scholarly journals Guardian of the Genome: An Alternative RAG/Transib Co-Evolution Hypothesis for the Origin of V(D)J Recombination

2021 ◽  
Vol 12 ◽  
Author(s):  
Iryna Yakovenko ◽  
Jacob Agronin ◽  
L. Courtney Smith ◽  
Matan Oren
Keyword(s):  
Receptor Gene ◽  
Big Bang ◽  
Published Data ◽  
Antigen Receptors ◽  
Evolutionary Time ◽  
Genomic Locus ◽  
Recombination System ◽  
Recombination Activating Gene ◽  
New Interpretation ◽  
Alternative Understanding

The appearance of adaptive immunity in jawed vertebrates is termed the immunological ‘Big Bang’ because of the short evolutionary time over which it developed. Underlying it is the recombination activating gene (RAG)-based V(D)J recombination system, which initiates the sequence diversification of the immunoglobulins and lymphocyte antigen receptors. It was convincingly argued that the RAG1 and RAG2 genes originated from a single transposon. The current dogma postulates that the V(D)J recombination system was established by the split of a primordial vertebrate immune receptor gene into V and J segments by a RAG1/2 transposon, in parallel with the domestication of the same transposable element in a separate genomic locus as the RAG recombinase. Here, based on a new interpretation of previously published data, we propose an alternative evolutionary hypothesis suggesting that two different elements, a RAG1/2 transposase and a Transib transposon invader with RSS-like terminal inverted repeats, co-evolved to work together, resulting in a functional recombination process. This hypothesis offers an alternative understanding of the acquisition of recombinase function by RAGs and the origin of the V(D)J system.

scholarly journals Defined αβ T Cell Receptors with Distinct Ligand Specificities Do Not Require Those Ligands to Signal Double Negative Thymocyte Differentiation

2004 ◽  
Vol 199 (12) ◽  
pp. 1719-1724 ◽  
Author(s):  
Batu Erman ◽  
Terry I. Guinter ◽  
Alfred Singer
Keyword(s):  
T Cell ◽  
T Cell Development ◽  
Cell Receptor ◽  
Peptide Ligands ◽  
Double Negative ◽  
Antigen Receptors ◽  
Double Positive ◽  
Recombination Activating Gene ◽  
Thymocyte Differentiation ◽  
Deficient Mice

During T cell development in the thymus, pre–T cell receptor (TCR) complexes signal CD4− CD8− (double negative [DN]) thymocytes to differentiate into CD4+ CD8+ (double positive [DP]) thymocytes, and they generate such signals without apparent ligand engagements. Although ligand-independent signaling is unusual and might be unique to the pre-TCR, it is possible that other TCR complexes such as αβ TCR or αγ TCR might also be able to signal the DN to DP transition in the absence of ligand engagement if they were expressed on DN thymocytes. Although αγ TCR complexes efficiently signal DN thymocyte differentiation, it is not yet certain if αβ TCR complexes are also capable of signaling DN thymocyte differentiation, nor is it certain if such signaling is dependent upon ligand engagement. This study has addressed these questions by expressing defined αβ TCR transgenes in recombination activating gene 2−/− pre-Tα−/− double deficient mice. In such double deficient mice, the only antigen receptors that can be expressed are those encoded by the αβ TCR transgenes. In this way, this study definitively demonstrates that αβ TCR can in fact signal the DN to DP transition. In addition, this study demonstrates that transgenic αβ TCRs signal the DN to DP transition even in the absence of their specific MHC–peptide ligands.

scholarly journals Somatic Hypermutation in the Absence of DNA-Dependent Protein Kinase Catalytic Subunit (DNA-Pkcs) or Recombination-Activating Gene (Rag)1 Activity

2000 ◽  
Vol 192 (10) ◽  
pp. 1509-1514 ◽  
Author(s):  
Mats Bemark ◽  
Julian E. Sale ◽  
Hye-Jung Kim ◽  
Claudia Berek ◽  
Ruth A. Cosgrove ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Somatic Hypermutation ◽  
Cell Receptor ◽  
Catalytic Subunit ◽  
Antigen Receptors ◽  
End Joining ◽  
Dependent Protein Kinase ◽  
Recombination Activating Gene ◽  
Dependent Protein ◽  
Rag 1

Somatic hypermutation and isotype switch recombination occur in germinal center B cells, are linked to transcription, and are similarly affected by deficiency in MutS homologue (MSH)2. Class-switch recombination is abrogated by disruption of genes encoding components of the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs)/Ku complex and likely involves nonhomologous end joining (NHEJ). That somatic hypermutation might also be associated with end joining is suggested by its association with the creation of deletions, duplications, and sites accessible to terminal transferase. However, a requirement for NHEJ in the mutation process has not been demonstrated. Here we show that somatic mutation in mice deficient in NHEJ can be tested by introduction of rearranged immunoglobulin and T cell receptor transgenes: the transgene combination not only permits reconstitution of peripheral lymphoid compartments but also allows formation of germinal centers, despite the wholly monoclonal nature of the lymphocyte antigen receptors in these animals. Using this strategy, we confirm that somatic hypermutation like class-switching can occur in the absence of recombination-activating gene (RAG)1 but show that the two processes differ in that hypermutation can proceed essentially unaffected by deficiency in DNA-PKcs activity.

scholarly journals Biallelic Germline Transcription at the κ Immunoglobulin Locus

2003 ◽  
Vol 197 (6) ◽  
pp. 743-750 ◽  
Author(s):  
Nandita Singh ◽  
Yehudit Bergman ◽  
Howard Cedar ◽  
Andrew Chess
Keyword(s):  
B Cells ◽  
Chromatin Structure ◽  
Replication Timing ◽  
Allelic Exclusion ◽  
Antigen Receptors ◽  
Germline Transcription ◽  
Immature B Cells ◽  
Recombination Activating Gene ◽  
Immunoglobulin Locus

Rearrangement of antigen receptor genes generates a vast array of antigen receptors on lymphocytes. The establishment of allelic exclusion in immunoglobulin genes requires differential treatment of the two sequence identical alleles. In the case of the κ immunoglobulin locus, changes in chromatin structure, methylation, and replication timing of the two alleles are all potentially involved in regulating rearrangement. Additionally, germline transcription of the κ locus which precedes rearrangement has been proposed to reflect an opening of the chromatin structure rendering it available for rearrangement. As the initial restriction of rearrangement to one allele is critical to the establishment of allelic exclusion, a key question is whether or not germline transcription at the κ locus is monoallelic or biallelic. We have used a sensitive reverse transcription-polymerase chain reaction (RT-PCR) assay and an RNA–fluorescence in situ hybridization (FISH) to show that germline transcription of the κ locus is biallelic in wild-type immature B cells and in recombination activating gene (RAG)−/−, μ+ B cells. Therefore, germline transcription is unlikely to dictate which allele will be rearranged first and rather reflects a general opening on both alleles that must be accompanied by a mechanism allowing one of the two alleles to be rearranged first.

Vertical disparity, egocentric distance and stereoscopic depth constancy: a new interpretation

1989 ◽  
Vol 237 (1289) ◽  
pp. 445-469 ◽  
Keyword(s):  
Visual System ◽  
Striate Cortex ◽  
Stereoscopic Depth ◽  
Published Data ◽  
Threshold Values ◽  
Egocentric Distance ◽  
Distance Information ◽  
Independent Information ◽  
New Interpretation ◽  
Depth Constancy

There has long been a problem concerning the presence in the visual cortex of binocularly activated cells that are selective for vertical stimulus disparities because it is generally believed that only horizontal dis­parities contribute to stereoscopic depth perception. The accepted view is that stereoscopic depth estimates are only relative to the fixation point and that independent information from an extraretinal source is needed to scale for absolute or egocentric distance. Recently, however, theor­etical computations have shown that egocentric distance can be esti­mated directly from vertical disparities without recourse to extraretinal sources. There has been little impetus to follow up these computations with experimental observations, because the vertical disparities that normally occur between the images in the two eyes have always been regarded as being too small to be of significance for visual perception and because experiments have consistently shown that our conscious appre­ciation of egocentric distance is rather crude and unreliable. Neverthe­less, the veridicality of stereoscopic depth constancy indicates that accurate distance information is available to the visual system and that the information about egocentric distance and horizontal disparity are processed together so as to continually recalibrate the horizontal dis­parity values for different absolute distances. Computations show that the recalibration can be based directly on vertical disparities without the need for any intervening estimates of absolute distance. This may partly explain the relative crudity of our conscious appreciation of egocentric distance. From published data it has been possible to calculate the magnitude of the vertical disparities that the human visual system must be able to discriminate in order for depth constancy to have the observed level of veridicality. From published data on the induced effect it has also been possible to calculate the threshold values for the detection of vertical disparities by the visual system. These threshold values are smaller than those needed to provide for the recalibration of the horizontal disparities in the interests of veridical depth constancy. An outline is given of the known properties of the binocularly activated cells in the striate cortex that are able to discriminate and assess the vertical disparities. Experi­ments are proposed that should validate, or otherwise, the concepts put forward in this paper.

Ventricular muscle-restricted targeting of the RXRalpha gene reveals a non-cell-autonomous requirement in cardiac chamber morphogenesis

Development ◽  
1998 ◽  
Vol 125 (10) ◽  
pp. 1943-1949 ◽  
Author(s):  
J. Chen ◽  
S.W. Kubalak ◽  
K.R. Chien
Keyword(s):  
Myosin Light Chain ◽  
Retinoic Acid Receptor ◽  
Wide Spectrum ◽  
Receptor Gene ◽  
Ventricular Myocardium ◽  
Specific Gene ◽  
Disease Phenotype ◽  
Genomic Locus ◽  
Ventricular Cardiomyocytes ◽  
Developing Heart

Mouse embryos lacking the retinoic acid receptor gene RXR(alpha) die in midgestation from hypoplastic development of the myocardium of the ventricular chambers and consequent cardiac failure. In this study, we address the issue of whether the RXRalpha gene is required in the cardiomyocyte lineage by generating mice that harbor a ventricular restricted deficiency in RXRalpha at the earliest stages of ventricular chamber specification. We first created a conditional ('floxed') allele of RXRalpha by flanking a required exon of the gene with loxP recombination sequences. To achieve ventricular myocardium-specific gene targeting, and to avoid potential transgenic artifacts, we employed a knock-in strategy to place cre recombinase coding sequences into the myosin light chain 2v (MLC2v) genomic locus, a gene which in the heart is expressed exclusively in ventricular cardiomyocytes at the earliest stages of ventricular specification. Crossing the MLC2v-cre allele with the floxed RXRalpha gene resulted in embryos in which approximately 80% of the ventricular cardiomyocytes lacked RXRalpha function, and yet which displayed a completely normal phenotype, without evidence of the wide spectrum of congenital heart disease phenotype seen in RXRa−/− embryos, and normal adult viability. We conclude that the RXRalpha mutant phenotype is not cell autonomous for the cardiomyocyte lineage, and suggest that RXRalpha functions in a neighboring compartment of the developing heart to generate a signal that is required for ventricular cardiomyocyte development and chamber maturation.

scholarly journals Antigen Receptor Engagement Turns off the V(D)J Recombination Machinery in Human Tonsil B Cells

1998 ◽  
Vol 188 (4) ◽  
pp. 765-772 ◽  
Author(s):  
Eric Meffre ◽  
Fotini Papavasiliou ◽  
Paul Cohen ◽  
Odette de Bouteiller ◽  
Diana Bell ◽  
...  
Keyword(s):  
B Cells ◽  
Somatic Mutation ◽  
Somatic Mutations ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Light Chains ◽  
Immunoglobulin Gene ◽  
Antigen Receptors ◽  
Human Tonsil ◽  
Recombination Activating Gene ◽  
Cognate Antigen

The germinal center (GC) is an anatomic compartment found in peripheral lymphoid organs, wherein B cells undergo clonal expansion, somatic mutation, switch recombination, and reactivate immunoglobulin gene V(D)J recombination. As a result of somatic mutation, some GC B cells develop higher affinity antibodies, whereas others suffer mutations that decrease affinity, and still others may become self-reactive. It has been proposed that secondary V(D)J rearrangements in GCs might rescue B cells whose receptors are damaged by somatic mutations. Here we present evidence that mature human tonsil B cells coexpress conventional light chains and recombination associated genes, and that they extinguish recombination activating gene and terminal deoxynucleotidyl transferase expression when their receptors are cross-linked. Thus, the response of the recombinase to receptor engagement in peripheral B cells is the opposite of the response in developing B cells to the same stimulus. These observations suggest that receptor revision is a mechanism for receptor diversification that is turned off when antigen receptors are cross-linked by the cognate antigen.

The 5′ flank of the rat estrogen receptor gene: structural characterization and evidence for tissue- and species-specific promoter utilization

1996 ◽  
Vol 17 (3) ◽  
pp. 197-206 ◽  
Author(s):  
B Freyschuss ◽  
K Grandien
Keyword(s):  
Estrogen Receptor ◽  
Receptor Gene ◽  
Published Data ◽  
Human Promoter ◽  
Untranslated Exon ◽  
Depth Analysis ◽  
Rapid Amplification ◽  
Race Pcr ◽  
Species Specific ◽  
Mrna Isoform

ABSTRACT Published data on the rat estrogen receptor (rER) gene have so far provided evidence for only one promoter. In contrast, the human ER (hER) gene has been reported to be transcribed from three different promoters A, B and C. In order to facilitate a more in-depth analysis of the promoter organization in the rER gene 4·5 kb of its 5′ flanking region were isolated. Sequence analysis suggests that the rER gene is transcribed from a promoter homologous to promoter B in the hER gene. However, the region corresponding to the human promoter A is much more divergent between the species and rapid amplification of cDNA ends (RACE)-PCR as well as RT-PCR experiments support the notion that the rER gene does not contain a functional A promoter. Interestingly, a novel rER mRNA isoform containing a previously unknown 5′ untranslated exon was isolated by RACE-PCR, suggesting the existence of a second, distal promoter in the rER gene. Our results show that this ER mRNA isoform C is the only one expressed in rat liver. It thus appears that the rER gene contains two promoters that are utilized in a tissue-specific fashion.

Structure-function relationships in insulin

1981 ◽  
Vol 1 (6) ◽  
pp. 485-495 ◽  
Author(s):  
D. J. Saunders
Keyword(s):  
Structure Function ◽  
Receptor Binding ◽  
Published Data ◽  
Negative Cooperativity ◽  
Insulin Molecule ◽  
Binding Surface ◽  
New Interpretation

A new interpretation of structure-function relationships in the insulin molecule is presented. Negative cooperativity is postulated to arise from a dimerization event occurring between two receptor-bound molecules. The receptor-binding surface of insulin can necessarily not involve residues involved in dimerization as has been generally accepted. Support for this interpretation is based on published data.

Lineage-specific regulation of the murine RAG-2 promoter: GATA-3 in T cells and Pax-5 in B cells

Blood ◽  
2000 ◽  
Vol 95 (12) ◽  
pp. 3845-3852 ◽  
Author(s):  
Hiroyuki Kishi ◽  
Xing-Cheng Wei ◽  
Zhe-Xiong Jin ◽  
Yoshiyuki Fujishiro ◽  
Takuya Nagata ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Promoter Activity ◽  
Receptor Gene ◽  
Lymphoid Cells ◽  
Mobility Shift ◽  
Recombination Activating Gene ◽  
Mobility Shift Assay ◽  
Rag 1 ◽  
Specific Regulation

Recombination activating gene-1 (RAG-1) andRAG-2 are expressed in lymphoid cells undergoing the antigen receptor gene rearrangement. A study of the regulation of the mouse RAG-2 promoter showed that the lymphocyte-specific promoter activity is conferred 80 nucleotide (nt) upstream of RAG-2. Using an electrophoretic mobility shift assay, it was shown that a B-cell–specific transcription protein, Pax-5, and a T-cell–specific transcription protein, GATA-3, bind to the −80 to −17 nt region in B cells and T cells, respectively. Mutation of the RAG-2 promoter for Pax-5– and GATA-3–binding sites results in the reduction of promoter activity in B cells and T cells. These results indicate that distinct DNA binding proteins, Pax-5 and GATA-3, may regulate the murine RAG-2 promoter in B and T lineage cells, respectively.

Lineage-specific regulation of the murine RAG-2 promoter: GATA-3 in T cells and Pax-5 in B cells

Blood ◽  
2000 ◽  
Vol 95 (12) ◽  
pp. 3845-3852 ◽  
Author(s):  
Hiroyuki Kishi ◽  
Xing-Cheng Wei ◽  
Zhe-Xiong Jin ◽  
Yoshiyuki Fujishiro ◽  
Takuya Nagata ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Promoter Activity ◽  
Receptor Gene ◽  
Lymphoid Cells ◽  
Mobility Shift ◽  
Recombination Activating Gene ◽  
Mobility Shift Assay ◽  
Rag 1 ◽  
Specific Regulation

Abstract Recombination activating gene-1 (RAG-1) andRAG-2 are expressed in lymphoid cells undergoing the antigen receptor gene rearrangement. A study of the regulation of the mouse RAG-2 promoter showed that the lymphocyte-specific promoter activity is conferred 80 nucleotide (nt) upstream of RAG-2. Using an electrophoretic mobility shift assay, it was shown that a B-cell–specific transcription protein, Pax-5, and a T-cell–specific transcription protein, GATA-3, bind to the −80 to −17 nt region in B cells and T cells, respectively. Mutation of the RAG-2 promoter for Pax-5– and GATA-3–binding sites results in the reduction of promoter activity in B cells and T cells. These results indicate that distinct DNA binding proteins, Pax-5 and GATA-3, may regulate the murine RAG-2 promoter in B and T lineage cells, respectively.

Sign in / Sign up

Export Citation Format

Share Document