Biomedical subjects

Mark Hoebeke

Publications and source records attributed to Mark Hoebeke.

4 recordsLinked to original sources

PubMed2006

Detecting local high-scoring segments: a first-stage approach for genome-wide association studies.

Genetic epidemiology aims at identifying biological mechanisms responsible for human diseases. Genome-wide association studies, made possible by recent improvements in genotyping technologies, are now promisingly investigated. In these studies, common first-stage strategies focus on marginal effects but lead to multiple-testing and are unable to capture the possibly complex interplay between genetic factors. We have adapted the use of the local score statistic, already successfully applied to analyse long molecular sequences. Via sum statistics, this method captures local and possible distant dependences between markers. Dedicated to genome-wide association studies, it is fast to compute, able to handle large datasets, circumvents the the multiple-testing problem and outlines a set of genomic regions (segments) for further analyses. Applied to simulated and real data, our approach outperforms classical Bonferroni and FDR corrections for multiple-testing. It is implemented in a software termed LHiSA for Local High-scoring Segments for Association and available at: http://stat.genopole.cnrs.fr/software/lhisa.

Algorithms↗

PubMed2006

DomainSieve: a protein domain-based screen that led to the identification of dam-associated genes with potential link to DNA maintenance.

MOTIVATION: The Dam methyltransferase (DamMT) activity, broadly distributed in association with restriction endonucleases, as part of the restriction-modification defense systems, has evolved to become intimately associated with essential biological functions in a few organisms. In Escherichia coli, DamMT is involved in multiple aspects of DNA maintenance, replication initiation, daughter chromosome segregation, DNA mismatch repair, gene expression control, etc. The participation of DamMT in such a diverse set of functions required that other genes adapted, or emerged through evolution, in response to the DamMT-induced modification of the genomic environment. One example is SeqA, a protein that senses the methylation status of the origin of replication of the chromosome to control the timing of replication initiation. Interestingly, seqA is only present in a few DamMT-specifying proteobacteria. This observation led us to hypothesize that other genes, specifying related functions, might also be found in these organisms. To test this hypothesis, we implemented a large-scale comparative genomic screen meant to identify genes specifying DNA methylation sensing domains, probably involved in DNA maintenance functions. RESULTS: We carried out a phylogenetic analysis of DamMT, identifying two contrasting behaviors of the protein. Based on this phylogeny, we defined precisely a set of genomes, in which the protein activity is likely to be involved in DNA maintenance functions, the 'resident' dam genomes. We defined a second set of genomes, in which DamMT is not resident. We developped a new tool, 'DomainSieve', in order to screen these two sets for protein domains that are strictly associated with 'resident' dam genomes. This approach was rewarding and generated a list of genes, among which some, at least, specify activities with clear linkage to DamMT-dependent DNA methylation and DNA maintenance. AVAILABILITY: DomainSieve is implemented as a web resource and is accessible at http://stat.genopole.cnrs.fr/ds/.

Algorithms↗

PubMed2003

MuGeN: simultaneous exploration of multiple genomes and computer analysis results.

MOTIVATION: The availability of increasing amounts of sequence data about completely sequenced genomes spurs the development of new methods in the fields of automated annotation, and of comparative genomics. Tools allowing the visualization of results produced by analysis methods, superimposed on possibly annotated sequence data, and enabling synchronized navigation in multiple genomes, provide new means for interactive genome exploration. This kind of visual inspection can be used as a basis to assess the quality of new analysis algorithms, or to discover genome portions to be subjected to in-depth studies. RESULTS: We propose a software package, MuGeN, built for navigating through multiple annotated genomes. It is capable of retrieving annotated sequences in several formats, stored in local files, or available in databases over the network. From these, it then generates an interactive display, or an image file, in most common formats suitable for printing, further editing or integrating in Web pages. Genome maps may be mixed with computer analysis results loaded from XML files, whose format is generic enough to be adapted to a majority of sequence oriented analysis methods. AVAILABILITY: MuGeN is available at http://www-mig.jouy.inra.fr/bdsi/MuGeN.

Computer Graphics↗

PubMed2002

Mining Bacillus subtilis chromosome heterogeneities using hidden Markov models.

We present here the use of a new statistical segmentation method on the Bacillus subtilis chromosome sequence. Maximum likelihood parameter estimation of a hidden Markov model, based on the expectation-maximization algorithm, enables one to segment the DNA sequence according to its local composition. This approach is not based on sliding windows; it enables different compositional classes to be separated without prior knowledge of their content, size and localization. We compared these compositional classes, obtained from the sequence, with the annotated DNA physical map, sequence homologies and repeat regions. The first heterogeneity revealed discriminates between the two coding strands and the non-coding regions. Other main heterogeneities arise; some are related to horizontal gene transfer, some to t-enriched composition of hydrophobic protein coding strands, and others to the codon usage fitness of highly expressed genes. Concerning potential and established gene transfers, we found 9 of the 10 known prophages, plus 14 new regions of atypical composition. Some of them are surrounded by repeats, most of their genes have unknown function or possess homology to genes involved in secondary catabolism, metal and antibiotic resistance. Surprisingly, we notice that all of these detected regions are a + t-richer than the host genome, raising the question of their remote sources.

Bacillus subtilis↗