene segments using a statistical model of RS. Scans of 135 mouse Vkappa gene segments revealed highly conserved cRS that were shown to be cleaved in the 103/BCL2 cell line and mouse bone marrow B cells. Analogous to results for VH cRS, we find that Vkappa cRS are conserved at multiple locations in Vkappa gene segments and are cleaved in pre-B cells.ConclusionOur results, together with those for VH cRS, support a model of cRS cleavage in which cleavage is independent of BCR-specificity. Our results are inconsistent with the hypothesis that cRS are conserved solely to support receptor editing. The extent to which these sequences are conserved, and their pattern of conservation, suggest that they may serve an as yet unidentified purpose.

Dataset Information

Prospective estimation of recombination signal efficiency and identification of functional cryptic signals in the genome by statistical modeling.

Publications

Prospective estimation of recombination signal efficiency and identification of functional cryptic signals in the genome by statistical modeling.

Similar Datasets

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