| 1. |
- Abel, Frida, 1974, et al.
(författare)
-
A 6-gene signature identifies four molecular subgroups of neuroblastoma
- 2011
-
Ingår i: Cancer Cell International. - : Springer Science and Business Media LLC. - 1475-2867. ; 11:9
-
Tidskriftsartikel (refereegranskat)abstract
- Abstract Background There are currently three postulated genomic subtypes of the childhood tumour neuroblastoma (NB); Type 1, Type 2A, and Type 2B. The most aggressive forms of NB are characterized by amplification of the oncogene MYCN (MNA) and low expression of the favourable marker NTRK1. Recently, mutations or high expression of the familial predisposition gene Anaplastic Lymphoma Kinase (ALK) was associated to unfavourable biology of sporadic NB. Also, various other genes have been linked to NB pathogenesis. Results The present study explores subgroup discrimination by gene expression profiling using three published microarray studies on NB (47 samples). Four distinct clusters were identified by Principal Components Analysis (PCA) in two separate data sets, which could be verified by an unsupervised hierarchical clustering in a third independent data set (101 NB samples) using a set of 74 discriminative genes. The expression signature of six NB-associated genes ALK, BIRC5, CCND1, MYCN, NTRK1, and PHOX2B, significantly discriminated the four clusters (p
|
|
| 2. |
- Dalevi, Daniel, 1974, et al.
(författare)
-
Expected Gene Order Distances and Model Selection in Bacteria
- 2007
-
Ingår i: Proceedings of German Conference on Bioinformatics, Potsdam, 26-28 september, 2007, LNI. - 1617-5468. - 9783885792093 ; 115, s. 135-144
-
Konferensbidrag (refereegranskat)abstract
- The most parsimonous distances calculated in pairwise gene order comparisons cannot accurately reflect the true number of events separating two species, unless the number of changes are few. Better is to use the expected distances. In this study we recapitulate previous results and derive new expected distances for models that have gained support in other studies, such as, symmetrical reversal distances and short reversals. Further, we investigate the patterns of dotplots between species of bacteria with the purpose of model selection in gene order problems. We find several categories of data which can be explained by carefully weighing the contributions of reversals, transpositions, symmetric reversals, single gene transpositions, and single gene reversals.
|
|
| 3. |
- Dalevi, Daniel, 1974, et al.
(författare)
-
Expected Gene Order Distances and Model Selection in Bacteria
- 2008
-
Ingår i: Bioinformatics. - Oxford, United Kingdom : Oxford University Press. - 1367-4803 .- 1367-4811. ; 24:11, s. 1332-1338
-
Tidskriftsartikel (refereegranskat)abstract
- Motivation: The evolutionary distance inferred from gene-order comparisons of related bacteria is dependent on the model. Therefore, it is highly important to establish reliable assumptions before inferring its magnitude. Results: We investigate the patterns of dotplots between species of bacteria with the purpose of model selection in gene-order problems. We find several categories of data which can be explained by carefully weighing the contributions of reversals, transpositions, symmetrical reversals, single gene transpositions and single gene reversals. We also derive method of moments distance estimates for some previously uncomputed cases, such as symmetrical reversals, single gene reversals and their combinations, as well as the single gene transpositions edit distance.
|
|
| 4. |
- Wilzén, Annica, et al.
(författare)
-
ERBB3 is a marker of a ganglioneuroblastoma/ganglioneuroma-like expression profile in neuroblastic tumours
- 2013
-
Ingår i: Molecular Cancer. - : Springer Science and Business Media LLC. - 1476-4598. ; 12
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Neuroblastoma (NB) tumours are commonly divided into three cytogenetic subgroups. However, by unsupervised principal components analysis of gene expression profiles we recently identified four distinct subgroups, r1-r4. In the current study we characterized these different subgroups in more detail, with a specific focus on the fourth divergent tumour subgroup (r4). Methods: Expression microarray data from four international studies corresponding to 148 neuroblastic tumour cases were subject to division into four expression subgroups using a previously described 6-gene signature. Differentially expressed genes between groups were identified using Significance Analysis of Microarray (SAM). Next, gene expression network modelling was performed to map signalling pathways and cellular processes representing each subgroup. Findings were validated at the protein level by immunohistochemistry and immunoblot analyses. Results: We identified several significantly up-regulated genes in the r4 subgroup of which the tyrosine kinase receptor ERBB3 was most prominent (fold change: 132-240). By gene set enrichment analysis (GSEA) the constructed gene network of ERBB3 (n = 38 network partners) was significantly enriched in the r4 subgroup in all four independent data sets. ERBB3 was also positively correlated to the ErbB family members EGFR and ERBB2 in all data sets, and a concurrent overexpression was seen in the r4 subgroup. Further studies of histopathology categories using a fifth data set of 110 neuroblastic tumours, showed a striking similarity between the expression profile of r4 to ganglioneuroblastoma (GNB) and ganglioneuroma (GN) tumours. In contrast, the NB histopathological subtype was dominated by mitotic regulating genes, characterizing unfavourable NB subgroups in particular. The high ErbB3 expression in GN tumour types was verified at the protein level, and showed mainly expression in the mature ganglion cells. Conclusions: Conclusively, this study demonstrates the importance of performing unsupervised clustering and subtype discovery of data sets prior to analyses to avoid a mixture of tumour subtypes, which may otherwise give distorted results and lead to incorrect conclusions. The current study identifies ERBB3 as a clear-cut marker of a GNB/GN-like expression profile, and we suggest a 7-gene expression signature (including ERBB3) as a complement to histopathology analysis of neuroblastic tumours. Further studies of ErbB3 and other ErbB family members and their role in neuroblastic differentiation and pathogenesis are warranted.
|
|
| 5. |
- Clermont, Gilles, et al.
(författare)
-
Bridging the gap between systems biology and medicine
- 2009
-
Ingår i: Genome Medicine. - : Springer Science and Business Media LLC. - 1756-994X. ; 1:9
-
Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT : Systems biology has matured considerably as a discipline over the last decade, yet some of the key challenges separating current research efforts in systems biology and clinically useful results are only now becoming apparent. As these gaps are better defined, the new discipline of systems medicine is emerging as a translational extension of systems biology. How is systems medicine defined? What are relevant ontologies for systems medicine? What are the key theoretic and methodologic challenges facing computational disease modeling? How are inaccurate and incomplete data, and uncertain biologic knowledge best synthesized in useful computational models? Does network analysis provide clinically useful insight? We discuss the outstanding difficulties in translating a rapidly growing body of data into knowledge usable at the bedside. Although core-specific challenges are best met by specialized groups, it appears fundamental that such efforts should be guided by a roadmap for systems medicine drafted by a coalition of scientists from the clinical, experimental, computational, and theoretic domains.
|
|
| 6. |
- Cvijovic, Marija, 1977, et al.
(författare)
-
Identification of putative regulatory upstream ORFs in the yeast genome using heuristics and evolutionary conservation
- 2007
-
Ingår i: BMC Bioinformatics. - : Springer Science and Business Media LLC. - 1471-2105. ; 8
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The translational efficiency of an mRNA can be modulated by upstream open reading frames (uORFs) present in certain genes. A uORF can attenuate translation of the main ORF by interfering with translational reinitiation at the main start codon. uORFs also occur by chance in the genome, in which case they do not have a regulatory role. Since the sequence determinants for functional uORFs are not understood, it is difficult to discriminate functional from spurious uORFs by sequence analysis. RESULTS: We have used comparative genomics to identify novel uORFs in yeast with a high likelihood of having a translational regulatory role. We examined uORFs, previously shown to play a role in regulation of translation in Saccharomyces cerevisiae, for evolutionary conservation within seven Saccharomyces species. Inspection of the set of conserved uORFs yielded the following three characteristics useful for discrimination of functional from spurious uORFs: a length between 4 and 6 codons, a distance from the start of the main ORF between 50 and 150 nucleotides, and finally a lack of overlap with, and clear separation from, neighbouring uORFs. These derived rules are inherently associated with uORFs with properties similar to the GCN4 locus, and may not detect most uORFs of other types. uORFs with high scores based on these rules showed a much higher evolutionary conservation than randomly selected uORFs. In a genome-wide scan in S. cerevisiae, we found 34 conserved uORFs from 32 genes that we predict to be functional; subsequent analysis showed the majority of these to be located within transcripts. A total of 252 genes were found containing conserved uORFs with properties indicative of a functional role; all but 7 are novel. Functional content analysis of this set identified an overrepresentation of genes involved in transcriptional control and development. CONCLUSION: Evolutionary conservation of uORFs in yeasts can be traced up to 100 million years of separation. The conserved uORFs have certain characteristics with respect to length, distance from each other and from the main start codon, and folding energy of the sequence. These newly found characteristics can be used to facilitate detection of other conserved uORFs.
|
|
| 7. |
- Dalevi, Daniel A., et al.
(författare)
-
Measuring genome divergence in bacteria : A case study using Chlamydian data
- 2002
-
Ingår i: Journal of Molecular Evolution. - New York, USA : Springer-Verlag New York. - 0022-2844 .- 1432-1432. ; 55, s. 24-36
-
Tidskriftsartikel (refereegranskat)abstract
- We have studied the relative contribution of inversions, transpositions, deletions, and nucleotide substitutions to the evolution of Chlamydia trachomatis and Chlamydia pneumoniae. The minimal number of rearrangement events required for converting the gene order structure of one genome into that of the other was estimated to 59 6 events, including 13% inversions, 38% short inversions, and 49% transpositions. In contrast to previous findings, no examples of horizontal gene transfer subsequent to species divergence were identified, nor any evidence for an excessive number of tandem gene duplications. A statistical model was used to compare nucleotide frequencies for a set of genes uniquely present in one species to a set of orthologous genes present in both species. The two data sets were not significantly different, which is indicative of a low frequency of horizontal gene transfer events. This is based on the assumption that a foreign gene of different nucleotide content will not have become completely ameliorated, as verified by simulations of the amelioration rate at twofold and fourfold degenerate codon sites. The frequencies of nucleotide substitutions at twofold and fourfold degenerate sites, deletions, inversions, and translocations were estimated to 1.42, 0.62, 0,18, 0.01, and 0.01 per site, respectively.
|
|
| 8. |
- Dalevi, Daniel, 1974, et al.
(författare)
-
A New Order Estimator for Fixed and Variable Length Markov Models with Applications to DNA Sequence Similarity
- 2006
-
Ingår i: Statistical Applications in Genetics and Molecular Biology. - : Walter de Gruyter GmbH. - 1544-6115. ; 5:1
-
Tidskriftsartikel (refereegranskat)abstract
- Recently Peres and Shields discovered a new method for estimating the order of a stationary fixed order Markov chain. They showed that the estimator is consistent by proving a threshold result. While this threshold is valid asymptotically in the limit, it is not very useful for DNA sequence analysis where data sizes are moderate. In this paper we give a novel interpretation of the Peres-Shields estimator as a sharp transition phenomenon. This yields a precise and powerful estimator that quickly identifies the core dependencies in data. We show that it compares favorably to other estimators, especially in the presence of variable dependencies. Motivated by this last point, we extend the Peres-Shields estimator to Variable Length Markov Chains. We compare it to a well-established estimator and show that it is superior in terms of the predictive likelihood. We give an application to the problem of detecting DNA sequence similarity in plasmids. Copyright ©2006 The Berkeley Electronic Press. All rights reserved.
|
|
| 9. |
- Dalevi, Daniel, 1974, et al.
(författare)
-
Bayesian classifiers for detecting HGT using fixed and variable order Markov models of genomic signatures
- 2006
-
Ingår i: Bioinformatics. - : Oxford University Press (OUP). - 1367-4803 .- 1367-4811. ; 22:5, s. 517-522
-
Tidskriftsartikel (refereegranskat)abstract
- Analyses of genomic signatures are gaining attention as they allow studies of species-specific relationships without involving alignments of homologous sequences. A naïve Bayesian classifier was built to discriminate between different bacterial compositions of short oligomers, also known as DNA words. The classifier has proven successful in identifying foreign genes in Neisseria meningitis. In this study we extend the classifier approach using either a fixed higher order Markov model (Mk) or a variable length Markov model (VLMk).
|
|
| 10. |
- Dalevi, Daniel, 1974
(författare)
-
Inferring evolution in bacteria using Markov chains and genomic signatures
- 2006
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis concerns the development of methods and models in evolutionary molecular biology. The techniques are also applicable to other similar biological problems. The first contribution is a novel classifier using fixed and variable length Markov chains that can discriminate between bacterial DNA of different species. The classifier assumes that the composition of oligomers, DNA words, is species-specific and represents global features of the species, a so called genomic signature. The direct applications of such a classifier are: identification of horizontal gene transfer and binning of metagenomic data. The former has been the primary focus as it is one of the central processes in the evolution of bacteria. We suggest a new method for locking the number of parameters in a variable length Markov model and propose a method for rejecting false candidates of horizontal gene transfer events. The second contribution is a novel estimator for finding the prediction suffix tree of a variable length Markov chain. This new estimator is highly efficient in finding the correct state-space and we show that it compares favorably to a popular estimator in terms of the predictive likelihood.The third contribution is to the analysis of gene order rearrangements in bacteria. We recapitulate previous results on expected distances and derive new ones for cases that have recently gained support in the literature, such as symmetrical and short reversals. We also describe new categories of gene order patterns and show how these can be explained with models using short, symmetric and uniformly distributed transpositions and reversals.The forth contribution is a part of the Greengenes project which is a chimera free database of 16S rDNA sequences.
|
|
| 11. |
- DeSantis, T, et al.
(författare)
-
Greengenes, a Chimera-Checked 16S rRNA Gene Database and Workbench Compatible with ARB
- 2006
-
Ingår i: AEM. ; 72, s. 5069-5072
-
Tidskriftsartikel (refereegranskat)abstract
- A 16S rRNA gene database (http://greengenes.lbl.gov) addresses limitations of public repositories by providing chimera screening, standard alignment, and taxonomic classification using multiple published taxonomies. It was found that there is incongruent taxonomic nomenclature among curators even at the phylum level. Putative chimeras were identified in 3% of environmental sequences and in 0.2% of records derived from isolates. Environmental sequences were classified into 100 phylum-level lineages in the Archaea and Bacteria.
|
|
| 12. |
|
|
| 13. |
- Fernandez-Ricaud, L., et al.
(författare)
-
Testing of Chromosomal Clumping of Gene Properties
- 2009
-
Ingår i: Statistical Applications in Genetics and Molecular Biology. - 1544-6115. ; 8:1
-
Tidskriftsartikel (refereegranskat)abstract
- Clumping of gene properties like expression or mutant phenotypes along chromosomes is commonly detected using completely random null-models where their location is equally likely across the chromosomes. Interpretation of statistical tests based on these assumptions may be misleading if dependencies exist that are unequal between chromosomes or in different chromosomal parts. One such regional dependency is the telomeric effect, observed in several studies of Saccharomyces cerevisiae, under which e. g. essential genes are less likely to reside near the chromosomal ends. In this study we demonstrate that standard randomisation test procedures are of limited applicability in the presence of telomeric effects. Several extensions of such standard tests are here suggested for handling clumping simultaneously with regional differences in essentiality frequencies in sub-telomeric and central gene positions. Furthermore, a general non-homogeneous discrete Markov approach for combining parametrically modelled position dependent probabilities of a dichotomous property with a simple single parameter clumping is suggested. This Markov model is adapted to the observed telomeric effects and then simulations are used to demonstrate properties of the suggested modified randomisation tests. The model is also applied as a direct alternative tool for statistical analysis of the S. cerevisiae genome for clumping of phenotypes.
|
|
| 14. |
- Kristiansson, Erik, 1978, et al.
(författare)
-
ShotgunFunctionalizeR: an R-package for functional comparison of metagenomes
- 2009
-
Ingår i: Bioinformatics. - 1367-4803 .- 1367-4811. ; 25:20, s. 2737-2738
-
Tidskriftsartikel (refereegranskat)abstract
- Summary: Microorganisms are ubiquitous in nature and constitute intrinsic parts of almost every ecosystem. A culture-independent and powerful way to study microbial communities is metagenomics. In such studies, functional analysis is performed on fragmented genetic material from multiple species in the community. The recent advances in high-throughput sequencing have greatly increased the amount of data in metagenomic projects. At present, there is an urgent need for efficient statistical tools to analyse these data. We have created ShotgunFunctionalizeR, an R-package for functional comparison of metagenomes. The package contains tools for importing, annotating and visualizing metagenomic data produced by shotgun high-throughput sequencing. ShotgunFunctionalizeR contains several statistical procedures for assessing functional differences between samples, both for individual genes and for entire pathways. In addition to standard and previously published methods, we have developed and implemented a novel approach based on a Poisson model. This procedure is highly flexible and thus applicable to a wide range of different experimental designs. We demonstrate the potential of ShotgunFunctionalizeR by performing a regression analysis on metagenomes sampled at multiple depths in the Pacific Ocean.
|
|
