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Gavrilov A.,Institute of Gene Biology | Razin S.V.,Moscow State University | Cavalli G.,Institute of Human Genetics
Briefings in Functional Genomics | Year: 2015

Formaldehyde cross-linking is an important component of many technologies, including chromatin immunoprecipitation and chromosome conformation capture. The procedure remains empirical and poorly characterized, however, despite a long history of its use in research. Little is known about the specificity of in vivo cross-linking, its efficiency and chemical adducts induced by the procedure. It is time to search this black box. © The Author 2014. Published by Oxford University Press. All rights reserved.


News Article | February 16, 2017
Site: www.eurekalert.org

They have found the molecules in the well-known glacier mummy "Ötzi". A number of facts have been scientifically proven about the glacier mummy, known as "the Iceman" or "Ötzi," found in the Ötztal Alps (South Tyrol) in 1991. Through imaging techniques, we know about degeneration in his lumbar spine and a fatal arrow wound in his left shoulder. DNA analyses showed that Ötzi was lactose intolerant, and had brown eyes and blood type 0. Now a study of Ötzi's microRNAs has also been completed. MicroRNAs are very small pieces of ribonucleic acid (RNA) and play a central role in the regulation of genes. Although these molecules are very stable in tissues, prior to this study it was unclear whether they could still be found in human tissues after thousands of years. Therefore, Professors Andreas Keller and Eckart Meese of Saarland University, Stephanie Kreis of the University of Luxembourg, and Professor Albert Zink and Frank Maixner of Eurac Research in Bozen took on the challenge. They analyzed not only tissue samples from the Iceman, but also those from a mummy of a soldier fallen in World War I. "Our investigation provides evidence that we can analyze microRNA even after thousands of years," explains Andreas Keller, Professor of Clinical Bioinformatics at Saarland University, who coordinated the study. The scientists took samples from Ötzi's skin, stomach, and stomach contents. "It was a challenge to extract this genetic material in significant quantities and sufficient quality from the mummified tissue samples, and to measure and quantify it with the newest, very precise methods," reports Stephanie Kreis, who isolated the microRNAs at the University of Luxembourg. Some molecules were found that were present predominantly in the ancient tissues. Conversely, some of the biomarkers that are well-known today were not found in Ötzi. According to Professor Zink from Eurac Research, the microRNAs are the next important class of molecules from Ötzi to receive intensive examination. Professor Meese, head of the Institute of Human Genetics at Saarland University, claims that the stability of these biomarkers is also important for people today. "It is vital for clinical applications," explains Meese. "It's evident that the potential of microRNA is much greater than we previously thought. We still don't know enough about how these molecules influence specific genes, entire gene families, or biochemical reaction pathways. When we investigate this further, it's possible microRNAs will become new stars in therapy. Until then, however, there is a lot more work to do," concludes Professor Keller. Publication "miRNAs in ancient tissue specimens of the Tyrolean Iceman" https:/ Questions can be directed to: Professor Albert Zink Institute for Mummies and the Iceman Eurac Research Tel.: +39 0471 055561 E-mail: albert.zink@eurac.edu


Martin M.,Institute of Human Genetics | Martin M.,TU Dortmund | Masshofer L.,University of Duisburg - Essen | Temming P.,University of Duisburg - Essen | And 9 more authors.
Nature Genetics | Year: 2013

Gene expression profiles and chromosome 3 copy number divide uveal melanomas into two distinct classes correlating with prognosis. Using exome sequencing, we identified recurrent somatic mutations in EIF1AX and SF3B1, specifically occurring in uveal melanomas with disomy 3, which rarely metastasize. Targeted resequencing showed that 24 of 31 tumors with disomy 3 (77%) had mutations in either EIF1AX (15; 48%) or SF3B1 (9; 29%). Mutations were infrequent (2/35; 5.7%) in uveal melanomas with monosomy 3, which are associated with poor prognosis. Resequencing of 13 uveal melanomas with partial monosomy 3 identified 8 tumors with a mutation in either SF3B1 (7; 54%) or EIF1AX (1; 8%). All EIF1AX mutations caused in-frame changes affecting the N terminus of the protein, whereas 17 of 19 SF3B1 mutations encoded an alteration of Arg625. Resequencing of ten uveal melanomas with disomy 3 that developed metastases identified SF3B1 mutations in three tumors, none of which targeted Arg625. © 2013 Nature America, Inc. All rights reserved.


News Article | February 16, 2017
Site: www.sciencedaily.com

They have found the molecules in the well-known glacier mummy "Ötzi." A number of facts have been scientifically proven about the glacier mummy, known as "the Iceman" or "Ötzi," found in the Ötztal Alps (South Tyrol) in 1991. Through imaging techniques, we know about degeneration in his lumbar spine and a fatal arrow wound in his left shoulder. DNA analyses showed that Ötzi was lactose intolerant, and had brown eyes and blood type 0. Now a study of Ötzi's microRNAs has also been completed. MicroRNAs are very small pieces of ribonucleic acid (RNA) and play a central role in the regulation of genes. Although these molecules are very stable in tissues, prior to this study it was unclear whether they could still be found in human tissues after thousands of years. Therefore, Professors Andreas Keller and Eckart Meese of Saarland University, Stephanie Kreis of the University of Luxembourg, and Professor Albert Zink and Frank Maixner of Eurac Research in Bozen took on the challenge. They analyzed not only tissue samples from the Iceman, but also those from a mummy of a soldier fallen in World War I. "Our investigation provides evidence that we can analyze microRNA even after thousands of years," explains Andreas Keller, Professor of Clinical Bioinformatics at Saarland University, who coordinated the study. The scientists took samples from Ötzi's skin, stomach, and stomach contents. "It was a challenge to extract this genetic material in significant quantities and sufficient quality from the mummified tissue samples, and to measure and quantify it with the newest, very precise methods," reports Stephanie Kreis, who isolated the microRNAs at the University of Luxembourg. Some molecules were found that were present predominantly in the ancient tissues. Conversely, some of the biomarkers that are well-known today were not found in Ötzi. According to Professor Zink from Eurac Research, the microRNAs are the next important class of molecules from Ötzi to receive intensive examination. Professor Meese, head of the Institute of Human Genetics at Saarland University, claims that the stability of these biomarkers is also important for people today. "It is vital for clinical applications," explains Meese. "It's evident that the potential of microRNA is much greater than we previously thought. We still don't know enough about how these molecules influence specific genes, entire gene families, or biochemical reaction pathways. When we investigate this further, it's possible microRNAs will become new stars in therapy. Until then, however, there is a lot more work to do," concludes Professor Keller.


News Article | February 16, 2017
Site: www.chromatographytechniques.com

A number of facts have been scientifically proven about the glacier mummy, known as "the Iceman" or "Ötzi," found in the Ötztal Alps (South Tyrol) in 1991. Through imaging techniques, we know about degeneration in his lumbar spine and a fatal arrow wound in his left shoulder. DNA analyses showed that Ötzi was lactose intolerant, and had brown eyes and blood type 0. Now, a study of Ötzi's microRNAs has also been completed. MicroRNAs are very small pieces of ribonucleic acid (RNA) and play a central role in the regulation of genes. Although these molecules are very stable in tissues, prior to this study it was unclear whether they could still be found in human tissues after thousands of years. Therefore, Professors Andreas Keller and Eckart Meese of Saarland University, Stephanie Kreis of the University of Luxembourg, and Albert Zink and Frank Maixner of Eurac Research in Bozen took on the challenge. They analyzed not only tissue samples from the Iceman, but also those from a mummy of a soldier fallen in World War I. "Our investigation provides evidence that we can analyze microRNA even after thousands of years," explains Keller, professor of clinical bioinformatics at Saarland University, who coordinated the study. The scientists took samples from Ötzi's skin, stomach, and stomach contents. "It was a challenge to extract this genetic material in significant quantities and sufficient quality from the mummified tissue samples, and to measure and quantify it with the newest, very precise methods," reports Kreis, who isolated the microRNAs at the University of Luxembourg. Some molecules were found that were present predominantly in the ancient tissues. Conversely, some of the biomarkers that are well-known today were not found in Ötzi. According to Zink from Eurac Research, the microRNAs are the next important class of molecules from Ötzi to receive intensive examination. Meese, head of the Institute of Human Genetics at Saarland University, claims that the stability of these biomarkers is also important for people today. "It is vital for clinical applications," explains Meese. "It's evident that the potential of microRNA is much greater than we previously thought. We still don't know enough about how these molecules influence specific genes, entire gene families, or biochemical reaction pathways. "When we investigate this further, it's possible microRNAs will become new stars in therapy. Until then, however, there is a lot more work to do," concludes Keller.


Meinke P.,Institute of Human Genetics | Thuy D.N.,Institute of Human Genetics | Thuy D.N.,Vietnam Academy of Science and Technology | Wehnert M.S.,Institute of Human Genetics
Biochemical Society Transactions | Year: 2011

The LINC (linker of nucleoskeleton and cytoskeleton) complex is a proposed mechanical link tethering the nucleo- and cyto-skeleton via the NE (nuclear envelope). The LINC components emerin, lamin A/C, SUN1, SUN2, nesprin-1 and nesprin-2 interact with each other at the NE and also with other binding partners including actin filaments and B-type lamins. Besides the mechanostructural functions, the LINC complex is also involved in signalling pathways and gene regulation. Emerin was the first LINC component associated with a human disease, namely EDMD (Emery-Dreifuss muscular dystrophy). Later on, other components of the LINC complex, such as lamins A/C and small isoforms of nesprin-1 and nesprin-2, were found to be associated with EDMD, reflecting a genetic heterogeneity that has not been resolved so far. Only approximately 46% of the EDMD patients can be linked to genes of LINC and non-LINC components, pointing to further genes involved in the pathology of EDMD. Obvious candidates are the LINC proteins SUN1 and SUN2. Recently, screening of binding partners of LINC components as candidates identified LUMA (TMEM43), encoding a binding partner of emerin and lamins, as a gene involved in atypical EDMD. Nevertheless, such mutations contribute only to a very small fraction of EDMD patients. EDMD-causing mutations in STA/EMD (encoding emerin) that disrupt emerin binding to Btf (Bcl-2-associated transcription factor), GCL (germ cell-less) and BAF (barrier to autointegration factor) provide the first glimpses into LINC being involved in gene regulation and thus opening new avenues for functional studies. Thus the association of LINC with human disease provides tools for understanding its functions within the cell. ©The Authors Journal compilation ©2011 Biochemical Society.


Ayers K.L.,Institute of Human Genetics | Cordell H.J.,Institute of Human Genetics
Genetic Epidemiology | Year: 2010

Penalized regression methods offer an attractive alternative to single marker testing in genetic association analysis. Penalized regression methods shrink down to zero the coefficient of markers that have little apparent effect on the trait of interest, resulting in a parsimonious subset of what we hope are true pertinent predictors. Here we explore the performance of penalization in selecting SNPs as predictors in genetic association studies. The strength of the penalty can be chosen either to select a good predictive model (via methods such as computationally expensive cross validation), through maximum likelihood-based model selection criterion (such as the BIC), or to select a model that controls for type I error, as done here. We have investigated the performance of several penalized logistic regression approaches, simulating data under a variety of disease locus effect size and linkage disequilibrium patterns. We compared several penalties, including the elastic net, ridge, Lasso, MCP and the normal-exponential-γ shrinkage prior implemented in the hyperlasso software, to standard single locus analysis and simple forward stepwise regression. We examined how markers enter the model as penalties and P-value thresholds are varied, and report the sensitivity and specificity of each of the methods. Results show that penalized methods outperform single marker analysis, with the main difference being that penalized methods allow the simultaneous inclusion of a number of markers, and generally do not allow correlated variables to enter the model, producing a sparse model in which most of the identified explanatory markers are accounted for. © 2010 Wiley-Liss, Inc.


Guglieri M.,Institute of Human Genetics | Bushby K.,Institute of Human Genetics
Current Opinion in Pharmacology | Year: 2010

Duchenne muscular dystrophy (DMD) is the most common childhood muscular dystrophy and results from mutations in the dystrophin gene. Currently no treatment is available for this devastating condition. Standards of care have been improving and are spreading world-wide, prolonging survival and increasing quality of life, however management of symptoms and complications remains the only interventions that can currently be offered to patients.New and promising experimental strategies to address DMD have been developed over the last few years and some of them are in or are approaching clinical trials. Different therapeutic options are being investigated, ranging from mutation-specific treatments, including nonsense codon suppressors and exon skipping, to gene therapy using viral and nonviral vectors and cell-based approaches.Here we review the current status of molecular investigational treatments in DMD, with a particular focus on those compounds and strategies that are currently in clinical trials or are likely to approach clinical application in the near future. © 2010 Elsevier Ltd.


Baudat F.,Institute of Human Genetics | Imai Y.,Institute of Human Genetics | De Massy B.,Institute of Human Genetics
Nature Reviews Genetics | Year: 2013

During meiosis, a programmed induction of DNA double-strand breaks (DSBs) leads to the exchange of genetic material between homologous chromosomes. These exchanges increase genome diversity and are essential for proper chromosome segregation at the first meiotic division. Recent findings have highlighted an unexpected molecular control of the distribution of meiotic DSBs in mammals by a rapidly evolving gene, PR domain-containing 9 (PRDM9), and genome-wide analyses have facilitated the characterization of meiotic DSB sites at unprecedented resolution. In addition, the identification of new players in DSB repair processes has allowed the delineation of recombination pathways that have two major outcomes, crossovers and non-crossovers, which have distinct mechanistic roles and consequences for genome evolution. © 2013 Macmillan Publishers Limited.


Mechali M.,Institute of Human Genetics | Yoshida K.,Institute of Human Genetics | Coulombe P.,Institute of Human Genetics | Pasero P.,Institute of Human Genetics
Current Opinion in Genetics and Development | Year: 2013

In the genome of eukaryotic cells, DNA synthesis is initiated at multiple sites called origins of DNA replication. Origins must fire only once per cell cycle and how this is achieved is now well understood. However, little is known about the mechanisms that determine when and where replication initiates in a given cell. A large body of evidence indicates that origins are not equal in terms of efficiency and timing of activation. Origin usage also changes concomitantly with the different cell differentiation programs. As DNA replication occurs in the context of chromatin, initiation could be influenced by multiple parameters, such as nucleosome positioning, histone modifications, and three-dimensional (3D) organization of the nucleus. This view is supported by recent genome-wide studies showing that DNA replication profiles are shaped by genetic and epigenetic processes that act both at the local and global levels to regulate origin function in eukaryotic cells. © 2013 Elsevier Ltd.

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