| 1. |
- Bornelöv, Susanne, et al.
(författare)
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Ciruvis : a web-based tool for rule networks and interaction detection using rule-based classifiers
- 2014
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Ingår i: BMC Bioinformatics. - : Springer Science and Business Media LLC. - 1471-2105. ; 15, s. 139-
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Tidskriftsartikel (refereegranskat)abstract
- Background: The use of classification algorithms is becoming increasingly important for the field of computational biology. However, not only the quality of the classification, but also its biological interpretation is important. This interpretation may be eased if interacting elements can be identified and visualized, something that requires appropriate tools and methods. Results: We developed a new approach to detecting interactions in complex systems based on classification. Using rule-based classifiers, we previously proposed a rule network visualization strategy that may be applied as a heuristic for finding interactions. We now complement this work with Ciruvis, a web-based tool for the construction of rule networks from classifiers made of IF-THEN rules. Simulated and biological data served as an illustration of how the tool may be used to visualize and interpret classifiers. Furthermore, we used the rule networks to identify feature interactions, compared them to alternative methods, and computationally validated the findings. Conclusions: Rule networks enable a fast method for model visualization and provide an exploratory heuristic to interaction detection. The tool is made freely available on the web and may thus be used to aid and improve rule-based classification.
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| 2. |
- Bornelöv, Susanne, 1984-, et al.
(författare)
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Comparative omics and feeding manipulations in chicken indicate a shift of the endocrine role of visceral fat towards reproduction
- 2018
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Ingår i: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 19
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Tidskriftsartikel (refereegranskat)abstract
- Background: The mammalian adipose tissue plays a central role in energy-balance control, whereas the avian visceral fat hardly expresses leptin, the key adipokine in mammals. Therefore, to assess the endocrine role of adipose tissue in birds, we compared the transcriptome and proteome between two metabolically different types of chickens, broilers and layers, bred towards efficient meat and egg production, respectively.Results: Broilers and layer hens, grown up to sexual maturation under free-feeding conditions, differed 4.0-fold in weight and 1.6-fold in ovarian-follicle counts, yet the relative accumulation of visceral fat was comparable. RNA-seq and mass-spectrometry (MS) analyses of visceral fat revealed differentially expressed genes between broilers and layers, 1106 at the mRNA level (FDR ≤ 0.05), and 203 at the protein level (P ≤ 0.05). In broilers, Ingenuity Pathway Analysis revealed activation of the PTEN-pathway, and in layers increased response to external signals. The expression pattern of genes encoding fat-secreted proteins in broilers and layers was characterized in the RNA-seq and MS data, as well as by qPCR on visceral fat under free feeding and 24 h-feed deprivation. This characterization was expanded using available RNA-seq data of tissues from red junglefowl, and of visceral fat from broilers of different types. These comparisons revealed expression of new adipokines and secreted proteins (LCAT, LECT2, SERPINE2, SFTP1, ZP1, ZP3, APOV1, VTG1 and VTG2) at the mRNA and/or protein levels, with dynamic gene expression patterns in the selected chicken lines (except for ZP1; FDR/P ≤ 0.05) and feed deprivation (NAMPT, SFTPA1 and ZP3) (P ≤ 0.05). In contrast, some of the most prominent adipokines in mammals, leptin, TNF, IFNG, and IL6 were expressed at a low level (FPKM/RPKM< 1) and did not show differential mRNA expression neither between broiler and layer lines nor between fed vs. feed-deprived chickens.Conclusions: Our study revealed that RNA and protein expression in visceral fat changes with selective breeding, suggesting endocrine roles of visceral fat in the selected phenotypes. In comparison to gene expression in visceral fat of mammals, our findings points to a more direct cross talk of the chicken visceral fat with the reproductive system and lower involvement in the regulation of appetite, inflammation and insulin resistance.
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| 3. |
- Bornelöv, Susanne, 1984-, et al.
(författare)
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Correspondence on Lovell et al. : identification of chicken genes previously assumed to be evolutionarily lost
- 2017
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Ingår i: Genome Biology. - : Springer Science and Business Media LLC. - 1465-6906 .- 1474-760X .- 1474-7596. ; 18
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Tidskriftsartikel (refereegranskat)abstract
- Through RNA-Seq analyses, we identified 137 genes that are missing in chicken, including the long-sought-after nephrin and tumor necrosis factor genes. These genes tended to cluster in GC-rich regions that have poor coverage in genome sequence databases. Hence, the occurrence of syntenic groups of vertebrate genes that have not been observed in Aves does not prove the evolutionary loss of such genes.
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| 4. |
- Bornelöv, Susanne, et al.
(författare)
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Different distribution of histone modifications in genes with unidirectional and bidirectional transcription and a role of CTCF and cohesin in directing transcription
- 2015
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Ingår i: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 16
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Tidskriftsartikel (refereegranskat)abstract
- Background: Several post-translational histone modifications are mainly found in gene promoters and are associated with the promoter activity. It has been hypothesized that histone modifications regulate the transcription, as opposed to the traditional view with transcription factors as the key regulators. Promoters of most active genes do not only initiate transcription of the coding sequence, but also a substantial amount of transcription of the antisense strand upstream of the transcription start site (TSS). This promoter feature has generally not been considered in previous studies of histone modifications and transcription factor binding.Results: We annotated protein-coding genes as bi- or unidirectional depending on their mode of transcription and compared histone modifications and transcription factor occurrences between them. We found that H3K4me3, H3K9ac, and H3K27ac were significantly more enriched upstream of the TSS in bidirectional genes compared with the unidirectional ones. In contrast, the downstream histone modification signals were similar, suggesting that the upstream histone modifications might be a consequence of transcription rather than a cause. Notably, we found well-positioned CTCF and RAD21 peaks approximately 60-80 bp upstream of the TSS in the unidirectional genes. The peak heights were related to the amount of antisense transcription and we hypothesized that CTCF and cohesin act as a barrier against antisense transcription.Conclusions: Our results provide insights into the distribution of histone modifications at promoters and suggest a novel role of CTCF and cohesin as regulators of transcriptional direction.
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| 5. |
- Bornelöv, Susanne, et al.
(författare)
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Rule-Based Models of the Interplay between Genetic and Environmental Factors in Childhood Allergy
- 2013
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:11, s. e80080-
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Tidskriftsartikel (refereegranskat)abstract
- Both genetic and environmental factors are important for the development of allergic diseases. However, a detailed understanding of how such factors act together is lacking. To elucidate the interplay between genetic and environmental factors in allergic diseases, we used a novel bioinformatics approach that combines feature selection and machine learning. In two materials, PARSIFAL (a European cross-sectional study of 3113 children) and BAMSE (a Swedish birth-cohort including 2033 children), genetic variants as well as environmental and lifestyle factors were evaluated for their contribution to allergic phenotypes. Monte Carlo feature selection and rule based models were used to identify and rank rules describing how combinations of genetic and environmental factors affect the risk of allergic diseases. Novel interactions between genes were suggested and replicated, such as between ORMDL3 and RORA, where certain genotype combinations gave odds ratios for current asthma of 2.1 (95% CI 1.2-3.6) and 3.2 (95% CI 2.0-5.0) in the BAMSE and PARSIFAL children, respectively. Several combinations of environmental factors appeared to be important for the development of allergic disease in children. For example, use of baby formula and antibiotics early in life was associated with an odds ratio of 7.4 (95% CI 4.5-12.0) of developing asthma. Furthermore, genetic variants together with environmental factors seemed to play a role for allergic diseases, such as the use of antibiotics early in life and COL29A1 variants for asthma, and farm living and NPSR1 variants for allergic eczema. Overall, combinations of environmental and life style factors appeared more frequently in the models than combinations solely involving genes. In conclusion, a new bioinformatics approach is described for analyzing complex data, including extensive genetic and environmental information. Interactions identified with this approach could provide useful hints for further in-depth studies of etiological mechanisms and may also strengthen the basis for risk assessment and prevention.
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| 6. |
- Bornelöv, Susanne, 1984-
(författare)
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Rule-based Models of Transcriptional Regulation and Complex Diseases : Applications and Development
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- As we gain increased understanding of genetic disorders and gene regulation more focus has turned towards complex interactions. Combinations of genes or gene and environmental factors have been suggested to explain the missing heritability behind complex diseases. Furthermore, gene activation and splicing seem to be governed by a complex machinery of histone modification (HM), transcription factor (TF), and DNA sequence signals. This thesis aimed to apply and develop multivariate machine learning methods for use on such biological problems. Monte Carlo feature selection was combined with rule-based classification to identify interactions between HMs and to study the interplay of factors with importance for asthma and allergy.Firstly, publicly available ChIP-seq data (Paper I) for 38 HMs was studied. We trained a classifier for predicting exon inclusion levels based on the HMs signals. We identified HMs important for splicing and illustrated that splicing could be predicted from the HM patterns. Next, we applied a similar methodology on data from two large birth cohorts describing asthma and allergy in children (Paper II). We identified genetic and environmental factors with importance for allergic diseases which confirmed earlier results and found candidate gene-gene and gene-environment interactions.In order to interpret and present the classifiers we developed Ciruvis, a web-based tool for network visualization of classification rules (Paper III). We applied Ciruvis on classifiers trained on both simulated and real data and compared our tool to another methodology for interaction detection using classification. Finally, we continued the earlier study on epigenetics by analyzing HM and TF signals in genes with or without evidence of bidirectional transcription (Paper IV). We identified several HMs and TFs with different signals between unidirectional and bidirectional genes. Among these, the CTCF TF was shown to have a well-positioned peak 60-80 bp upstream of the transcription start site in unidirectional genes.
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| 7. |
- Bornelöv, Susanne, et al.
(författare)
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Visualization of Rules in Rule-Based Classifiers
- 2012
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Ingår i: INTELLIGENT DECISION TECHNOLOGIES (IDT'2012), VOL 1. - Berlin, Heidelberg : Springer Berlin Heidelberg. - 9783642299773 ; , s. 329-338
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Konferensbidrag (refereegranskat)abstract
- Interpretation and visualization of the classification models are important parts of machine learning. Rule-based classifiers often contain too many rules to be easily interpreted by humans, and methods for post-classification analysis of the rules are needed. Here we present a strategy for circular visualization of sets of classification rules. The Circos software was used to generate graphs showing all pairs of conditions that were present in the rules as edges inside a circle. We showed using simulated data that all two-way interactions in the data were found by the classifier and displayed in the graph, although the single attributes were constructed to have no correlation to the decision class. For all examples we used rules trained using the rough set theory, but the visualization would by applicable to any sort of classification rules. This method for rule visualization may be useful for applications where interaction terms are expected, and the size of the model limits the interpretability.
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| 8. |
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| 9. |
- Bysani, Madhu Sudhan Reddy, et al.
(författare)
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ChIP-seq in steatohepatitis and normal liver tissue identifies candidate disease mechanisms related to progression to cancer
- 2013
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Ingår i: BMC Medical Genomics. - : Springer Science and Business Media LLC. - 1755-8794. ; 6, s. 50-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Steatohepatitis occurs in alcoholic liver disease and may progress to liver cirrhosis and hepatocellular carcinoma. Its molecular pathogenesis is to a large degree unknown. Histone modifications play a key role in transcriptional regulations as marks for silencing and activation of gene expression and as marks for functional elements. Many transcription factors (TFs) are crucial for the control of the genes involved in metabolism, and abnormality in their function may lead to disease. Methods: We performed ChIP-seq of the histone modifications H3K4me1, H3K4me3 and H3K27ac and a candidate transcription factor (USF1) in liver tissue from patients with steatohepatitis and normal livers and correlated results to mRNA-expression and genotypes. Results: We found several regions that are differentially enriched for histone modifications between disease and normal tissue, and qRT-PCR results indicated that the expression of the tested genes strongly correlated with differential enrichment of histone modifications but is independent of USF1 enrichment. By gene ontology analysis of differentially modified genes we found many disease associated genes, some of which had previously been implicated in the etiology of steatohepatitis. Importantly, the genes associated to the strongest histone peaks in the patient were over-represented in cancer specific pathways suggesting that the tissue was on a path to develop to cancer, a common complication to the disease. We also found several novel SNPs and GWAS catalogue SNPs that are candidates to be functional and therefore needs further study. Conclusion: In summary we find that analysis of chromatin features in tissue samples provides insight into disease mechanisms.
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| 10. |
- Dabrowski, M. J., et al.
(författare)
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'True' null allele detection in microsatellite loci : a comparison of methods, assessment of difficulties and survey of possible improvements
- 2015
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Ingår i: Molecular Ecology Resources. - : Wiley. - 1755-098X .- 1755-0998. ; 15:3, s. 477-488
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Tidskriftsartikel (refereegranskat)abstract
- Null alleles are alleles that for various reasons fail to amplify in a PCR assay. The presence of null alleles in microsatellite data is known to bias the genetic parameter estimates. Thus, efficient detection of null alleles is crucial, but the methods available for indirect null allele detection return inconsistent results. Here, our aim was to compare different methods for null allele detection, to explain their respective performance and to provide improvements. We applied several approaches to identify the true' null alleles based on the predictions made by five different methods, used either individually or in combination. First, we introduced simulated true' null alleles into 240 population data sets and applied the methods to measure their success in detecting the simulated null alleles. The single best-performing method was ML-NullFreq_frequency. Furthermore, we applied different noise reduction approaches to improve the results. For instance, by combining the results of several methods, we obtained more reliable results than using a single one. Rule-based classification was applied to identify population properties linked to the false discovery rate. Rules obtained from the classifier described which population genetic estimates and loci characteristics were linked to the success of each method. We have shown that by simulating true' null alleles into a population data set, we may define a null allele frequency threshold, related to a desired true or false discovery rate. Moreover, using such simulated data sets, the expected null allele homozygote frequency may be estimated independently of the equilibrium state of the population.
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