Recombination signal sequences restrict chromosomal V(D)J recombination beyond the 12/23 rule

Nature ◽  
2000 ◽  
Vol 405 (6786) ◽  
pp. 583-586 ◽  
Author(s):  
Craig H. Bassing ◽  
Frederick W. Alt ◽  
Maureen M. Hughes ◽  
Margaux D'Auteuil ◽  
Tara D. Wehrly ◽  
...  
Keyword(s):  
Signal Sequences ◽  
Recombination Signal ◽  
Recombination Signal Sequences

scholarly journals RSSsite: a reference database and prediction tool for the identification of cryptic Recombination Signal Sequences in human and murine genomes

2010 ◽  
Vol 38 (Web Server) ◽  
pp. W262-W267 ◽  
Author(s):  
I. Merelli ◽  
A. Guffanti ◽  
M. Fabbri ◽  
A. Cocito ◽  
L. Furia ◽  
...  
Keyword(s):  
Reference Database ◽  
Prediction Tool ◽  
Signal Sequences ◽  
Recombination Signal ◽  
Recombination Signal Sequences

scholarly journals The role of components of recombination signal sequences in immunoglobulin gene segment usage: a V81x model

1999 ◽  
Vol 27 (11) ◽  
pp. 2304-2309 ◽  
Author(s):  
M. Larijani ◽  
C. C. K. Yu ◽  
R. Golub ◽  
Q. L. K. Lam ◽  
G. E. Wu
Keyword(s):  
Gene Segment ◽  
Immunoglobulin Gene ◽  
Signal Sequences ◽  
Recombination Signal ◽  
Recombination Signal Sequences

scholarly journals Synapsis of Recombination Signal Sequences Located in cis and DNA Underwinding in V(D)J Recombination

2004 ◽  
Vol 24 (19) ◽  
pp. 8727-8744 ◽  
Author(s):  
Mihai Ciubotaru ◽  
David G. Schatz
Keyword(s):  
Conformational Changes ◽  
Dna Cleavage ◽  
High Mobility ◽  
Experimental System ◽  
High Mobility Group Protein ◽  
Signal Sequences ◽  
Recombination Signal ◽  
Recombination Signal Sequences ◽  
Group Protein ◽  
Dna Substrates

ABSTRACT V(D)J recombination requires binding and synapsis of a complementary (12/23) pair of recombination signal sequences (RSSs) by the RAG1 and RAG2 proteins, aided by a high-mobility group protein, HMG1 or HMG2. Double-strand DNA cleavage within this synaptic, or paired, complex is thought to involve DNA distortion or melting near the site of cleavage. Although V(D)J recombination normally occurs between RSSs located on the same DNA molecule (in cis), all previous studies that directly assessed RSS synapsis were performed with the two DNA substrates in trans. To overcome this limitation, we have developed a facilitated circularization assay using DNA substrates of reduced length to assess synapsis of RSSs in cis. We show that a 12/23 pair of RSSs is the preferred substrate for synapsis of cis RSSs and that the efficiency of pairing is dependent upon RAG1-RAG2 stoichiometry. Synapsis in cis occurs rapidly and is kinetically favored over synapsis of RSSs located in trans. This experimental system also allowed the generation of underwound DNA substrates containing pairs of RSSs in cis. Importantly, we found that the RAG proteins cleave such substrates substantially more efficiently than relaxed substrates and that underwinding may enhance RSS synapsis as well as RAG1/2-mediated catalysis. The energy stored in such underwound substrates may be used in the generation of DNA distortion and/or protein conformational changes needed for synapsis and cleavage. We propose that this unwinding is uniquely sensed during synapsis of an appropriate 12/23 pair of RSSs.

scholarly journals Population matched (PM) germline allelic variants of immunoglobulin (IG) loci: New pmIG database to better understand IG repertoire and selection processes in disease and vaccination

2020 ◽  
Author(s):  
Indu Khatri ◽  
Magdalena A. Berkowska ◽  
Erik B. van den Akker ◽  
Cristina Teodosio ◽  
Marcel J.T. Reinders ◽  
...  
Keyword(s):  
B Cell ◽  
Human Populations ◽  
Signal Sequences ◽  
Allelic Variants ◽  
Recombination Signal ◽  
Evolutionary Selection ◽  
1000 Genomes ◽  
Recombination Signal Sequences ◽  
Selection Processes ◽  
Over Time

AbstractAt the population level, immunoglobulin (IG) loci harbor inter-individual allelic variants in the many different germline IG variable (V), Diversity (D) and Joining (J) genes of the IG heavy (IGH), IG kappa (IGK) and IG lambda (IGL) loci, which together form the genetic basis of the highly diverse antigen-specific B-cell receptors. These inter-individual allelic variants can be shared between or be specific to human populations. The current IG databases IMGT, VBASE2 and IgPdb hold information about germline alleles, most of which are partial sequences, obtained from a mixture of human (B-cell) samples, many with sequence errors and/or acquired (non-germline) IG variations, induced by somatic hypermutation (SHM) during antigen-specific B-cell responses. We systematically identified true germline alleles (without SHM) from 26 different human populations around the world, profiled by the “1000 Genomes data”. Our resource is uniquely enriched with complete IG allele sequences and their frequencies across human populations. We identified 409 IGHV, 179 IGKV, and 199 IGLV germline alleles supported by at least seven haplotypes (= minimum of four individuals), after removal of potential false-positives, based on using other genomic databases, i.e. ENSEMBL, TopMed, ExAC, ProjectMine. Remarkably, the positions of the identified variant nucleotides of the different alleles are not at random (as observed in case of SHM), but show striking patterns, restricted to limited nucleotide positions, the same as found in other IG data bases, suggesting over-time evolutionary selection processes. The identification of these specific patterns provides extra evidence that the identified variant nucleotides are not sequencing errors, but genuine allelic variants. The diversity of germline allelic variants in IGH and IGL loci is the highest in Africans, while the IGK locus is most diverse in Europeans. We also report on the presence of recombination signal sequences (RSS) in V pseudogenes, explaining their usage in V(D)J rearrangements. We propose that this new set of genuine germline IG sequences can serve as a new population-matched IG (pmIG) database for better understanding B-cell repertoire and B-cell receptor selection processes in disease and vaccination within and between different human populations. The database in format of fasta is available via GitHub (https://github.com/InduKhatri/pmIG).Contribution to the Field StatementWe present a catalogue of immunoglobulin (IG) germline-alleles of unprecedented completeness and accuracy from 26 different human populations belonging to five different large ethnicities (Source: 1000 Genomes). We identified the population distribution of several known germline alleles and identified multiple new alleles, especially in African populations, indicative of high allelic diversity of IG genes in Africa. Strikingly, the identified variant nucleotides of the different alleles are not at random, but show striking patterns, restricted to limited nucleotide positions, the same as found in other IG databases, suggesting over-time evolutionary selection processes. Furthermore, we identified recombination signal sequences in pseudogenes (previously not known). We provide an overview of IG germline alleles shared with and between known databases and also point to potential sources of non-germline variation and incompleteness of the existing IG databases. More importantly, we believe that this information can serve as a novel population-matched IG (pmIG) database, highly valuable for the research community in supporting the dissection and understanding of differences in effectiveness of antibody-based immune responses in infectious diseases, other (immune) diseases and vaccination within and between human populations. Such knowledge might be used in developing population-specific vaccination strategies e.g. for currently ongoing SARS-CoV2 pandemic.

scholarly journals RSSs set the odds for exclusion

2020 ◽  
Vol 217 (9) ◽  
Author(s):  
Michael S. Krangel
Keyword(s):  
Allelic Exclusion ◽  
Signal Sequences ◽  
Recombination Signal ◽  
Recombination Signal Sequences

In this issue of JEM, Wu et al. (https://doi.org/10.1084/jem.20200412) provide new insights into allelic exclusion. They demonstrate that Vβ-to-DβJβ rearrangement occurs stochastically on two competing Tcrb alleles, with suboptimal Vβ recombination signal sequences limiting synchronous rearrangements and essential for allelic exclusion.

Frequency of Human V?3+Cells Correlates with Polymorphism in Recombination Signal Sequences

1995 ◽  
Vol 756 (1 T-Cell Recept) ◽  
pp. 90-93
Author(s):  
C. S. VISSINGA ◽  
S. WEI ◽  
D. N. POSNETT ◽  
AND P. CONCANNON
Keyword(s):  
Signal Sequences ◽  
Recombination Signal ◽  
Recombination Signal Sequences
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