| 1. |
- Alexeyenko, Andrey, et al.
(författare)
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Global networks of functional coupling in eukaryotes from comprehensive data integration
- 2009
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Ingår i: Genome Research. - : Cold Spring Harbor Laboratory. - 1088-9051 .- 1549-5469. ; 19:6, s. 1107-16
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Tidskriftsartikel (refereegranskat)abstract
- No single experimental method can discover all connections in the interactome. A computational approach can help by integrating data from multiple, often unrelated, proteomics and genomics pipelines. Reconstructing global networks of functional coupling (FC) faces the challenges of scale and heterogeneity--how to efficiently integrate huge amounts of diverse data from multiple organisms, yet ensuring high accuracy. We developed FunCoup, an optimized Bayesian framework, to resolve these issues. Because interactomes comprise functional coupling of many types, FunCoup annotates network edges with confidence scores in support of different kinds of interactions: physical interaction, protein complex member, metabolic, or signaling link. This capability boosted overall accuracy. On the whole, the constructed framework was comprehensively tested to optimize the overall confidence and ensure seamless, automated incorporation of new data sets of heterogeneous types. Using over 50 data sets in seven organisms and extensively transferring information between orthologs, FunCoup predicted global networks in eight eukaryotes. For the Ciona intestinalis network, only orthologous information was used, and it recovered a significant number of experimental facts. FunCoup predictions were validated on independent cancer mutation data. We show how FunCoup can be used for discovering candidate members of the Parkinson and Alzheimer pathways. Cross-species pathway conservation analysis provided further support to these observations.
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| 2. |
- Andersson, Robin, et al.
(författare)
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Nucleosomes are well positioned in exons and carry characteristic histone modifications
- 2009
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Ingår i: Genome Research. - : Cold Spring Harbor Laboratory. - 1088-9051 .- 1549-5469. ; 19:10, s. 1732-1741
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Tidskriftsartikel (refereegranskat)abstract
- The genomes of higher organisms are packaged in nucleosomes with functional histone modifications. Until now, genome-wide nucleosome and histone modification studies have focused on transcription start sites (TSSs) where nucleosomes in RNA polymerase II (RNAPII) occupied genes are well positioned and have histone modifications that are characteristic of expression status. Using public data, we here show that there is a higher nucleosome-positioning signal in internal human exons and that this positioning is independent of expression. We observed a similarly strong nucleosome-positioning signal in internal exons of C. elegans. Among the 38 histone modifications analyzed in man, H3K36me3, H3K79me1, H2BK5me1, H3K27me1, H3K27me2 and H3K27me3 had evidently higher signal in internal exons than in the following introns and were clearly related to exon expression. These observations are suggestive of roles in splicing. Thus, exons are not only characterized by their coding capacity but also by their nucleosome organization, which seems evolutionary conserved since it is present in both primates and nematodes.
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| 3. |
- Bengtsson, Martin, et al.
(författare)
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Gene expression profiling in single cells from the pancreatic islets of Langerhans reveals lognormal distribution of mRNA levels.
- 2005
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Ingår i: Genome Research. - : Cold Spring Harbor Laboratory. - 1549-5469 .- 1088-9051. ; 15:10, s. 1388-1392
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Tidskriftsartikel (refereegranskat)abstract
- The transcriptional machinery in individual cells is controlled by a relatively small number of molecules, which may result in stochastic behavior in gene activity. Because of technical limitations in current collection and recording methods, most gene expression measurements are carried out on populations of cells and therefore reflect average mRNA levels. The variability of the transcript levels between different cells remains undefined, although it may have profound effects on cellular activities. Here we have measured gene expression levels of the five genes ActB, Ins1, Ins2, Abcc8, and Kcnj11 in individual cells from mouse pancreatic islets. Whereas Ins1 and Ins2 expression show a strong cell-cell correlation, this is not the case for the other genes. We further found that the transcript levels of the different genes are lognormally distributed. Hence, the geometric mean of expression levels provides a better estimate of gene activity of the typical cell than does the arithmetic mean measured on a cell population.
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| 4. |
- Bertone, Paul, et al.
(författare)
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Design optimization methods for genomic DNA tiling arrays.
- 2006
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Ingår i: Genome Research. - : Cold Spring Harbor Laboratory. - 1088-9051 .- 1549-5469. ; 16:2, s. 271-281
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Tidskriftsartikel (refereegranskat)abstract
- A recent development in microarray research entails the unbiased coverage, or tiling, of genomic DNA for the large-scale identification of transcribed sequences and regulatory elements. A central issue in designing tiling arrays is that of arriving at a single-copy tile path, as significant sequence cross-hybridization can result from the presence of non-unique probes on the array. Due to the fragmentation of genomic DNA caused by the widespread distribution of repetitive elements, the problem of obtaining adequate sequence coverage increases with the sizes of subsequence tiles that are to be included in the design. This becomes increasingly problematic when considering complex eukaryotic genomes that contain many thousands of interspersed repeats. The general problem of sequence tiling can be framed as finding an optimal partitioning of non-repetitive subsequences over a prescribed range of tile sizes, on a DNA sequence comprising repetitive and non-repetitive regions. Exact solutions to the tiling problem become computationally infeasible when applied to large genomes, but successive optimizations are developed that allow their practical implementation. These include an efficient method for determining the degree of similarity of many oligonucleotide sequences over large genomes, and two algorithms for finding an optimal tile path composed of longer sequence tiles. The first algorithm, a dynamic programming approach, finds an optimal tiling in linear time and space; the second applies a heuristic search to reduce the space complexity to a constant requirement. A Web resource has also been developed, accessible at http://tiling.gersteinlab.org, to generate optimal tile paths from user-provided DNA sequences.
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| 5. |
- Björnerfeldt, Susanne, et al.
(författare)
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Relaxation of selective constraint on dog mitochondrial DNA following domestication
- 2006
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Ingår i: Genome Research. - : Cold Spring Harbor Laboratory. - 1088-9051 .- 1549-5469. ; 16:8, s. 990-994
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Tidskriftsartikel (refereegranskat)abstract
- The domestication of dogs caused a dramatic change in their way of life compared with that of their ancestor, the gray wolf. We hypothesize that this new life style changed the selective forces that acted upon the species, which in turn had an effect on the dog's genome. We sequenced the complete mitochondrial DNA genome in 14 dogs, six wolves, and three coyotes. Here we show that dogs have accumulated nonsynonymous changes in mitochondrial genes at a faster rate than wolves, leading to elevated levels of variation in their proteins. This suggests that a major consequence of domestication in dogs was a general relaxation of selective constraint on their mitochondrial genome. If this change also affected other parts of the dog genome, it could have facilitated the generation of novel functional genetic diversity. This diversity could thus have contributed raw material upon which artificial selection has shaped modern breeds and may therefore be an important source of the extreme phenotypic variation present in modern-day dogs.
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| 6. |
- Brandström, Miakel, et al.
(författare)
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Genome-wide analysis of microsatellite polymorphism in chicken circumventing the ascertainment bias
- 2008
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Ingår i: Genome Research. - : Cold Spring Harbor Laboratory. - 1088-9051 .- 1549-5469. ; 18:6, s. 881-887
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Tidskriftsartikel (refereegranskat)abstract
- Studies of microsatellites evolution based on marker data almost inherently suffer from an ascertainment bias because there is selection for the most mutable and polymorphic loci during marker development. To circumvent this bias we took advantage of whole-genome shotgun sequence data from three unrelated chicken individuals that, when aligned to the genome reference sequence, give sequence information on two chromosomes from about one-fourth (375,000) of all microsatellite loci containing di- through pentanucleotide repeat motifs in the chicken genome. Polymorphism is seen at loci with as few as five repeat units, and the proportion of dimorphic loci then increases to 50% for sequences with similar to 10 repeat units, to reach a maximum of 75%-80% for sequences with 15 or more repeat units. For any given repeat length, polymorphism increases with decreasing GC content of repeat motifs for dinucleotides, nonhairpin-forming trinucleotides, and tetranucleotides. For trinucleotide repeats which are likely to form hairpin structures, polymorphism increases with increasing GC content, indicating that the relative stability of hairpins affects the rate of replication slippage. For any given repeat length, polymorphism is significantly lower for imperfect compared to perfect repeats and repeat interruptions occur in >15% of loci. However, interruptions are not randomly distributed within repeat arrays but are preferentially located toward the ends. There is negative correlation between microsatellite abundance and single nucleotide polymorphism ( SNP) density, providing large-scale genomic support for the hypothesis that equilibrium microsatellite distributions are governed by a balance between rate of replication slippage and rate of point mutation.
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| 7. |
- Elhai, Jeff, et al.
(författare)
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Very small mobile repeated elements in cyanobacterial genomes
- 2008
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Ingår i: Genome Research. - : Cold Spring Harbor Laboratory. - 1088-9051 .- 1549-5469. ; 18:9, s. 1484-1499
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Tidskriftsartikel (refereegranskat)abstract
- Mobile DNA elements play a major role in genome plasticity and other evolutionary processes, an insight gained primarily through the study of transposons and retrotransposons (generally similar to 1000 nt or longer). These elements spawn smaller parasitic versions (generally > ; 100 nt) that propagate through proteins encoded by the full elements. Highly repeated sequences smaller than 100 nt have been described, but they are either nonmobile or their origins are not known. We have surveyed the genome of the multicellular cyanobacterium, Nostoc punctiforme, and its relatives for small dispersed repeat (SDR) sequences and have identified eight families in the range of from 21 to 27 nucleotides. Three of the families (SDR4, SDR5, and SDR6), despite little sequence similarity, share a common predicted secondary structure, a conclusion supported by patterns of compensatory mutations. The SDR elements are found in a diverse set of contexts, often embedded within tandemly repeated heptameric sequences or within minitransposons. One element ( SDR5) is found exclusively within instances of an octamer, HIP1, that is highly over-represented in the genomes of many cyanobacteria. Two elements (SDR1 and SDR4) often are found within copies of themselves, producing complex nested insertions. An analysis of SDR elements within cyanobacterial genomes indicate that they are essentially confined to a coherent subgroup. The evidence indicates that some of the SDR elements, probably working through RNA intermediates, have been mobile in recent evolutionary time, making them perhaps the smallest known mobile elements.
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| 8. |
- Emanuelsson, Olof, et al.
(författare)
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Assessing the performance of different high-density tiling microarray strategies for mapping transcribed regions of the human genome.
- 2007
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Ingår i: Genome Research. - : Cold Spring Harbor Laboratory. - 1088-9051 .- 1549-5469. ; 17:6, s. 886-897
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Tidskriftsartikel (refereegranskat)abstract
- Genomic tiling microarrays have become a popular tool for interrogating the transcriptional activity of large regions of the genome in an unbiased fashion. There are several key parameters associated with each tiling experiment (e.g., experimental protocols and genomic tiling density). Here, we assess the role of these parameters as they are manifest in different tiling-array platforms used for transcription mapping. First, we analyze how a number of published tiling-array experiments agree with established gene annotation on human chromosome 22. We observe that the transcription detected from high-density arrays correlates substantially better with annotation than that from other array types. Next, we analyze the transcription-mapping performance of the two main high-density oligonucleotide array platforms in the ENCODE regions of the human genome. We hybridize identical biological samples and develop several ways of scoring the arrays and segmenting the genome into transcribed and nontranscribed regions, with the aim of making the platforms most comparable to each other. Finally, we develop a platform comparison approach based on agreement with known annotation. Overall, we find that the performance improves with more data points per locus, coupled with statistical scoring approaches that properly take advantage of this, where this larger number of data points arises from higher genomic tiling density and the use of replicate arrays and mismatches. While we do find significant differences in the performance of the two high-density platforms, we also find that they complement each other to some extent. Finally, our experiments reveal a significant amount of novel transcription outside of known genes, and an appreciable sample of this was validated by independent experiments.
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| 9. |
- Euskirchen, Ghia M, et al.
(författare)
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Mapping of transcription factor binding regions in mammalian cells by ChIP : comparison of array- and sequencing-based technologies.
- 2007
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Ingår i: Genome Research. - : Cold Spring Harbor Laboratory. - 1088-9051 .- 1549-5469. ; 17:6, s. 898-909
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Tidskriftsartikel (refereegranskat)abstract
- Recent progress in mapping transcription factor (TF) binding regions can largely be credited to chromatin immunoprecipitation (ChIP) technologies. We compared strategies for mapping TF binding regions in mammalian cells using two different ChIP schemes: ChIP with DNA microarray analysis (ChIP-chip) and ChIP with DNA sequencing (ChIP-PET). We first investigated parameters central to obtaining robust ChIP-chip data sets by analyzing STAT1 targets in the ENCODE regions of the human genome, and then compared ChIP-chip to ChIP-PET. We devised methods for scoring and comparing results among various tiling arrays and examined parameters such as DNA microarray format, oligonucleotide length, hybridization conditions, and the use of competitor Cot-1 DNA. The best performance was achieved with high-density oligonucleotide arrays, oligonucleotides >/=50 bases (b), the presence of competitor Cot-1 DNA and hybridizations conducted in microfluidics stations. When target identification was evaluated as a function of array number, 80%-86% of targets were identified with three or more arrays. Comparison of ChIP-chip with ChIP-PET revealed strong agreement for the highest ranked targets with less overlap for the low ranked targets. With advantages and disadvantages unique to each approach, we found that ChIP-chip and ChIP-PET are frequently complementary in their relative abilities to detect STAT1 targets for the lower ranked targets; each method detected validated targets that were missed by the other method. The most comprehensive list of STAT1 binding regions is obtained by merging results from ChIP-chip and ChIP-sequencing. Overall, this study provides information for robust identification, scoring, and validation of TF targets using ChIP-based technologies.
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| 10. |
- Freyhult, Eva, et al.
(författare)
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Exploring genomic dark matter : A critical assessment of the performance of homology search methods on noncoding RNA
- 2007
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Ingår i: Genome Research. - : Cold Spring Harbor Laboratory. - 1088-9051 .- 1549-5469. ; 17:1, s. 117-125
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Tidskriftsartikel (refereegranskat)abstract
- Homology search is one of the most ubiquitous bioinformatic tasks, yet it is unknown how effective the currently available tools are for identifying noncoding RNAs (ncRNAs). In this work, we use reliable ncRNA data sets to assess the effectiveness of methods such as BLAST, FASTA, HMMer, and Infernal. Surprisingly, the most popular homology search methods are often the least accurate. As a result, many studies have used inappropriate tools for their analyses. On the basis of our results, we suggest homology search strategies using the currently available tools and some directions for future development.
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