Gene Conversion Events Contribute to the Polymorphic Variation of the Surrogate Light Chain Gene λ5/14.1

Conley, Mary Ellen; Rapalus, Lisa; Boylin, Elizabeth C.; Rohrer, Jurg; Minegishi, Yoshiyuki

doi:10.1006/clim.1999.4785

Cited by 13 publications

(5 citation statements)

References 40 publications

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“…However, EST depth accounts for only part of the variance (because the correlation coefficient was relatively low), and other factors are likely to be involved. These include differences in selective constraints between genes, the nature of the sequence, the presence of recombination hot spots, pseudogenes, and Alu/LINE elements (Nachman et al 1998;Conley et al 1999;Fahsold et al 2000). In addition, we observed that two-thirds of the cSNPs were located primarily in the 3Ј-UTR regions, whereas with direct screening approaches the distribution is generally uniform (Cargill et al 1999).…”

Section: Discussionmentioning

confidence: 71%

The Human ATP-Binding Cassette (ABC) Transporter Superfamily

Dean¹

2001

Genome Research

1,854

1,701

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Single nucleotide polymorphisms (SNPs) are likely to contribute to the study of complex genetic diseases. The genomic sequence of human chromosome 21q was recently completed with 225 annotated genes, thus permitting efficient identification and precise mapping of potential cSNPs by bioinformatics approaches. Here we present a human chromosome 21 (HC21) cSNP database and the first chromosome-specific cSNP map. Potential cSNPs were generated using three approaches: (1) Alignment of the complete HC21 genomic sequence to cognate ESTs and mRNAs. Candidate cSNPs were automatically extracted using a novel program for context-dependent SNP identification that efficiently discriminates between true variation, poor quality sequencing, and paralogous gene alignments. (2) Multiple alignment of all known HC21 genes to all other human database entries. (3) Gene-targeted cSNP discovery. To date we have identified 377 cSNPs averaging ∼1 SNP per 1.5 kb of transcribed sequence, covering 65% of known genes in the chromosome. Validation of our bioinformatics approach was demonstrated by a confirmation rate of 78% for the predicted cSNPs, and in total 32% of the cSNPs in our database have been confirmed. The database is publicly available at

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Section: Discussionmentioning

confidence: 71%

The Human ATP-Binding Cassette (ABC) Transporter Superfamily

Dean¹

2001

Genome Research

1,854

1,701

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“…Nevertheless, we cannot exclude the possibility that these VH replacement events were mediated by a non-sitespecific, general recombination process such as gene conversion, a mechanism that is involved in the diversification of the 5/14.1 component of the pre-BCR in humans (62) as well as the BCR of chickens (63,64) and rabbits (65,66). If gene conversion is responsible for these secondary recombination events, the site of cross-strand exchange could be located anywhere downstream of the first mismatch and upstream of the next mismatch between the incoming/donor germline V H gene sequence and the outgoing/recipient rearranged gene segment.…”

Section: Discussionmentioning

confidence: 99%

Immunoglobulin Heavy Chain Variable Region Gene Replacement as a Mechanism for Receptor Revision in Rheumatoid Arthritis Synovial Tissue B Lymphocytes

Itoh

Meffre

Albesiano

et al. 2000

The Journal of Experimental Medicine

120

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Mature B cells can alter their antibody repertoires by several mechanisms, including immunoglobulin heavy chain variable region (VH) replacement. This process changes the antigen combining site by replacing a portion of the original VH/diversity/heavy chain joining region (VHDJH) rearrangement with a corresponding portion of a new VH segment. This exchange can involve cryptic heptamer-like sequences embedded in the coding regions of VH genes.While studying the B lymphocytes that expand in the synovial tissues of patients with rheumatoid arthritis (RA), clones with VHDJH variants that were apparently generated by VH replacement were identified with surprising frequency (∼8%). Examples of multiple independent VH replacement events occurring in distinct progeny clones were also identified. These secondary VH rearrangements were documented at both the cDNA and genomic DNA levels and involved several heptamer-like sequences at four distinct locations within VH (three sites in framework region 3 and one in complementarity determining region 2). The identification of blunt-ended double-stranded DNA breaks at the embedded heptamers and the demonstration of recombinase activating gene (RAG) expression suggested that these rearrangements could occur in the synovial tissues, presumably in pseudo-germinal centers, and that they could be mediated by RAG in a recognition signal sequence–specific manner. The presence of VH mutations in the clones that had undergone replacement indicated that these B cells were immunocompetent and could receive and respond to diversification signals. A relationship between these secondary VH gene rearrangements and the autoimmunity characteristic of RA should be considered.

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“…Figure S1). Whereas the majority of gene conversion events were listed in the collation of Chen et al (2007), an additional eight cases associated respectively with congenital adrenal hyperplasia (Globerman et al 1988), increased CYP3A7 gene expression in adult liver and intestine (Kuehl et al 2001), agammaglobulinemia (Conley et al 1999) and conversion events in the GYPA (Huang et al 2000), HBA1 (Law et al 2006), Sec1 (Soejima et al 2008), CD46 (Fremeaux-Bacchi et al 2006) and KRT17 (Hashiguchi et al 2002) genes were included.…”

Section: Methodsmentioning

confidence: 99%

Gene conversion causing human inherited disease: Evidence for involvement of non-B-DNA-forming sequences and recombination-promoting motifs in DNA breakage and repair

et al. 2009

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A variety of DNA sequence motifs including inverted repeats, minisatellites, and the χ recombination hotspot, have been reported in association with gene conversion in human genes causing inherited disease. However, no methodical statistically-based analysis has been performed to formalize these observations. We have performed an in silico analysis of the DNA sequence tracts involved in 27 non-overlapping gene conversion events in 19 different genes reported in the context of inherited disease. We found that gene conversion events tend to occur within (C+G)- and CpG-rich regions and that sequences with the potential to form non-B-DNA structures, and which may be involved in the generation of double-strand breaks that could in turn serve to promote gene conversion, occur disproportionately within maximal converted tracts and/or short flanking regions. Maximal converted tracts were also found to be enriched (p<0.01) in a truncated version of the χ-element (a TGGTGG motif), immunoglobulin heavy chain class switch repeats, translin target sites and several novel motifs including (or overlapping) the classical meiotic recombination hotspot, CCTCCCCT. Finally, gene conversions tend to occur in genomic regions that have the potential to fold into stable hairpin conformations. These findings support the concept that recombination-inducing motifs, in association with alternative DNA conformations, can promote recombination in the human genome.

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Gene Conversion Events Contribute to the Polymorphic Variation of the Surrogate Light Chain Gene λ5/14.1

Cited by 13 publications

References 40 publications

The Human ATP-Binding Cassette (ABC) Transporter Superfamily

The Human ATP-Binding Cassette (ABC) Transporter Superfamily

Immunoglobulin Heavy Chain Variable Region Gene Replacement as a Mechanism for Receptor Revision in Rheumatoid Arthritis Synovial Tissue B Lymphocytes

Gene conversion causing human inherited disease: Evidence for involvement of non-B-DNA-forming sequences and recombination-promoting motifs in DNA breakage and repair

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