Comparative (computational) analysis of the DNA methylation status of trinucleotide repeat expansion diseases

Copyright © 2013 Mohammadmersad Ghorbani et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.This article has been made available through the Brunel Open Access Publishing Fund.Previous studies have examined DNA methylation in different trinucleotide repeat diseases. We have combined this data and used a pattern searching algorithm to identify motifs in the DNA surrounding aberrantly methylated CpGs found in the DNA of patients with one of the three trinucleotide repeat (TNR) expansion diseases: fragile X syndrome (FRAXA), myotonic dystrophy type I (DM1), or Friedreich’s ataxia (FRDA). We examined sequences surrounding both the variably methylated (VM) CpGs, which are hypermethylated in patients compared with unaffected controls, and the nonvariably methylated CpGs which remain either always methylated (AM) or never methylated (NM) in both patients and controls. Using the J48 algorithm of WEKA analysis, we identified that two patterns are all that is necessary to classify our three regions CCGG* which is found in VM and not in AM regions and AATT* which distinguished between NM and VM + AM using proportional frequency. Furthermore, comparing our software with MEME software, we have demonstrated that our software identifies more patterns than MEME in these short DNA sequences. Thus, we present evidence that the DNA sequence surrounding CpG can influence its susceptibility to be de novo methylated in a disease state associated with a trinucleotide repeat.European Union Seventh Framework Programme and The Brunel University Graduate Program

Multifractal properties of critical eigenstates in two-dimensional systems with symplectic symmetry

The multifractal properties of electronic eigenstates at the metal-insulator transition of a two-dimensional disordered tight-binding model with spin-orbit interaction are investigated numerically. The correlation dimensions of the spectral measure $\widetilde{D}_{2}$ and of the fractal eigenstate $D_{2}$ are calculated and shown to be related by $D_{2}=2\widetilde{D}_{2}$. The exponent $\eta=0.35\pm 0.05$ describing the energy correlations of the critical eigenstates is found to satisfy the relation $\eta=2-D_{2}$.Comment: 6 pages RevTeX; 3 uuencoded, gzipped ps-figures to appear in J. Phys. Condensed Matte

Partitioning Schemes and Non-Integer Box Sizes for the Box-Counting Algorithm in Multifractal Analysis

We compare different partitioning schemes for the box-counting algorithm in the multifractal analysis by computing the singularity spectrum and the distribution of the box probabilities. As model system we use the Anderson model of localization in two and three dimensions. We show that a partitioning scheme which includes unrestricted values of the box size and an average over all box origins leads to smaller error bounds than the standard method using only integer ratios of the linear system size and the box size which was found by Rodriguez et al. (Eur. Phys. J. B 67, 77-82 (2009)) to yield the most reliable results.Comment: 10 pages, 13 figure

Surface Morphology and Strain Relief in Surfactant Mediated Growth of Germanium on Silicon (111)

The growth of Ge on Si is strongly modified by adsorbates called surfactants. The relevance of the stress on surface morphology and the growth mode of Ge on Si(111) is presented in a detailed in situ study by high resolution low energy electron diffraction (LEED) during the deposition. The change from islanding to layer-by-layer growth mode is seen in the oscillatory intensity behaviour of the 00-spot. As a strain relief mechanism, the Ge-film forms a microscopic rough surface of small triangular and defect-free pyramids in the pseudomorphic growth regime up to 8 monolayers. As soon as the pyramids are completed and start to coalesce, strain relieving defects are created at their base, finally arranging to the dislocation network. Without the driving force for the micro-roughness, the stress, the surface flattens again showing a much larger terrace length. The formation process of the dislocation network results in a spot splitting in LEED, since the periodic dislocations at the interface give rise to elastic deformation of the surface. Surprisingly the Ge-film is relaxed to 70% immediately after 8 monolayers of coverage, which is attributed to the micro rough surface morphology, providing innumerous nucleation sites for dislocation

Novel frataxin isoforms may contribute to the pathological mechanism of friedreich ataxia

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.Friedreich ataxia (FRDA) is an inherited neurodegenerative disease caused by frataxin (FXN) deficiency. The nervous system and heart are the most severely affected tissues. However, highly mitochondria-dependent tissues, such as kidney and liver, are not obviously affected, although the abundance of FXN is normally high in these tissues. In this study we have revealed two novel FXN isoforms (II and III), which are specifically expressed in affected cerebellum and heart tissues, respectively, and are functional in vitro and in vivo. Increasing the abundance of the heart-specific isoform III significantly increased the mitochondrial aconitase activity, while over-expression of the cerebellum-specific isoform II protected against oxidative damage of Fe-S cluster-containing aconitase. Further, we observed that the protein level of isoform III decreased in FRDA patient heart, while the mRNA level of isoform II decreased more in FRDA patient cerebellum compared to total FXN mRNA. Our novel findings are highly relevant to understanding the mechanism of tissue-specific pathology in FRDA.This work was supported by the intramural program of the National Institute of Child Health and Human Development, National Institutes of Health, and in part by Friedreich ataxia research association; by the National Nature Science Foundation of China (NSFC) (No. 31071085), by the Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry, and by State Key Laboratory of Pharmaceutical Biotechnology (No. ZZYJ-SN-201006). Zvonimir Marelja was supported by a grant from the Studienstiftung des Deutschen Volkes and by Deutscher Akademischer Austauschdienst scholarship. Additional support was obtained from the Deutsche Forschungsgemeinschaft Grant SL1171/5-3

Somatic instability of the expanded GAA triplet-repeat sequence in Friedreich ataxia progresses throughout life

Friedreich ataxia (FRDA) patients are homozygous for expanded GAA triplet-repeat alleles in the FXN gene. Primary neurodegeneration involving the dorsal root ganglia (DRG) results in progressive ataxia. While it is known that DRG are inherently sensitive to frataxin deficiency, recent observations also indicate that they show age-dependent, further expansion of the GAA triplet-repeat mutation. Whether somatic instability is progressive has not been systematically investigated in FRDA patients. Small pool PCR analysis of ~2300 individual molecules from tissues of an 18-week fetus, homozygous for expanded alleles, revealed very low levels of instability compared with adult-derived tissues (4.2% versus 30.6%, P<0.0001). Mutation load in blood samples from multiple patients and carriers increased significantly with age, ranging from 7.5% at 18-weeks gestation to 78.7% at 49y (R=0.91; P=0.0001). Therefore, somatic instability in FRDA occurs mostly after early embryonic development and progresses throughout life, lending further support to the role of postnatal somatic instability in disease pathogenesis

Cellular, molecular and functional characterisation of YAC transgenic mouse models of Friedreich Ataxia

Copyright © 2014 Anjomani Virmouni et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article has been made available through the Brunel Open Access Publishing Fund.Background - Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder, caused by a GAA repeat expansion mutation within intron 1 of the FXN gene. We have previously established and performed preliminary characterisation of several human FXN yeast artificial chromosome (YAC) transgenic FRDA mouse models containing GAA repeat expansions, Y47R (9 GAA repeats), YG8R (90 and 190 GAA repeats) and YG22R (190 GAA repeats). Methodology/Principal Findings - We now report extended cellular, molecular and functional characterisation of these FXN YAC transgenic mouse models. FXN transgene copy number analysis of the FRDA mice demonstrated that the YG22R and Y47R lines each have a single copy of the FXN transgene while the YG8R line has two copies. Single integration sites of all transgenes were confirmed by fluorescence in situ hybridisation (FISH) analysis of metaphase and interphase chromosomes. We identified significant functional deficits, together with a degree of glucose intolerance and insulin hypersensitivity, in YG8R and YG22R FRDA mice compared to Y47R and wild-type control mice. We also confirmed increased somatic GAA repeat instability in the cerebellum and brain of YG22R and YG8R mice, together with significantly reduced levels of FXN mRNA and protein in the brain and liver of YG8R and YG22R compared to Y47R. Conclusions/Significance - Together these studies provide a detailed characterisation of our GAA repeat expansion-based YAC transgenic FRDA mouse models that will help investigations of FRDA disease mechanisms and therapy.European Union, Ataxia UK and FARA

Disordered Electrons in a Strong Magnetic Field: Transfer Matrix Approaches to the Statistics of the Local Density of States

We present two novel approaches to establish the local density of states as an order parameter field for the Anderson transition problem. We first demonstrate for 2D quantum Hall systems the validity of conformal scaling relations which are characteristic of order parameter fields. Second we show the equivalence between the critical statistics of eigenvectors of the Hamiltonian and of the transfer matrix, respectively. Based on this equivalence we obtain the order parameter exponent $\alpha_0\approx 3.4$ for 3D quantum Hall systems.Comment: 4 pages, 3 Postscript figures, corrected scale in Fig.

New Class of Random Matrix Ensembles with Multifractal Eigenvectors

Three recently suggested random matrix ensembles (RME) are linked together by an exact mapping and plausible conjections. Since it is known that in one of these ensembles the eigenvector statistics is multifractal, we argue that all three ensembles belong to a new class of critical RME with multifractal eigenfunction statistics and a universal critical spectral statitics. The generic form of the two-level correlation function for weak and extremely strong multifractality is suggested. Applications to the spectral statistics at the Anderson transition and for certain systems on the border of chaos and integrability is discussed.Comment: 4 pages RevTeX, resubmitte

Termination of Multifractal Behaviour for Critical Disordered Dirac Fermions

We consider Dirac fermions interacting with a disordered non-Abelian vector potential. The exact solution is obtained through a special type of conformal field theory including logarithmic correlators, without resorting to the replica or supersymmetry approaches. It is shown that the proper treatment of the conformal theory leads to a different multifractal scaling behaviour than initially expected. Moreover, the previous replica solution is found to be incorrect at the level of higher correlation functions.Comment: 4 pages, no figure