Publications (75) View all
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Article: High-resolution genomic profiling of chronic lymphocytic leukemia reveals new recurrent genomic alterations.
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ABSTRACT: To identify genomic alterations in chronic lymphocytic leukemia (CLL), we performed single-nucleotide polymorphism (SNP)-array analysis (Affymetrix 6.0) on 353 samples from untreated patients entered on the CLL8 treatment trial. Based on paired-sample analysis (n=144), a mean of 1.8 copy number alterations (CNAs) per case were identified; about 60% of cases carried no CNAs other than those detected by fluorescence in-situ hybridization analysis. Copy-neutral loss-of-heterozygosity was detected in 6% of cases, and most frequently found on 13q, 17p and 11q. Minimally deleted regions were refined on 13q14 (deleted in 61% of cases) to the DLEU1 and DLEU2 genes, on 11q22.3 (27%) to ATM, on 2p16.1-2p15 (gained in 7%) to a 1.9 Mb fragment containing 9 genes, and on 8q24.21 (5%) to a segment 486 Kb proximal of the MYC locus. 13q deletions exhibited proximal and distal breakpoint cluster regions. Among the most common novel lesions were deletions at 15q15.1 (4%), with the smallest deletion (70.48 Kb) found in the MGA locus. Sequence analysis of MGA in 59 samples revealed a truncating mutation in one case lacking a 15q deletion. MNT at 17p13.3, which in addition to MGA and MYC encodes for the network of MAX-interacting proteins, was also found recurrently deleted.Blood 10/2012; · 9.90 Impact Factor -
Article: A map of human genome variation from population-scale sequencing
Nature 10/2010; 467:1061-1073. · 36.28 Impact Factor -
Article: PEMer: a computational framework with simulation-based error models for inferring genomic structural variants from massive paired-end sequencing data.
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ABSTRACT: Personal-genomics endeavors, such as the 1000 Genomes project, are generating maps of genomic structural variants by analyzing ends of massively sequenced genome fragments. To process these we developed Paired-End Mapper (PEMer; http://sv.gersteinlab.org/pemer). This comprises an analysis pipeline, compatible with several next-generation sequencing platforms; simulation-based error models, yielding confidence-values for each structural variant; and a back-end database. The simulations demonstrated high structural variant reconstruction efficiency for PEMer's coverage-adjusted multi-cutoff scoring-strategy and showed its relative insensitivity to base-calling errors.Genome biology 03/2009; 10(2):R23. · 6.63 Impact Factor -
Article: Use of pathway analysis and genome context methods for functional genomics of Mycoplasma pneumoniae nucleotide metabolism.
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ABSTRACT: Elementary modes analysis allows one to reveal whether a set of known enzymes is sufficient to sustain functionality of the cell. Moreover, it is helpful in detecting missing reactions and predicting which enzymes could fill these gaps. Here, we perform a comprehensive elementary modes analysis and a genomic context analysis of Mycoplasma pneumoniae nucleotide metabolism, and search for new enzyme activities. The purine and pyrimidine networks are reconstructed by assembling enzymes annotated in the genome or found experimentally. We show that these reaction sets are sufficient for enabling synthesis of DNA and RNA in M. pneumoniae. Special focus is on the key modes for growth. Moreover, we make an educated guess on the nutritional requirements of this micro-organism. For the case that M. pneumoniae does not require adenine as a substrate, we suggest adenylosuccinate synthetase (EC 6.3.4.4), adenylosuccinate lyase (EC 4.3.2.2) and GMP reductase (EC 1.7.1.7) to be operative. GMP reductase activity is putatively assigned to the NRDI_MYCPN gene on the basis of the genomic context analysis. For the pyrimidine network, we suggest CTP synthase (EC 6.3.4.2) to be active. Further experiments on the nutritional requirements are needed to make a decision. Pyrimidine metabolism appears to be more appropriate as a drug target than purine metabolism since it shows lower plasticity.Gene 08/2007; 396(2):215-25. · 2.34 Impact Factor -
Article: Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project.
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ABSTRACT: We report the generation and analysis of functional data from multiple, diverse experiments performed on a targeted 1% of the human genome as part of the pilot phase of the ENCODE Project. These data have been further integrated and augmented by a number of evolutionary and computational analyses. Together, our results advance the collective knowledge about human genome function in several major areas. First, our studies provide convincing evidence that the genome is pervasively transcribed, such that the majority of its bases can be found in primary transcripts, including non-protein-coding transcripts, and those that extensively overlap one another. Second, systematic examination of transcriptional regulation has yielded new understanding about transcription start sites, including their relationship to specific regulatory sequences and features of chromatin accessibility and histone modification. Third, a more sophisticated view of chromatin structure has emerged, including its inter-relationship with DNA replication and transcriptional regulation. Finally, integration of these new sources of information, in particular with respect to mammalian evolution based on inter- and intra-species sequence comparisons, has yielded new mechanistic and evolutionary insights concerning the functional landscape of the human genome. Together, these studies are defining a path for pursuit of a more comprehensive characterization of human genome function.Nature 07/2007; 447(7146):799-816. · 36.28 Impact Factor
