Dataset Information

Quadruplex-single nucleotide polymorphisms (Quad-SNP) influence gene expression difference among individuals.

ABSTRACT: Non-canonical guanine quadruplex structures are not only predominant but also conserved among bacterial and mammalian promoters. Moreover recent findings directly implicate quadruplex structures in transcription. These argue for an intrinsic role of the structural motif and thereby posit that single nucleotide polymorphisms (SNP) that compromise the quadruplex architecture could influence function. To test this, we analysed SNPs within quadruplex motifs (Quad-SNP) and gene expression in 270 individuals across four populations (HapMap) representing more than 14,500 genotypes. Findings reveal significant association between quadruplex-SNPs and expression of the corresponding gene in individuals (P < 0.0001). Furthermore, analysis of Quad-SNPs obtained from population-scale sequencing of 1000 human genomes showed relative selection bias against alteration of the structural motif. To directly test the quadruplex-SNP-transcription connection, we constructed a reporter system using the RPS3 promoter-remarkable difference in promoter activity in the 'quadruplex-destabilized' versus 'quadruplex-intact' promoter was noticed. As a further test, we incorporated a quadruplex motif or its disrupted counterpart within a synthetic promoter reporter construct. The quadruplex motif, and not the disrupted-motif, enhanced transcription in human cell lines of different origin. Together, these findings build direct support for quadruplex-mediated transcription and suggest quadruplex-SNPs may play significant role in mechanistically understanding variations in gene expression among individuals.

SUBMITTER: Baral A

PROVIDER: S-EPMC3351168 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Quadruplex-single nucleotide polymorphisms (Quad-SNP) influence gene expression difference among individuals.

Baral Aradhita A Kumar Pankaj P Halder Rashi R Mani Prithvi P Yadav Vinod Kumar VK Singh Ankita A Das Swapan K SK Chowdhury Shantanu S

Nucleic acids research 20120111 9

Non-canonical guanine quadruplex structures are not only predominant but also conserved among bacterial and mammalian promoters. Moreover recent findings directly implicate quadruplex structures in transcription. These argue for an intrinsic role of the structural motif and thereby posit that single nucleotide polymorphisms (SNP) that compromise the quadruplex architecture could influence function. To test this, we analysed SNPs within quadruplex motifs (Quad-SNP) and gene expression in 270 indi ...[more]

PMID: 22238381

Similar Datasets

Project description:Isogenic, toxin B (tcdB) mutants of two independently isolated erythromycin-sensitive derivatives (630E and 630Δerm) of the Clostridium difficile strain CD630 have previously been shown to behave differently in the hamster model of infection. Those based on strain 630E failed to cause disease, whereas those based on 630Δerm did. Here we show that whilst 630Δerm and its derivatives behave in a comparable way to the parental strain CD630 in terms of growth rate, motility, sporulation, toxin production and virulence, strain 630E and its derivatives do not. They grow more slowly, achieve lower final cell densities, exhibit a reduced capacity for spore formation, express lower levels of toxin and are less virulent in the hamster model. Using Next Generation Sequencing, a total of three SNPs were found that were in both CD630 and 630Δerm. In addition to these, 630Δerm had eight unique SNPs compared to CD630 and 630E, while 630E had 11 SNPs not found in the other two strains. The strain-specific SNPs most likely arose during the repeated subculture experiments undertaken to isolate these ermB deletion strains. The relatively large number of mutations present meant that the identification of those SNPs responsible for the altered properties of 630E was not possible. Allelic exchange was used to correct three mutational changes in 630E, but with essentially no effect on phenotype. These were a 150 bp inversion in the promoter region of a flagella operon, the truncation of CD630_12740 (topoisomerase I), and the correction of a SNP that results in the fusion of two components of a glucose phosphor-transferase-system. To complete the analysis we performed RNAseq, comparing the transcriptome of the three strains at three different time points. The finding corroborated the many differences between the strains, but also highlighted that one SNP cannot necessarily be attributed to one particular expression pattern or even phenotype. In conclusion 630Δerm more accurately mirrors the behaviour of the parental strain CD630, hence if genetic-based studies with C. difficile strain CD630 are necessary, then the use of strain 630∆erm should be favoured over strain 630E. At a fundamental level, our data underlines the importance of effective strain curation and the need to genome re-sequence master seed banks wherever possible.

Project description:BackgroundThe mapping of quantitative trait loci in rat and mouse has been extremely successful in identifying chromosomal regions associated with human disease-related phenotypes. However, identifying the specific phenotype-causing DNA sequence variations within a quantitative trait locus has been much more difficult. The recent availability of genomic sequence from several mouse inbred strains (including C57BL/6J, 129X1/SvJ, 129S1/SvImJ, A/J, and DBA/2J) has made it possible to catalog DNA sequence differences within a quantitative trait locus derived from crosses between these strains. However, even for well-defined quantitative trait loci (<10 Mb) the identification of candidate functional DNA sequence changes remains challenging due to the high density of sequence variation between strains.DescriptionTo help identify functional DNA sequence variations within quantitative trait loci we have used the Ensembl annotated genome sequence to compile a database of mouse single nucleotide polymorphisms (SNPs) that are predicted to cause missense, nonsense, frameshift, or splice site mutations (available at http://bioinfo.embl.it/SnpApplet/). For missense mutations we have used the PolyPhen and PANTHER algorithms to predict whether amino acid changes are likely to disrupt protein function.ConclusionWe have developed a database of mouse SNPs predicted to cause missense, nonsense, frameshift, and splice-site mutations. Our analysis revealed that 20% and 14% of missense SNPs are likely to be deleterious according to PolyPhen and PANTHER, respectively, and 6% are considered deleterious by both algorithms. The database also provides gene expression and functional annotations from the Symatlas, Gene Ontology, and OMIM databases to further assess candidate phenotype-causing mutations. To demonstrate its utility, we show that Mouse SNP Miner successfully finds a previously identified candidate SNP in the taste receptor, Tas1r3, that underlies sucrose preference in the C57BL/6J strain. We also use Mouse SNP Miner to derive a list of candidate phenotype-causing mutations within a previously uncharacterized QTL for response to morphine in the 129/Sv strain.

Dataset Information

Quadruplex-single nucleotide polymorphisms (Quad-SNP) influence gene expression difference among individuals.

Publications

Quadruplex-single nucleotide polymorphisms (Quad-SNP) influence gene expression difference among individuals.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets