| 1. |
- Altenhoff, Adrian M., et al.
(författare)
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Standardized benchmarking in the quest for orthologs
- 2016
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Ingår i: Nature Methods. - 1548-7091 .- 1548-7105. ; 13:5, s. 425-
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Tidskriftsartikel (refereegranskat)abstract
- Achieving high accuracy in orthology inference is essential for many comparative, evolutionary and functional genomic analyses, yet the true evolutionary history of genes is generally unknown and orthologs are used for very different applications across phyla, requiring different precision-recall trade-offs. As a result, it is difficult to assess the performance of orthology inference methods. Here, we present a community effort to establish standards and an automated web-based service to facilitate orthology benchmarking. Using this service, we characterize 15 well-established inference methods and resources on a battery of 20 different benchmarks. Standardized benchmarking provides a way for users to identify the most effective methods for the problem at hand, sets a minimum requirement for new tools and resources, and guides the development of more accurate orthology inference methods.
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| 2. |
- Finn, Robert D., et al.
(författare)
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The Pfam protein families database
- 2010
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Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 38, s. d211-d222
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Tidskriftsartikel (refereegranskat)abstract
- Pfam is a widely used database of protein families and domains. This article describes a set of major updates that we have implemented in the latest release (version 24.0). The most important change is that we now use HMMER3, the latest version of the popular profile hidden Markov model package. This software is similar to 100 times faster than HMMER2 and is more sensitive due to the routine use of the forward algorithm. The move to HMMER3 has necessitated numerous changes to Pfam that are described in detail. Pfam release 24.0 contains 11 912 families, of which a large number have been significantly updated during the past two years. Pfam is available via servers in the UK (http://pfam.sanger.ac.uk/), the USA (http://pfam.janelia.org/) and Sweden (http://pfam.sbc.su.se/).
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| 3. |
- Forslund, Kristoffer, et al.
(författare)
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Benchmarking homology detection procedures with low complexity filters
- 2009
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Ingår i: Bioinformatics. - : Oxford University Press (OUP). - 1367-4803 .- 1367-4811. ; 25:19, s. 2500-2505
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Low-complexity sequence regions present a common problem in finding true homologs to a protein query sequence. Several solutions to this have been suggested, but a detailed comparison between these on challenging data has so far been lacking. A common benchmark for homology detection procedures is to use SCOP/ASTRAL domain sequences belonging to the same or different superfamilies, but these contain almost no low complexity sequences. RESULTS: We here introduce an alternative benchmarking strategy based around Pfam domains and clans on whole-proteome data sets. This gives a realistic level of low complexity sequences. We used it to evaluate all six built-in BLAST low complexity filter settings as well as a range of settings in the MSPcrunch post-processing filter. The effect on alignment length was also assessed. CONCLUSION: Score matrix adjustment methods provide a low false positive rate at a relatively small loss in sensitivity relative to no filtering, across the range of test conditions we apply. MSPcrunch achieved even less loss in sensitivity, but at a higher false positive rate. A drawback of the score matrix adjustment methods is however that the alignments often become truncated. AVAILABILITY: Perl scripts for MSPcrunch BLAST filtering and for generating the benchmark dataset are available at http://sonnhammer.sbc.su.se/download/software/MSPcrunch+Blixem/benchmark.tar.gz
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| 4. |
- Forslund, Kristoffer, et al.
(författare)
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Domain architecture conservation in orthologs
- 2011
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Ingår i: BMC Bioinformatics. - : Springer Science and Business Media LLC. - 1471-2105. ; 12, s. 326-
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Tidskriftsartikel (refereegranskat)abstract
- Background. As orthologous proteins are expected to retain function more often than other homologs, they are often used for functional annotation transfer between species. However, ortholog identification methods do not take into account changes in domain architecture, which are likely to modify a protein's function. By domain architecture we refer to the sequential arrangement of domains along a protein sequence. To assess the level of domain architecture conservation among orthologs, we carried out a large-scale study of such events between human and 40 other species spanning the entire evolutionary range. We designed a score to measure domain architecture similarity and used it to analyze differences in domain architecture conservation between orthologs and paralogs relative to the conservation of primary sequence. We also statistically characterized the extents of different types of domain swapping events across pairs of orthologs and paralogs. Results. The analysis shows that orthologs exhibit greater domain architecture conservation than paralogous homologs, even when differences in average sequence divergence are compensated for, for homologs that have diverged beyond a certain threshold. We interpret this as an indication of a stronger selective pressure on orthologs than paralogs to retain the domain architecture required for the proteins to perform a specific function. In general, orthologs as well as the closest paralogous homologs have very similar domain architectures, even at large evolutionary separation. The most common domain architecture changes observed in both ortholog and paralog pairs involved insertion/deletion of new domains, while domain shuffling and segment duplication/deletion were very infrequent. Conclusions. On the whole, our results support the hypothesis that function conservation between orthologs demands higher domain architecture conservation than other types of homologs, relative to primary sequence conservation. This supports the notion that orthologs are functionally more similar than other types of homologs at the same evolutionary distance.
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| 5. |
- Forslund, Kristoffer, et al.
(författare)
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Domain tree-based analysis of protein architecture evolution
- 2008
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Ingår i: Molecular biology and evolution. - : Oxford University Press (OUP). - 0737-4038 .- 1537-1719. ; 25:2, s. 254-264
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Tidskriftsartikel (refereegranskat)abstract
- Understanding the dynamics behind domain architecture evolution is of great importance to unravel the functions of proteins. Complex architectures have been created throughout evolution by rearrangement and duplication events. An interesting question is how many times a particular architecture has been created, a form of convergent evolution or domain architecture reinvention. Previous studies have approached this issue by comparing architectures found in different species. We wanted to achieve a finer-grained analysis by reconstructing protein architectures on complete domain trees. The prevalence of domain architecture reinvention in 96 genomes was investigated with a novel domain tree-based method that uses maximum parsimony for inferring ancestral protein architectures. Domain architectures were taken from Pfam. To ensure robustness, we applied the method to bootstrap trees and only considered results with strong statistical support. We detected multiple origins for 12.4% of the scored architectures. In a much smaller data set, the subset of completely domain-assigned proteins, the figure was 5.6%. These results indicate that domain architecture reinvention is a much more common phenomenon than previously thought. We also determined which domains are most frequent in multiply created architectures and assessed whether specific functions could be attributed to them. However, no strong functional bias was found in architectures with multiple origins.
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| 6. |
- Forslund, Kristoffer, et al.
(författare)
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Evolution of Protein Domain Architectures
- 2012
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Ingår i: Evolutionary Genomics. - Totowa, NJ : Humana Press. - 9781617795848 ; , s. 187-216
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Bokkapitel (refereegranskat)abstract
- This chapter reviews the current research on how protein domain architectures evolve. We begin by summarizing work on the phylogenetic distribution of proteins, as this directly impacts which domain architectures can be formed in different species. Studies relating domain family size to occurrence have shown that they generally follow power law distributions, both within genomes and larger evolutionary groups. These findings were subsequently extended to multidomain architectures. Genome evolution models that have been suggested to explain the shape of these distributions arc reviewed, as well as evidence for selective pressure to expand certain domain families more than others. Each domain has an intrinsic combinatorial propensity, and the effects of this have been studied using measures of domain versatility or promiscuity. Next, we study the principles of protein domain architecture evolution and how these have been inferred from distributions of extant domain arrangements. Following this, we review inferences of ancestral domain architecture and the conclusions concerning domain architecture evolution mechanisms that can be drawn from these. Finally, we examine whether all known cases of a given domain architecture can be assumed to have a single common origin (monophyly) or have evolved convergently (polyphyly).
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| 7. |
- Forslund, Kristoffer, et al.
(författare)
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Gearing up to handle the mosaic nature of life in the quest for orthologs
- 2018
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Ingår i: Bioinformatics. - : Oxford University Press (OUP). - 1367-4803 .- 1367-4811. ; 34:2, s. 323-329
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Tidskriftsartikel (refereegranskat)abstract
- The Quest for Orthologs (QfO) is an open collaboration framework for experts in comparative phylogenomics and related research areas who have an interest in highly accurate orthology predictions and their applications. We here report highlights and discussion points from the QfO meeting 2015 held in Barcelona. Achievements in recent years have established a basis to support developments for improved orthology prediction and to explore new approaches. Central to the QfO effort is proper benchmarking of methods and services, as well as design of standardized datasets and standardized formats to allow sharing and comparison of results. Simultaneously, analysis pipelines have been improved, evaluated and adapted to handle large datasets. All this would not have occurred without the long-term collaboration of Consortium members. Meeting regularly to review and coordinate complementary activities from a broad spectrum of innovative researchers clearly benefits the community. Highlights of the meeting include addressing sources of and legitimacy of disagreements between orthology calls, the context dependency of orthology definitions, special challenges encountered when analyzing very anciently rooted orthologies, orthology in the light of whole-genome duplications, and the concept of orthologous versus paralogous relationships at different levels, including domain-level orthology. Furthermore, particular needs for different applications (e.g. plant genomics, ancient gene families and others) and the infrastructure for making orthology inferences available (e.g. interfaces with model organism databases) were discussed, with several ongoing efforts that are expected to be reported on during the upcoming 2017 QfO meeting.
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| 8. |
- Forslund, Kristoffer, et al.
(författare)
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OrthoDisease : tracking disease gene orthologs across 100 species
- 2011
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Ingår i: Briefings in Bioinformatics. - : Oxford University Press (OUP). - 1467-5463 .- 1477-4054. ; 12:5, s. 463-473
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Tidskriftsartikel (refereegranskat)abstract
- Orthology is one of the most important tools available to modern biology, as it allows making inferences from easily studied model systems to much less tractable systems of interest, such as ourselves. This becomes important not least in the study of genetic diseases. We here review work on the orthology of disease-associated genes and also present an updated version of the InParanoid-based disease orthology database and web site OrthoDisease, with 14-fold increased species coverage since the previous version. Using this resource, we survey the taxonomic distribution of orthologs of human genes involved in different disease categories. The hypothesis that paralogs can mask the effect of deleterious mutations predicts that known heritable disease genes should have fewer close paralogs. We found large-scale support for this hypothesis as significantly fewer duplications were observed for disease genes in the OrthoDisease ortholog groups.
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| 9. |
- Forslund, Kristoffer, et al.
(författare)
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Predicting protein function from domain content
- 2008
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Ingår i: Bioinformatics. - : Oxford University Press (OUP). - 1367-4803 .- 1367-4811. ; 24:15, s. 1681-1687
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Tidskriftsartikel (refereegranskat)abstract
- MOTIVATION: Computational assignment of protein function may be the single most vital application of bioinformatics in the post-genome era. These assignments are made based on various protein features, where one is the presence of identifiable domains. The relationship between protein domain content and function is important to investigate, to understand how domain combinations encode complex functions. RESULTS: Two different models are presented on how protein domain combinations yield specific functions: one rule-based and one probabilistic. We demonstrate how these are useful for Gene Ontology annotation transfer. The first is an intuitive generalization of the Pfam2GO mapping, and detects cases of strict functional implications of sets of domains. The second uses a probabilistic model to represent the relationship between domain content and annotation terms, and was found to be better suited for incomplete training sets. We implemented these models as predictors of Gene Ontology functional annotation terms. Both predictors were more accurate than conventional best BLAST-hit annotation transfer and more sensitive than a single-domain model on a large-scale dataset. We present a number of cases where combinations of Pfam-A protein domains predict functional terms that do not follow from the individual domains. AVAILABILITY: Scripts and documentation are available for download at http://sonnhammer.sbc.su.se/multipfam2go_source_docs.tar
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| 10. |
- Forslund, Kristoffer, 1980-
(författare)
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The relationship between orthology, protein domain architecture and protein function
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Lacking experimental data, protein function is often predicted from evolutionary and protein structure theory. Under the 'domain grammar' hypothesis the function of a protein follows from the domains it encodes. Under the 'orthology conjecture', orthologs, related through species formation, are expected to be more functionally similar than paralogs, which are homologs in the same or different species descended from a gene duplication event. However, these assumptions have not thus far been systematically evaluated. To test the 'domain grammar' hypothesis, we built models for predicting function from the domain combinations present in a protein, and demonstrated that multi-domain combinations imply functions that the individual domains do not. We also developed a novel gene-tree based method for reconstructing the evolutionary histories of domain architectures, to search for cases of architectures that have arisen multiple times in parallel, and found this to be more common than previously reported. To test the 'orthology conjecture', we first benchmarked methods for homology inference under the obfuscating influence of low-complexity regions, in order to improve the InParanoid orthology inference algorithm. InParanoid was then used to test the relative conservation of functionally relevant properties between orthologs and paralogs at various evolutionary distances, including intron positions, domain architectures, and Gene Ontology functional annotations. We found an increased conservation of domain architectures in orthologs relative to paralogs, in support of the 'orthology conjecture' and the 'domain grammar' hypotheses acting in tandem. However, equivalent analysis of Gene Ontology functional conservation yielded spurious results, which may be an artifact of species-specific annotation biases in functional annotation databases. I discuss possible ways of circumventing this bias so the 'orthology conjecture' can be tested more conclusively.
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| 11. |
- Forslund, Kristoffer, et al.
(författare)
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VisRD--visual recombination detection.
- 2004
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Ingår i: Bioinformatics. - 1367-4803 .- 1367-4811. ; 20:18, s. 3654-5
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Tidskriftsartikel (refereegranskat)
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| 12. |
- Grünewald, Stefan, et al.
(författare)
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QNet : an agglomerative method for the construction of phylogenetic networks from weighted quartets.
- 2007
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Ingår i: Mol Biol Evol. - 0737-4038. ; 24:2, s. 532-8
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Tidskriftsartikel (refereegranskat)abstract
- We present QNet, a method for constructing split networks from weighted quartet trees. QNet can be viewed as a quartet analogue of the distance-based Neighbor-Net (NNet) method for network construction. Just as NNet, QNet works by agglomeratively computing a collection of circular weighted splits of the taxa set which is subsequently represented by a planar split network. To illustrate the applicability of QNet, we apply it to a previously published Salmonella data set. We conclude that QNet can provide a useful alternative to NNet if distance data are not available or a character-based approach is preferred. Moreover, it can be used as an aid for determining when a quartet-based tree-building method may or may not be appropriate for a given data set. QNet is freely available for download.
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| 13. |
- Henricson, Anna, et al.
(författare)
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Orthology confers intron position conservation
- 2010
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Ingår i: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 11:412
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Tidskriftsartikel (refereegranskat)abstract
- Background: With the wealth of genomic data available it has become increasingly important to assign putative protein function through functional transfer between orthologs. Therefore, correct elucidation of the evolutionary relationships among genes is a critical task, and attempts should be made to further improve the phylogenetic inference by adding relevant discriminating features. It has been shown that introns can maintain their position over long evolutionary timescales. For this reason, it could be possible to use conservation of intron positions as a discriminating factor when assigning orthology. Therefore, we wanted to investigate whether orthologs have a higher degree of intron position conservation (IPC) compared to non-orthologous sequences that are equally similar in sequence. Results: To this end, we developed a new score for IPC and applied it to ortholog groups between human and six other species. For comparison, we also gathered the closest non-orthologs, meaning sequences close in sequence space, yet falling just outside the ortholog cluster. We found that ortholog-ortholog gene pairs on average have a significantly higher degree of IPC compared to ortholog-closest non-ortholog pairs. Also pairs of inparalogs were found to have a higher IPC score than inparalog-closest non-inparalog pairs. We verified that these differences can not simply be attributed to the generally higher sequence identity of the ortholog-ortholog and the inparalog-inparalog pairs. Furthermore, we analyzed the agreement between IPC score and the ortholog score assigned by the InParanoid algorithm, and found that it was consistently high for all species comparisons. In a minority of cases, the IPC and InParanoid score ranked inparalogs differently. These represent cases where sequence and intron position divergence are discordant. We further analyzed the discordant clusters to identify any possible preference for protein functions by looking for enriched GO terms and Pfam protein domains. They were enriched for functions important for multicellularity, which implies a connection between shifts in intronic structure and the origin of multicellularity. Conclusions: We conclude that orthologous genes tend to have more conserved intron positions compared to non-orthologous genes. As a consequence, our IPC score is useful as an additional discriminating factor when assigning orthology.
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| 14. |
- Pedersen, Helle Krogh, et al.
(författare)
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Human gut microbes impact host serum metabolome and insulin sensitivity
- 2016
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Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 535:7612, s. 376-381
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Tidskriftsartikel (refereegranskat)abstract
- Insulin resistance is a forerunner state of ischaemic cardiovascular disease and type 2 diabetes. Here we show how the human gut microbiome impacts the serum metabolome and associates with insulin resistance in 277 non-diabetic Danish individuals. The serum metabolome of insulin-resistant individuals is characterized by increased levels of branched-chain amino acids (BCAAs), which correlate with a gut microbiome that has an enriched biosynthetic potential for BCAAs and is deprived of genes encoding bacterial inward transporters for these amino acids. Prevotella copri and Bacteroides vulgatus are identified as the main species driving the association between biosynthesis of BCAAs and insulin resistance, and in mice we demonstrate that P. copri can induce insulin resistance, aggravate glucose intolerance and augment circulating levels of BCAAs. Our findings suggest that microbial targets may have the potential to diminish insulin resistance and reduce the incidence of common metabolic and cardiovascular disorders.
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| 15. |
- Punta, Marco, et al.
(författare)
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The Pfam protein families database
- 2012
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Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 40:D1, s. D290-D301
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Tidskriftsartikel (refereegranskat)abstract
- Pfam is a widely used database of protein families, currently containing more than 13 000 manually curated protein families as of release 26.0. Pfam is available via servers in the UK (http://pfam.sanger.ac.uk/), the USA (http://pfam.janelia.org/) and Sweden (http://pfam.sbc.su.se/). Here, we report on changes that have occurred since our 2010 NAR paper (release 24.0). Over the last 2 years, we have generated 1840 new families and increased coverage of the UniProt Knowledgebase (UniProtKB) to nearly 80%. Notably, we have taken the step of opening up the annotation of our families to the Wikipedia community, by linking Pfam families to relevant Wikipedia pages and encouraging the Pfam and Wikipedia communities to improve and expand those pages. We continue to improve the Pfam website and add new visualizations, such as the 'sunburst' representation of taxonomic distribution of families. In this work we additionally address two topics that will be of particular interest to the Pfam community. First, we explain the definition and use of family-specific, manually curated gathering thresholds. Second, we discuss some of the features of domains of unknown function (also known as DUFs), which constitute a rapidly growing class of families within Pfam.
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| 16. |
- Saripella, Ganapathi Varma, et al.
(författare)
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Benchmarking the next generation of homology inference tools
- 2016
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Ingår i: Bioinformatics. - : Oxford University Press (OUP). - 1367-4803 .- 1367-4811. ; 32:17, s. 2636-2641
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Tidskriftsartikel (refereegranskat)abstract
- Motivation: Over the last decades, vast numbers of sequences were deposited in public databases. Bioinformatics tools allow homology and consequently functional inference for these sequences. New profile-based homology search tools have been introduced, allowing reliable detection of remote homologs, but have not been systematically benchmarked. To provide such a comparison, which can guide bioinformatics workflows, we extend and apply our previously developed benchmark approach to evaluate the 'next generation' of profile-based approaches, including CS-BLAST, HHSEARCH and PHMMER, in comparison with the non-profile based search tools NCBI-BLAST, USEARCH, UBLAST and FASTA. Method: We generated challenging benchmark datasets based on protein domain architectures within either the PFAM+Clan, SCOP/Superfamily or CATH/Gene3D domain definition schemes. From each dataset, homologous and non-homologous protein pairs were aligned using each tool, and standard performance metrics calculated. We further measured congruence of domain architecture assignments in the three domain databases. Results: CSBLAST and PHMMER had overall highest accuracy. FASTA, UBLAST and USEARCH showed large trade-offs of accuracy for speed optimization. Conclusion: Profile methods are superior at inferring remote homologs but the difference in accuracy between methods is relatively small. PHMMER and CSBLAST stand out with the highest accuracy, yet still at a reasonable computational cost. Additionally, we show that less than 0.1% of Swiss-Prot protein pairs considered homologous by one database are considered non-homologous by another, implying that these classifications represent equivalent underlying biological phenomena, differing mostly in coverage and granularity.
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| 17. |
- Östlund, Gabriel, 1980-, et al.
(författare)
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InParanoid 7 : new algorithms and tools for eukaryotic orthology analysis
- 2010
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Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 38:1, s. D196-D203
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Tidskriftsartikel (refereegranskat)abstract
- The InParanoid project gathers proteomes of completely sequenced eukaryotic species plus Escherichia coli and calculates pairwise ortholog relationships among them. The new release 7.0 of the database has grown by an order of magnitude over the previous version and now includes 100 species and their collective 1.3 million proteins organized into 42.7 million pairwise ortholog groups. The InParanoid algorithm itself has been revised and is now both more specific and sensitive. Based on results from our recent benchmarking of low-complexity filters in homology assignment, a two-pass BLAST approach was developed that makes use of high-precision compositional score matrix adjustment, but avoids the alignment truncation that sometimes follows. We have also updated the InParanoid web site (http://InParanoid.sbc.su.se). Several features have been added, the response times have been improved and the site now sports a new, clearer look. As the number of ortholog databases has grown, it has become difficult to compare among these resources due to a lack of standardized source data and incompatible representations of ortholog relationships. To facilitate data exchange and comparisons among ortholog databases, we have developed and are making available two XML schemas: SeqXML for the input sequences and OrthoXML for the output ortholog clusters.
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