115 research outputs found
A method of predicting changes in human gene splicing induced by genetic variants in context of cis-acting elements
No full textBackground: polymorphic variants and mutations disrupting canonical splicing isoforms are among the
leading causes of human hereditary disorders. While there is a substantial evidence of aberrant splicing
causing Mendelian diseases, the implication of such events in multi-genic disorders is yet to be well
understood. We have developed a new tool (SpliceScan II) for predicting the effects of genetic
variants on splicing and cis-regulatory elements. The novel Bayesian non-canonical 5’GC splice site (SS)
sensor used in our tool allows inference on non-canonical exons. Result: our tool performed favorably when compared with the existing methods in the context of genes
linked to the Autism Spectrum Disorder (ASD). SpliceScan II was able to predict more aberrant
splicing isoforms triggered by the mutations, as documented in DBASS5 and DBASS3 aberrant splicing
databases, than other existing methods. Detrimental effects behind some of the polymorphic variations
previously associated with Alzheimer’s and breast cancer could be explained by changes in predicted
splicing patterns. Conclusions: we have developed SpliceScan II, an effective and sensitive tool for predicting the
detrimental effects of genomic variants on splicing leading to Mendelian and complex hereditary
disorders. The method could potentially be used to screen resequenced patient DNA to identify de novo
mutations and polymorphic variants that could contribute to a genetic disorde
BACH1 517C-->T transition impairs protein translocation to nucleus: a role in breast cancer susceptibility?
No full textMapping genes underlying complex disorders: progress on IgA deficiency and common variable immunodeficiency
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Genetic linkage of IgA deficiency due to the Major Histocompatibility Complex: evidence for segregation distortion, parent-of-origin penetrance differences, and the role of anti-IgA sntibodies in disease predisposition.
No full textIdentification of U2AF(35)-dependent exons by RNA-Seq reveals a link between 3' splice-site organization and activity of U2AF-related proteins
No full textThe auxiliary factor of U2 small nuclear RNA (U2AF) is a heterodimer consisting of 65- and 35-kD proteins that bind the polypyrimidine tract (PPT) and AG dinucleotides at the 3? splice site (3?ss). The gene encoding U2AF35 (U2AF1) is alternatively spliced, giving rise to two isoforms U2AF35a and U2AF35b. Here, we knocked down U2AF35 and each isoform and characterized transcriptomes of HEK293 cells with varying U2AF35/U2AF65 and U2AF35a/b ratios. Depletion of both isoforms preferentially modified alternative RNA processing events without widespread failure to recognize 3?ss or constitutive exons. Over a third of differentially used exons were terminal, resulting largely from the use of known alternative polyadenylation (APA) sites. Intronic APA sites activated in depleted cultures were mostly proximal whereas tandem 3?UTR APA was biased toward distal sites. Exons upregulated in depleted cells were preceded by longer AG exclusion zones and PPTs than downregulated or control exons and were largely activated by PUF60 and repressed by CAPER?. The U2AF(35) repression and activation was associated with a significant interchange in the average probabilities to form single-stranded RNA in the optimal PPT and branch site locations and sequences further upstream. Although most differentially used exons were responsive to both U2AF subunits and their inclusion correlated with U2AF levels, a small number of transcripts exhibited distinct responses to U2AF35a and U2AF35b, supporting the existence of isoform-specific interactions. These results provide new insights into function of U2AF and U2AF35 in alternative RNA processing
Recurrent ATM mutations in T-PLL on diverse haplotypes: no support for their germline origin
No full textDBASS3 and DBASS5: databases of aberrant 3'- and 5'-splice sites
No full textDBASS3 and DBASS5 provide comprehensive repositories of new exon boundaries that were induced by pathogenic mutations in human disease genes. Aberrant 5?- and 3?-splice sites were activated either by mutations in the consensus sequences of natural exon–intron junctions (cryptic sites) or elsewhere (‘de novo’ sites). DBASS3 and DBASS5 currently contain approximately 900 records of cryptic and de novo 3?- and 5?-splice sites that were produced by over a thousand different mutations in approximately 360 genes. DBASS3 and DBASS5 data can be searched by disease phenotype, gene, mutation, location of aberrant splice sites in introns and exons and their distance from authentic counterparts, by bibliographic references and by the splice-site strength estimated with several prediction algorithms. The user can also retrieve reference sequences of both aberrant and authentic splice sites with the underlying mutation. These data will facilitate identification of introns or exons frequently involved in aberrant splicing, mutation analysis of human disease genes and study of germline or somatic mutations that impair RNA processing. Finally, this resource will be useful for fine-tuning splice-site prediction algorithms, better definition of auxiliary splicing signals and design of new reporter assays. DBASS3 and DBASS5 are freely available at http://www.dbass.org.uk/
The HLA-DRA*0102 allele: correct nucleotide sequence and associated HLA haplotypes
No full textHere we correct the nucleotide sequence of a single known variant of the HLA-DRA gene. We show that the coding regions of the HLA-DRA*0101 and HLA-DRA*0102 alleles do not differ at two codons as reported previously, but only in codon 217. Using nucleotide sequencing and DNA samples from individuals homozygous in the major histocompatibility complex, we found that the variant, leucine 217-encoding HLA-DRA*0102 allele was present on the haplotypes HLA-B*0801, DRB1*03011, DQB1*0201 (ancestral haplotype AH8.1), HLA-B*07021, DRB1*15011, DQB1*0602 (AH7.1), HLA-B*1501, DRB1*15011, DQB1*0602, HLA-B*1501, DRB1*1402, DQB1*03011 and HLA-A3, B*07021, DRB1*1301, DQB1*0603. The HLA-DRA*0101 allele coding for valine 217 was observed on the haplotypes HLA-B*5701, DRB1*0701, DQB1*03032 (AH57.1), HLA-DRB1*04011, DQB1*0302, HLA-DRB1*0701, DQB1*0202, and HLA-DRB1*0101, DQB1*05011
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