dbCRID: a database of chromosomal rearrangements in human diseases

Kong, Fanlou; Zhu, Jing; Wu, Jingping; Peng, Jianjian; Wang, Ying; Wang, Qing; Fu, Songbin; Yuan, Long; Li, Tongbin

doi:10.1093/nar/gkq1038

Cited by 44 publications

(49 citation statements)

References 31 publications

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“…These findings corroborate those of other studies showing that some fusion transcripts originate from normal tissues (Akiva et al 2006;Parra et al 2006). Of note, as a negative control we used the data set of 300 fusion proteins found in cancers, generated by translocations and listed in the dbCRID database (Kong et al 2011). Remarkably, we did not find (Kim et al 2010).…”

Section: Expression Of Chimeric Transcripts In Normal Cellssupporting

confidence: 89%

Chimeras taking shape: Potential functions of proteins encoded by chimeric RNA transcripts

Frenkel‐Morgenstern¹,

Lacroix²,

Ezkurdia³

et al. 2012

Genome Res.

124

154

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Chimeric RNAs comprise exons from two or more different genes and have the potential to encode novel proteins that alter cellular phenotypes. To date, numerous putative chimeric transcripts have been identified among the ESTs isolated from several organisms and using high throughput RNA sequencing. The few corresponding protein products that have been characterized mostly result from chromosomal translocations and are associated with cancer. Here, we systematically establish that some of the putative chimeric transcripts are genuinely expressed in human cells. Using high throughput RNA sequencing, mass spectrometry experimental data, and functional annotation, we studied 7424 putative human chimeric RNAs. We confirmed the expression of 175 chimeric RNAs in 16 human tissues, with an abundance varying from 0.06 to 17 RPKM (Reads Per Kilobase per Million mapped reads). We show that these chimeric RNAs are significantly more tissue-specific than non-chimeric transcripts. Moreover, we present evidence that chimeras tend to incorporate highly expressed genes. Despite the low expression level of most chimeric RNAs, we show that 12 novel chimeras are translated into proteins detectable in multiple shotgun mass spectrometry experiments. Furthermore, we confirm the expression of three novel chimeric proteins using targeted mass spectrometry. Finally, based on our functional annotation of exon organization and preserved domains, we discuss the potential features of chimeric proteins with illustrative examples and suggest that chimeras significantly exploit signal peptides and transmembrane domains, which can alter the cellular localization of cognate proteins. Taken together, these findings establish that some chimeric RNAs are translated into potentially functional proteins in humans.

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Section: Expression Of Chimeric Transcripts In Normal Cellssupporting

confidence: 89%

Chimeras taking shape: Potential functions of proteins encoded by chimeric RNA transcripts

Frenkel‐Morgenstern¹,

Lacroix²,

Ezkurdia³

et al. 2012

Genome Res.

124

154

View full text Add to dashboard Cite

show abstract

“…These databases are mainly 'populated' by CNVs, such that the reported SVs are biased towards those that contain dosage-sensitive genes, which may affect the individual's phenotype via haploinsufficiency or triplosufficiency [Poot et al, 2011a]. A recently developed database contains 2,643 individually curated breakpoints of congenital and somatic chromosomal rearrangements (dbCRID, http://dbCRID.biolead.org) [Kong et al, 2011]. Since there is no clinical need to karyotype randomly selected, healthy individuals, the number of true CCR carriers is underestimated, and no database of 'phenotypically neutral' CCR breakpoints, similar to the Database of Genomic Variants for CNVs, exists.…”

Section: Multiple Possibly Pathogenic Mechanisms Provoked By Ccrs: Twmentioning

confidence: 99%

Mechanisms of Origin, Phenotypic Effects and Diagnostic Implications of Complex Chromosome Rearrangements

Poot

Haaf

2015

Mol Syndromol

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Complex chromosome rearrangements (CCRs) are currently defined as structural genome variations that involve more than 2 chromosome breaks and result in exchanges of chromosomal segments. They are thought to be extremely rare, but their detection rate is rising because of improvements in molecular cytogenetic technology. Their population frequency is also underestimated, since many CCRs may not elicit a phenotypic effect. CCRs may be the result of fork stalling and template switching, microhomology-mediated break-induced repair, breakage-fusion-bridge cycles, or chromothripsis. Patients with chromosomal instability syndromes show elevated rates of CCRs due to impaired DNA double-strand break responses during meiosis. Therefore, the putative functions of the proteins encoded by ATM, BLM, WRN, ATR, MRE11, NBS1, and RAD51 in preventing CCRs are discussed. CCRs may exert a pathogenic effect by either (1) gene dosage-dependent mechanisms, e.g. haploinsufficiency, (2) mechanisms based on disruption of the genomic architecture, such that genes, parts of genes or regulatory elements are truncated, fused or relocated and thus their interactions disturbed - these mechanisms will predominantly affect gene expression - or (3) mixed mutation mechanisms in which a CCR on one chromosome is combined with a different type of mutation on the other chromosome. Such inferred mechanisms of pathogenicity need corroboration by mRNA sequencing. Also, future studies with in vitro models, such as inducible pluripotent stem cells from patients with CCRs, and transgenic model organisms should substantiate current inferences regarding putative pathogenic effects of CCRs. The ramifications of the growing body of information on CCRs for clinical and experimental genetics and future treatment modalities are briefly illustrated with 2 cases, one of which suggests KDM4C(JMJD2C) as a novel candidate gene for mental retardation.

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“…We built an ALL gene list using an unbiased strategy based on Mitelman and dbCRID databases (Kong et al 2011;Mitelman et al 2011) as of July 2011. Translocations were selected only if they were reported in more than 10 entries for ALL in these databases (Supplemental Table S8A).…”

Section: Mapping Prdm9 Binding Motifs Within the All Gene Listmentioning

confidence: 99%

Rare allelic forms of PRDM9 associated with childhood leukemogenesis

et al. 2012

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One of the most rapidly evolving genes in humans, PRDM9, is a key determinant of the distribution of meiotic recombination events. Mutations in this meiotic-specific gene have previously been associated with male infertility in humans and recent studies suggest that PRDM9 may be involved in pathological genomic rearrangements. In studying genomes from families with children affected by B-cell precursor acute lymphoblastic leukemia (B-ALL), we characterized meiotic recombination patterns within a family with two siblings having hyperdiploid childhood B-ALL and observed unusual localization of maternal recombination events. The mother of the family carries a rare PRDM9 allele, potentially explaining the unusual patterns found. From exomes sequenced in 44 additional parents of children affected with B-ALL, we discovered a substantial and significant excess of rare allelic forms of PRDM9. The rare PRDM9 alleles are transmitted to the affected children in half the cases; nonetheless there remains a significant excess of rare alleles among patients relative to controls. We successfully replicated this latter observation in an independent cohort of 50 children with B-ALL, where we found an excess of rare PRDM9 alleles in aneuploid and infant B-ALL patients. PRDM9 variability in humans is thought to influence genomic instability, and these data support a potential role for PRDM9 variation in risk of acquiring aneuploidies or genomic rearrangements associated with childhood leukemogenesis.

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dbCRID: a database of chromosomal rearrangements in human diseases

Cited by 44 publications

References 31 publications

Chimeras taking shape: Potential functions of proteins encoded by chimeric RNA transcripts

Chimeras taking shape: Potential functions of proteins encoded by chimeric RNA transcripts

Mechanisms of Origin, Phenotypic Effects and Diagnostic Implications of Complex Chromosome Rearrangements

Rare allelic forms of PRDM9 associated with childhood leukemogenesis

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