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  • 1.
    Anil, Anandashankar
    et al.
    KTH, School of Biotechnology (BIO). KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Spalinskas, Rapolas
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Biotechnology (BIO).
    Åkerborg, Örjan
    KTH, School of Biotechnology (BIO). KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Sahlén, Pelin
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Biotechnology (BIO).
    HiCapTools: a software suite for probe design and proximity detection for targeted chromosome conformation capture applications2018In: Bioinformatics, ISSN 1367-4803, E-ISSN 1367-4811, Vol. 34, no 4, p. 675-677Article in journal (Refereed)
    Abstract [en]

    Folding of eukaryotic genomes within nuclear space enables physical and functional contacts between regions that are otherwise kilobases away in sequence space. Targeted chromosome conformation capture methods (T2C, chi-C and HiCap) are capable of informing genomic contacts for a subset of regions targeted by probes. We here present HiCapTools, a software package that can design sequence capture probes for targeted chromosome capture applications and analyse sequencing output to detect proximities involving targeted fragments. Two probes are designed for each feature while avoiding repeat elements and non-unique regions. The data analysis suite processes alignment files to report genomic proximities for each feature at restriction fragment level and is isoform-aware for gene features. Statistical significance of contact frequencies is evaluated using an empirically derived background distribution. Targeted chromosome conformation capture applications are invaluable for locating target genes of disease-associated variants found by genome-wide association studies. Hence, we believe our software suite will prove to be useful for a wider user base within clinical and functional applications.

  • 2.
    Ensterö, Mats
    et al.
    Department of Molecular Biology and Functional Genomics, Stockholm University.
    Åkerborg, Örjan
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Lundin, Daniel
    Department of Molecular Biology and Functional Genomics, Stockholm University.
    Wang, Bei
    Department of Computer Science, Duke University, Durham, United States.
    Furey, Terrence S.
    Department of Computer Science, Duke University, Durham, United States.
    Öhman, Marie
    Department of Molecular Biology and Functional Genomics, Stockholm University.
    Lagergren, Jens
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    A computational screen for site selective A-to-I editing detects novel sites in neuron specific Hu proteins2010In: BMC Bioinformatics, ISSN 1471-2105, E-ISSN 1471-2105, Vol. 11Article in journal (Refereed)
    Abstract [en]

    Background: Several bioinformatic approaches have previously been used to find novel sites of ADAR mediated A-to-I RNA editing in human. These studies have discovered thousands of genes that are hyper-edited in their non-coding intronic regions, especially in alu retrotransposable elements, but very few substrates that are site-selectively edited in coding regions. Known RNA edited substrates suggest, however, that site selective A-to-I editing is particularly important for normal brain development in mammals. Results: We have compiled a screen that enables the identification of new sites of site-selective editing, primarily in coding sequences. To avoid hyper-edited repeat regions, we applied our screen to the alu-free mouse genome. Focusing on the mouse also facilitated better experimental verification. To identify candidate sites of RNA editing, we first performed an explorative screen based on RNA structure and genomic sequence conservation. We further evaluated the results of the explorative screen by determining which transcripts were enriched for A-G mismatches between the genomic template and the expressed sequence since the editing product, inosine (I), is read as guanosine (G) by the translational machinery. For expressed sequences, we only considered coding regions to focus entirely on re-coding events. Lastly, we refined the results from the explorative screen using a novel scoring scheme based on characteristics for known A-to-I edited sites. The extent of editing in the final candidate genes was verified using total RNA from mouse brain and 454 sequencing. Conclusions: Using this method, we identified and confirmed efficient editing at one site in the Gabra3 gene. Editing was also verified at several other novel sites within candidates predicted to be edited. Five of these sites are situated in genes coding for the neuron-specific RNA binding proteins HuB and HuD.

  • 3.
    Svensson, Örjan
    et al.
    KTH, School of Computer Science and Communication (CSC).
    Arvestad, Lars
    KTH, School of Computer Science and Communication (CSC).
    Lagergren, Jens
    KTH, School of Computer Science and Communication (CSC).
    Genome-wide survey for biologically functional pseudogenes2006In: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 2, no 5, p. 358-369Article in journal (Refereed)
    Abstract [en]

    According to current estimates there exist about 20,000 pseudogenes in a mammalian genome. The vast majority of these are disabled and nonfunctional copies of protein-coding genes which, therefore, evolve neutrally. Recent findings that a Makorin1 pseudogene, residing on mouse Chromosome 5, is, indeed, in vivo vital and also evolutionarily preserved, encouraged us to conduct a genome-wide survey for other functional pseudogenes in human, mouse, and chimpanzee. We identify to our knowledge the first examples of conserved pseudogenes common to human and mouse, originating from one duplication predating the human-mouse species split and having evolved as pseudogenes since the species split. Functionality is one possible way to explain the apparently contradictory properties of such pseudogene pairs, i. e., high conservation and ancient origin. The hypothesis of functionality is tested by comparing expression evidence and synteny of the candidates with proper test sets. The tests suggest potential biological function. Our candidate set includes a small set of long-lived pseudogenes whose unknown potential function is retained since before the human - mouse species split, and also a larger group of primate-specific ones found from human - chimpanzee searches. Two processed sequences are notable, their conservation since the human - mouse split being as high as most protein-coding genes; one is derived from the protein Ataxin 7- like 3 ( ATX7NL3), and one from the Spinocerebellar ataxia type 1 protein (ATX1). Our approach is comparative and can be applied to any pair of species. It is implemented by a semi-automated pipeline based on cross- species BLAST comparisons and maximum-likelihood phylogeny estimations. To separate pseudogenes from protein- coding genes, we use standard methods, utilizing in- frame disablements, as well as a probabilistic filter based on Ka/ Ks ratios.

  • 4.
    Åkerborg, Örjan
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Taking advantage of phylogenetic trees in comparative genomics2008Doctoral thesis, comprehensive summary (Other scientific)
    Abstract [en]

    Phylogenomics can be regarded as evolution and genomics in co-operation. Various kinds of evolutionary studies, gene family analysis among them, demand access to genome-scale datasets. But it is also clear that many genomics studies, such as assignment of gene function, are much improved by evolutionary analysis. The work leading to this thesis is a contribution to the phylogenomics field. We have used phylogenetic relationships between species in genome-scale searches for two intriguing genomic features, namely and A-to-I RNA editing. In the first case we used pairwise species comparisons, specifically human-mouse and human-chimpanzee, to infer existence of functional mammalian pseudogenes. In the second case we profited upon later years' rapid growth of the number of sequenced genomes, and used 17-species multiple sequence alignments. In both these studies we have used non-genomic data, gene expression data and synteny relations among these, to verify predictions. In the A-to-I editing project we used 454 sequencing for experimental verification.

    We have further contributed a maximum a posteriori (MAP) method for fast and accurate dating analysis of speciations and other evolutionary events. This work follows recent years' trend of leaving the strict molecular clock when performing phylogenetic inference. We discretised the time interval from the leaves to the root in the tree, and used a dynamic programming (DP) algorithm to optimally factorise branch lengths into substitution rates and divergence times. We analysed two biological datasets and compared our results with recent MCMC-based methodologies. The dating point estimates that our method delivers were found to be of high quality while the gain in speed was dramatic.

    Finally we applied the DP strategy in a new setting. This time we used a grid laid out on a species tree instead of on an interval. The discretisation gives together with speciation times a common timeframe for a gene tree and the corresponding species tree. This is the key to integration of the sequence evolution process and the gene evolution process. Out of several potential application areas we chose gene tree reconstruction. We performed genome-wide analysis of yeast gene families and found that our methodology performs very well.

  • 5.
    Åkerborg, Örjan
    et al.
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Sennblad, Bengt
    Arvestad, Lars
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Lagergren, Jens
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Simultaneous Bayesian gene tree reconstruction and reconciliation analysis2009In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 106, p. 5714-5719Article in journal (Refereed)
    Abstract [en]

    We present GSR, a probabilistic model integrating gene duplication, sequence evolution, and a relaxed molecular clock for substitution rates, that enables genomewide analysis of gene families. The gene duplication and loss process is a major cause for incongruence between gene and species tree, and deterministic methods have been developed to explain such differences through tree reconciliations. Although probabilistic methods for phylogenetic inference have been around for decades, probabilistic reconciliation methods are far less established. Based on our model, we have implemented a Bayesian analysis tool, PrIME-GSR, for gene tree inference that takes a known species tree into account. Our implementation is sound and we demonstrate its utility for genomewide gene-family analysis by applying it to recently presented yeast data. We validate PrIME-GSR by comparing with previous analyses of these data that take advantage of gene order information. In a case study we apply our method to the ADH gene family and are able to draw biologically relevant conclusions concerning gene duplications creating key yeast phenotypes. On a higher level this shows the biological relevance of our method. The obtained results demonstrate the value of a relaxed molecular clock. Our good performance will extend to species where gene order conservation is insufficient.

  • 6.
    Åkerborg, Örjan
    et al.
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Sennblad, Bengt
    Lagergren, Jens
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Birth-death prior on phylogeny and speed dating2008In: BMC Evolutionary Biology, ISSN 1471-2148, E-ISSN 1471-2148, Vol. 8, no 1, p. 77-Article in journal (Refereed)
    Abstract [en]

    Background: In recent years there has been a trend of leaving the strict molecular clock in order to infer dating of speciations and other evolutionary events. Explicit modeling of substitution rates and divergence times makes formulation of informative prior distributions for branch lengths possible. Models with birth-death priors on tree branching and auto-correlated or iid substitution rates among lineages have been proposed, enabling simultaneous inference of substitution rates and divergence times. This problem has, however, mainly been analysed in the Markov chain Monte Carlo (MCMC) framework, an approach requiring computation times of hours or days when applied to large phylogenies.

    Results: We demonstrate that a hill-climbing maximum a posteriori (MAP) adaptation of the MCMC scheme results in considerable gain in computational efficiency. We demonstrate also that a novel dynamic programming (DP) algorithm for branch length factorization, useful both in the hill-climbing and in the MCMC setting, further reduces computation time. For the problem of inferring rates and times parameters on a fixed tree, we perform simulations, comparisons between hill-climbing and MCMC on a plant rbcL gene dataset, and dating analysis on an animal mtDNA dataset, showing that our methodology enables efficient, highly accurate analysis of very large trees. Datasets requiring a computation time of several days with MCMC can with our MAP algorithm be accurately analysed in less than a minute. From the results of our example analyses, we conclude that our methodology generally avoids getting trapped early in local optima. For the cases where this nevertheless can be a problem, for instance when we in addition to the parameters also infer the tree topology, we show that the problem can be evaded by using a simulated-annealing like (SAL) method in which we favour tree swaps early in the inference while biasing our focus towards rate and time parameter changes later on.

    Conclusion: Our contribution leaves the field open for fast and accurate dating analysis of nucleotide sequence data. Modeling branch substitutions rates and divergence times separately allows us to include birth-death priors on the times without the assumption of a molecular clock. The methodology is easily adapted to take data from fossil records into account and it can be used together with a broad range of rate and substitution models.

  • 7.
    Åkerborg, Örjan
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Spalinskas, Rapolas
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Pradhananga, Sailendra
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Anil, Anandashankar
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Höjer, Pontus
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Poujade, Flore-Anne
    Karolinska Inst, Cardiovasc Med Unit, Dept Med, Ctr Mol Med, Stockholm, Sweden..
    Folkersen, Lasse
    Tech Univ Denmark, Dept Bioinformat, Copenhagen, Denmark..
    Sahlén, Pelin
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Eriksson, Per
    Karolinska Inst, Cardiovasc Med Unit, Dept Med, Ctr Mol Med, Stockholm, Sweden..
    High-Resolution Regulatory Maps Connect Vascular Risk Variants to Disease-Related Pathways2019In: Circulation. Genomic and precision medicine, ISSN 2574-8300, Vol. 12, no 3, article id e002353Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Genetic variant landscape of coronary artery disease is dominated by noncoding variants among which many occur within putative enhancers regulating the expression levels of relevant genes. It is crucial to assign the genetic variants to their correct genes both to gain insights into perturbed functions and better assess the risk of disease. METHODS: In this study, we generated high-resolution genomic interaction maps (similar to 750 bases) in aortic endothelial, smooth muscle cells and THP-1 (human leukemia monocytic cell line) macrophages stimulated with lipopolysaccharide using Hi-C coupled with sequence capture targeting 25 429 features, including variants associated with coronary artery disease. We also sequenced their transcriptomes and mapped putative enhancers using chromatin immunoprecipitation with an antibody against H3K27Ac. RESULTS: The regions interacting with promoters showed strong enrichment for enhancer elements and validated several previously known interactions and enhancers. We detected interactions for 727 risk variants obtained by genome-wide association studies and identified novel, as well as established genes and functions associated with cardiovascular diseases. We were able to assign potential target genes for additional 398 genome-wide association studies variants using haplotype information, thereby identifying additional relevant genes and functions. Importantly, we discovered that a subset of risk variants interact with multiple promoters and their expression levels were strongly correlated. CONCLUSIONS: In summary, we present a catalog of candidate genes regulated by coronary artery disease-related variants and think that it will be an invaluable resource to further the investigation of cardiovascular pathologies and disease.

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