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

Merelli, Ivan; Guffanti, Alessandro; Fabbri, Marco; Cocito, Andrea; Furia, Laura; Grazini, Ursula; Bonnal, Raoul Jean Pierre; Milanesi, Luciano; McBlane, Fraser

doi:10.1093/nar/gkq391

Cited by 63 publications

(68 citation statements)

References 11 publications

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“…S7). The mechanical model fits the data much better than a genetic model (23,24,26) that is based on sequence conservation of RSSs flanking individual Jβ genes (SI Appendix, Fig. S8A).…”

Section: Mechanical Model Of Chromatin Explains Observed Biases In Jβ-dβmentioning

confidence: 95%

“…In particular, the model provides a mechanistic explanation for the different pattern of Jβ 2.1-2.7 frequencies found between the two species. In contrast, a genetic model based on sequence conservation of RSSs (23,24,26) for individual human Jβ genes cannot explain the human data (SI Appendix, Fig. S8B).…”

Section: Differences In Tcr Jβ Gene Frequencies Between Humans and Micementioning

confidence: 98%

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Chromatin conformation governs T-cell receptor Jβ gene segment usage

Ndifon

Gal

Shifrut

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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T cells play fundamental roles in adaptive immunity, relying on a diverse repertoire of T-cell receptor (TCR) α and β chains. Diversity of the TCR β chain is generated in part by a random yet intrinsically biased combinatorial rearrangement of variable (Vβ), diversity (Dβ), and joining (Jβ) gene segments. The mechanisms that determine biases in gene segment use remain unclear. Here we show, using a high-throughput TCR sequencing approach, that a physical model of chromatin conformation at the DJβ genomic locus explains more than 80% of the biases in Jβ use that we measured in murine T cells. This model also predicts correctly how differences in intersegment genomic distances between humans and mice translate into differences in Jβ bias between TCR repertoires of these two species. As a consequence of these structural and other biases, TCR sequences are produced with different a priori frequencies, thus affecting their probability of becoming public TCRs that are shared among individuals. Surprisingly, we find that many more TCR sequences are shared among all five mice we studied than among only subgroups of three or four mice. We derive a necessary mathematical condition explaining this finding, which indicates that the TCR repertoire contains a core set of receptor sequences that are highly abundant among individuals, if their a priori probability of being produced by the recombination process is higher than a defined threshold. Our results provide evidence for an expanded role of chromatin conformation in VDJ rearrangement, from control of gene accessibility to precise determination of gene segment use.lymphocyte receptor repertoires | public T-cell clones | VDJ recombination | epigenetics | next generation sequencing

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“…S7). The mechanical model fits the data much better than a genetic model (23,24,26) that is based on sequence conservation of RSSs flanking individual Jβ genes (SI Appendix, Fig. S8A).…”

Section: Mechanical Model Of Chromatin Explains Observed Biases In Jβ-dβmentioning

confidence: 95%

Section: Differences In Tcr Jβ Gene Frequencies Between Humans and Micementioning

confidence: 98%

Chromatin conformation governs T-cell receptor Jβ gene segment usage

Ndifon

Gal

Shifrut

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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show abstract

“…Nucleotide sequences were analyzed using BLAST (Altschul et al, 1990), MapViewer (Wolfsberg, 2010), other web tools provided by the NCBI (Sayers et al, 2010) and the resources of the IMGT database (Lefranc, 2003). Chromosomal breakpoint regions were analyzed for cryptic recombination signal sequences (cRSS) with 12 bp spacer or 23 bp spacer using RSSsite (Merelli et al, 2010). All chromosomal breakpoint sequences were submitted to the EMBL/Genbank/ DDBJ database (Acc no FR666906-FR666914, FR669109-FR669113, FR819778-FR819780).…”

Section: In Silico Analysis Of Nucleotide Sequencesmentioning

confidence: 99%

Molecular analysis of the t(2;8)/MYC–IGK translocation in high‐grade lymphoma/leukemia by long‐distance inverse PCR

Kroenlein

Schwartz

Reinhardt³

et al. 2011

Genes Chromosomes & Cancer

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Burkitt lymphoma and a subset of diffuse large B-cell lymphomas are characterized by chromosomal alterations affecting the MYC oncogene on 8q24. In most cases MYC is found juxtaposed to the immunoglobulin heavy chain (IGH) gene locus. Translocations to the immunoglobulin kappa (IGK) gene locus on 2p11 are observed in around 5-10% of cases. Little data exist on the molecular mechanisms leading to this aberration. The chromosomal breakpoints on chromosome 8 have been found dispersed over a large area 3' of MYC. In order to obtain a better understanding of this chromosomal translocation we developed a long-distance inverse (LDI) PCR method for the identification of chromosomal translocations affecting the IGK locus. We investigated a number of cytogenetically mostly uncharacterized high-grade lymphoma samples and identified a MYC-IGK juxtaposition in seven patients and three t(2;8)-positive cell lines. The chromosomal breakpoints were molecularly characterized and analyzed. The linear distance of the breakpoints on chromosome 8 to MYC ranged from some 100 bp to more than 0.5 MB. The reciprocal translocated allele could be characterized in the majority of cases. This study represents the largest series of t(2;8)-positive cases analyzed so far. The LDI PCR method developed here should also be useful for the analysis of chromosomal translocations affecting the IGK locus in general.

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“…74 The LMO2 locus comprised 109 cRSS, of which only 5 (<4%) were associated with a BP site. The 12 bp spacer cRSS with the highest RIC score (-29.21) was identified at the LMO2 BCR 1 .…”

Section: Crsss In Oncogene Loci Are Not Randomly Involved In T-all Trmentioning

confidence: 99%

Breakpoint sites disclose the role of the V(D)J recombination machinery in the formation of T-cell receptor (TCR) and non-TCR associated aberrations in T-cell acute lymphoblastic leukemia

et al. 2013

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Aberrant recombination between T-cell receptor genes and oncogenes gives rise to chromosomal translocations that are genetic hallmarks in several subsets of human T-cell acute lymphoblastic leukemias. The V(D)J recombination machinery has been shown to play a role in the formation of these T-cell receptor translocations. Other, non-T-cell receptor chromosomal aberrations, such as SIL-TAL1 deletions, have likewise been recognized as V(D)J recombination associated aberrations. Despite the postulated role of V(D)J recombination, the extent of the V(D)J recombination machinery involvement in the formation of T-cell receptor and non-T-cell receptor aberrations in T-cell acute lymphoblastic leukemia is still poorly understood. We performed a comprehensive in silico and ex vivo evaluation of 117 breakpoint sites from 22 different T-cell receptor translocation partners as well as 118 breakpoint sites from non-T-cell receptor chromosomal aberrations. Based on this extensive set of breakpoint data, we provide a comprehensive overview of T-cell receptor and oncogene involvement in T-ALL. Moreover, we assessed the role of the V(D)J recombination machinery in the formation of chromosomal aberrations, and propose an up-dated mechanistic classification on how the V(D)J recombination machinery contributes to the formation of T-cell receptor and non-T-cell receptor aberrations in human T-cell acute lymphoblastic leukemia.

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

Cited by 63 publications

References 11 publications

Chromatin conformation governs T-cell receptor Jβ gene segment usage

Chromatin conformation governs T-cell receptor Jβ gene segment usage

Molecular analysis of the t(2;8)/MYC–IGK translocation in high‐grade lymphoma/leukemia by long‐distance inverse PCR

Breakpoint sites disclose the role of the V(D)J recombination machinery in the formation of T-cell receptor (TCR) and non-TCR associated aberrations in T-cell acute lymphoblastic leukemia

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