78 research outputs found
The Interplay Between GUT and Flavour Symmetries in a Pati-Salam x S4 Model
Both Grand Unified symmetries and discrete flavour symmetries are appealing
ways to describe apparent structures in the gauge and flavour sectors of the
Standard Model. Both symmetries put constraints on the high energy behaviour of
the theory. This can give rise to unexpected interplay when building models
that possess both symmetries. We investigate on the possibility to combine a
Pati-Salam model with the discrete flavour symmetry that gives rise to
quark-lepton complementarity. Under appropriate assumptions at the GUT scale,
the model reproduces fermion masses and mixings both in the quark and in the
lepton sectors. We show that in particular the Higgs sector and the running
Yukawa couplings are strongly affected by the combined constraints of the Grand
Unified and family symmetries. This in turn reduces the phenomenologically
viable parameter space, with high energy mass scales confined to a small region
and some parameters in the neutrino sector slightly unnatural. In the allowed
regions, we can reproduce the quark masses and the CKM matrix. In the lepton
sector, we reproduce the charged lepton masses, including bottom-tau
unification and the Georgi-Jarlskog relation as well as the two known angles of
the PMNS matrix. The neutrino mass spectrum can present a normal or an inverse
hierarchy, and only allowing the neutrino parameters to spread into a range of
values between and , with .
Finally, our model suggests that the reactor mixing angle is close to its
current experimental bound.Comment: 62 pages, 4 figures; references added, version accepted for
publication in JHE
Models of Neutrino Masses and Mixings
We review theoretical ideas, problems and implications of neutrino masses and
mixing angles. We give a general discussion of schemes with three light
neutrinos. Several specific examples are analyzed in some detail, particularly
those that can be embedded into grand unified theories.Comment: 44 pages, 2 figures, version accepted for publication on the Focus
Issue on 'Neutrino Physics' edited by F.Halzen, M.Lindner and A. Suzuki, to
be published in New Journal of Physics
MtSNPscore: a combined evidence approach for assessing cumulative impact of mitochondrial variations in disease
Human mitochondrial DNA (mtDNA) variations have been implicated in a broad spectrum of diseases. With over 3000 mtDNA variations reported across databases, establishing pathogenicity of variations in mtDNA is a major challenge. We have designed and developed a comprehensive weighted scoring system (MtSNPscore) for identification of mtDNA variations that can impact pathogenicity and would likely be associated with disease. The criteria for pathogenicity include information available in the literature, predictions made by various in silico tools and frequency of variation in normal and patient datasets. The scoring scheme also assigns scores to patients and normal individuals to estimate the cumulative impact of variations. The method has been implemented in an automated pipeline and has been tested on Indian ataxia dataset (92 individuals), sequenced in this study, and other publicly available mtSNP dataset comprising of 576 mitochondrial genomes of Japanese individuals from six different groups, namely, patients with Parkinson's disease, patients with Alzheimer's disease, young obese males, young non-obese males, and type-2 diabetes patients with or without severe vascular involvement. MtSNPscore, for analysis can extract information from variation data or from mitochondrial DNA sequences. It has a web-interface http://bioinformatics.ccmb.res.in/cgi-bin/snpscore/Mtsnpscore.pl webcite that provides flexibility to update/modify the parameters for estimating pathogenicity
Cellular differentiation determines the expression of the hypoxia-inducible protein NDRG1 in pancreatic cancer
N-myc downstream-regulated gene-1 (NDRG1) is a recently described hypoxia-inducible protein that is upregulated in various human cancers. Pancreatic ductal adenocarcinoma, called pancreatic cancer, is a highly aggressive cancer that is characterised by its avascular structure, which results in a severe hypoxic environment. In this study, we investigated whether NDRG1 is upregulated in these tumours, thus providing a novel marker for malignant cells in the pancreas. By immunohistochemistry, we observed that NDRG1 was highly expressed in well-differentiated cells of pancreatic cancer, whereas the poorly differentiated tumour cells were negative. In addition, hyperplastic islets and ducts of nonquiescent pancreatic tissue were positive. To further explore its selective expression in tumours, two well-established pancreatic cancer cell lines of unequal differentiation status were exposed to 2% oxygen. NDRG1 mRNA and protein were upregulated by hypoxia in the moderately differentiated Capan-1 cells; however, its levels remained unchanged in the poorly differentiated Panc-1 cell line. Taken together, our data suggest that NDRG1 will not serve as a reliable marker of tumour cells in the pancreas, but may serve as a marker of differentiation. Furthermore, we present the novel finding that cellular differentiation may be an important factor that determines the hypoxia-induced regulation of NDRG1
Structural Annotation of Mycobacterium tuberculosis Proteome
Of the ∼4000 ORFs identified through the genome sequence of Mycobacterium tuberculosis (TB) H37Rv, experimentally determined structures are available for 312. Since knowledge of protein structures is essential to obtain a high-resolution understanding of the underlying biology, we seek to obtain a structural annotation for the genome, using computational methods. Structural models were obtained and validated for ∼2877 ORFs, covering ∼70% of the genome. Functional annotation of each protein was based on fold-based functional assignments and a novel binding site based ligand association. New algorithms for binding site detection and genome scale binding site comparison at the structural level, recently reported from the laboratory, were utilized. Besides these, the annotation covers detection of various sequence and sub-structural motifs and quaternary structure predictions based on the corresponding templates. The study provides an opportunity to obtain a global perspective of the fold distribution in the genome. The annotation indicates that cellular metabolism can be achieved with only 219 folds. New insights about the folds that predominate in the genome, as well as the fold-combinations that make up multi-domain proteins are also obtained. 1728 binding pockets have been associated with ligands through binding site identification and sub-structure similarity analyses. The resource (http://proline.physics.iisc.ernet.in/Tbstructuralannotation), being one of the first to be based on structure-derived functional annotations at a genome scale, is expected to be useful for better understanding of TB and for application in drug discovery. The reported annotation pipeline is fairly generic and can be applied to other genomes as well
Interaction of the chromatin remodeling protein hINO80 with DNA
The presence of a highly conserved DNA binding domain in INO80 subfamily predicted that INO80 directly interacts with DNA and we demonstrated its DNA binding activity in vitro. Here we report the consensus motif recognized by the DBINO domain identified by SELEX method and demonstrate the specific interaction of INO80 with the consensus motif. We show that INO80 significantly down regulates the reporter gene expression through its binding motif, and the repression is dependent on the presence of INO80 but not YY1 in the cell. The interaction is lost if specific residues within the consensus motif are altered. We identify a large number of potential target sites of INO80 in the human genome through in silico analysis that can grouped into three classes; sites that contain the recognition sequence for INO80 and YY1, only YY1 and only INO80. We demonstrate the binding of INO80 to a representative set of sites in HEK cells and the correlated repressive histone modifications around the binding motif. In the light of the role of INO80 in homeotic gene regulation in Drosophila as an Enhancer of trithorax and polycomb protein (ETP) that can modify the effect of both repressive complexes like polycomb as well as the activating complex like trithorax, it remains to be seen if INO80 can act as a recruiter of chromatin modifying complexes
Mapping human genetic diversity in Asia
Asia harbors substantial cultural and linguistic diversity, but the geographic structure of genetic variation across the continent remains enigmatic. Here we report a large-scale survey of autosomal variation from a broad geographic sample of Asian human populations. Our results show that genetic ancestry is strongly correlated with linguistic affiliations as well as geography. Most populations show relatedness within ethnic/linguistic groups, despite prevalent gene flow
among populations. More than 90% of East Asian (EA) haplotypes could be found in either Southeast Asian (SEA) or Central-South Asian (CSA) populations and show clinal structure with haplotype diversity decreasing from south to north. Furthermore, 50% of EA haplotypes were found in SEA only and 5% were found in CSA only, indicating that SEA was a major geographic source of EA populations
Analysis of CAG/CTG triplet repeats in the human genome: Implication in transcription factor gene regulation
Instability and polymorphism at several CAG/CTG trinucleotide repeat loci have been associated with human genetic disorders. In an attempt to identify novel sites that may be possible loci for expansion of CAG/CTG repeats, we searched all human sequences in the EMBL nucleotide sequence database for (CAG)(5) and (CTG)(5) repeats. We have identified 121 human DNA sequences of known and unknown functions that contain stretches of five or more CAG or CTG repeats. Many repeat stretches were interrupted by variant triplets, a significant number of which differ from the repeat triplet only by a single base, suggesting that these evolved from the parent triplet by point mutations. A large number of human transcription factor genes mere found to contain CAG repeats within their coding sequences. Analysis of the EMBL transcription factors database showed that many transcription factor genes of other eukaryotes, including genes involved in Drosophila embryo development, possess these repeats. Interestingly, CAG repeats are absent from prokaryotic transcription factors. Different sequence entries for the human TATA box binding protein showed a polymorphism in the length of the CAG repeat in this gene, suggesting that loci other than those already known to be associated with genetic diseases may be possible sites for repeat instability related disorders. On the basis of our findings in this database analysis, we propose a role for CAG repeats as cis-acting regulatory elements involved in fine-tuning gene expression
Sequence specificity in spermine-induced structural changes in CG-oligomers
The role of spermine in inducing A-DNA conformation in deoxyoligonucleotides has been studied using CCGG and GGCC as model sequences. It has been found that while CCGG adopts an alternating B-DNA conformation in low salt solution at low temperature, addition of spermine to this medium induces a B --greater than A transition. In contrast, the A-DNA-like structure of GGCC in low salt solution at low temperature does not change under the influence of spermine. This suggests a sequence-dependent behaviour of spermine. Further these results suggest that the A-DNA conformation observed in the crystals of d(iCCGG) and d(GGCC)2 might have been due to the presence of spermine in the crystallization cocktail
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