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  • 1.
    Alexeyenko, Andrey
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Sonnhammer, Erik L L
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Global networks of functional coupling in eukaryotes from comprehensive data integration2009In: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 19, no 6, p. 1107-16Article in journal (Refereed)
    Abstract [en]

    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.

  • 2.
    Ekdahl, Ylva
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Farahani, Hossein Shahrabi
    Behm, Mikaela
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Lagergren, Jens
    Öhman, Marie
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    A-to-I editing of microRNAs in the mammalian brain increases during development2012In: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 22, no 8, p. 1477-1487Article in journal (Refereed)
    Abstract [en]

    Adenosine-to-inosine (A-to-I) RNA editing targets double-stranded RNA stem-loop structures in the mammalian brain. It has previously been shown that miRNAs are substrates for A-to-I editing. For the first time, we show that for several definitions of edited miRNA, the level of editing increases with development, thereby indicating a regulatory role for editing during brain maturation. We use high-throughput RNA sequencing to determine editing levels in mature miRNA, from the mouse transcriptome, and compare these with the levels of editing in pri-miRNA. We show that increased editing during development gradually changes the proportions of the two miR-376a isoforms, which previously have been shown to have different targets. Several other miRNAs that also are edited in the seed sequence show an increased level of editing through development. By comparing editing of pri-miRNA with editing and expression of the corresponding mature miRNA, we also show an editing-induced developmental regulation of miRNA expression. Taken together, our results imply that RNA editing influences the miRNA repertoire during brain maturation.

  • 3. Ekim, Baris
    et al.
    Sahlin, Kristoffer
    Stockholm University, Faculty of Science, Department of Mathematics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Medvedev, Paul
    Berger, Bonnie
    Chikhi, Rayan
    Efficient mapping of accurate long reads in minimizer space with mapquik2023In: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 33, no 7, p. 1188-1197Article in journal (Refereed)
    Abstract [en]

    DNA sequencing data continue to progress toward longer reads with increasingly lower sequencing error rates. We focus on the critical problem of mapping, or aligning, low-divergence sequences from long reads (e.g., Pacific Biosciences [PacBio] HiFi) to a reference genome, which poses challenges in terms of accuracy and computational resources when using cutting-edge read mapping approaches that are designed for all types of alignments. A natural idea would be to optimize efficiency with longer seeds to reduce the probability of extraneous matches; however, contiguous exact seeds quickly reach a sensitivity limit. We introduce mapquik, a novel strategy that creates accurate longer seeds by anchoring alignments through matches of k consecutively sampled minimizers (k-min-mers) and only indexing k-min-mers that occur once in the reference genome, thereby unlocking ultrafast mapping while retaining high sensitivity. We show that mapquik significantly accelerates the seeding and chaining steps-fundamental bottlenecks to read mapping-for both the human and maize genomes with >96% sensitivity and near-perfect specificity. On the human genome, for both real and simulated reads, mapquik achieves a 37x speedup over the state-of-the-art tool minimap2, and on the maize genome, mapquik achieves a 410x speedup over minimap2, making mapquik the fastest mapper to date. These accelerations are enabled from not only minimizer-space seeding but also a novel heuristic O(n) pseudochaining algorithm, which improves upon the long-standing O(nlogn) bound. Minimizer-space computation builds the foundation for achieving real-time analysis of long-read sequencing data.

  • 4. Hagey, Daniel W.
    et al.
    Zaouter, Cecile
    Combeau, Gaelle
    Andersson Lendahl, Monika
    Andersson, Olov
    Huss, Mikael
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Muhr, Jonas
    Distinct transcription factor complexes act on a permissive chromatin landscape to establish regionalized gene expression in CNS stem cells2016In: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 26, no 7, p. 908-917Article in journal (Refereed)
    Abstract [en]

    Spatially distinct gene expression profiles in neural stem cells (NSCs) are a prerequisite to the formation of neuronal diversity, but how these arise from the regulatory interactions between chromatin accessibility and transcription factor activity has remained unclear. Here, we demonstrate that, despite their distinct gene expression profiles, NSCs of the mouse cortex and spinal cord share the majority of their DNase I hypersensitive sites (DHSs). Regardless of this similarity, domain-specific gene expression is highly correlated with the relative accessibility of associated DHSs, as determined by sequence read density. Notably, the binding pattern of the general NSC transcription factor SOX2 is also largely cell type specific and coincides with an enrichment of LHX2 motifs in the cortex and HOXA9 motifs in the spinal cord. Interestingly, in a zebrafish reporter gene system, these motifs were critical determinants of patterned gene expression along the rostral-caudal axis. Our findings establish a predictive model for patterned NSC gene expression, whereby domain-specific expression of LHX2 and HOX proteins act on their target motifs within commonly accessible cis-regulatory regions to specify SOX2 binding. In turn, this binding correlates strongly with these DHSs relative accessibility-a robust predictor of neighboring gene expression.

  • 5.
    Maier, Benjamin Dominik
    et al.
    Stockholm University, Faculty of Science, Department of Mathematics.
    Sahlin, Kristoffer
    Stockholm University, Faculty of Science, Department of Mathematics.
    Entropy predicts sensitivity of pseudorandom seeds2023In: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 33, no 7, p. 1162-1174Article in journal (Refereed)
    Abstract [en]

    Seed design is important for sequence similarity search applications such as read mapping and average nucleotide identity (ANI) estimation. Although k-mers and spaced k-mers are likely the most well-known and used seeds, sensitivity suffers at high error rates, particularly when indels are present. Recently, we developed a pseudorandom seeding construct, strobemers, which was empirically shown to have high sensitivity also at high indel rates. However, the study lacked a deeper understanding of why. In this study, we propose a model to estimate the entropy of a seed and find that seeds with high entropy, according to our model, in most cases have high match sensitivity. Our discovered seed randomness–sensitivity relationship explains why some seeds perform better than others, and the relationship provides a framework for designing even more sensitive seeds. We also present three new strobemer seed constructs: mixedstrobes, altstrobes, and multistrobes. We use both simulated and biological data to show that our new seed constructs improve sequence-matching sensitivity to other strobemers. We show that the three new seed constructs are useful for read mapping and ANI estimation. For read mapping, we implement strobemers into minimap2 and observe 30% faster alignment time and 0.2% higher accuracy than using k-mers when mapping reads at high error rates. As for ANI estimation, we find that higher entropy seeds have a higher rank correlation between estimated and true ANI.

  • 6. Mugal, Carina F.
    et al.
    Wang, Mi
    Backström, Niclas
    Wheatcroft, David
    Stockholm University, Faculty of Science, Department of Zoology. Uppsala University, Sweden.
    Ålund, Murielle
    Sémon, Marie
    McFarlane, S. Eryn
    Dutoit, Ludovic
    Qvarnström, Anna
    Ellegren, Hans
    Tissue-specific patterns of regulatory changes underlying gene expression differences among Ficedula flycatchers and their naturally occurring F1 hybrids2020In: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 30, no 12, p. 1727-1739Article in journal (Refereed)
    Abstract [en]

    Changes in interacting cis- and trans-regulatory elements are important candidates for Dobzhansky-Muller hybrid incompatibilities and may contribute to hybrid dysfunction by giving rise to misexpression in hybrids. To gain insight into the molecular mechanisms and determinants of gene expression evolution in natural populations, we analyzed the transcriptome from multiple tissues of two recently diverged Ficedula flycatcher species and their naturally occurring F1 hybrids. Differential gene expression analysis revealed that the extent of differentiation between species and the set of differentially expressed genes varied across tissues. Common to all tissues, a higher proportion of Z-linked genes than autosomal genes showed differential expression, providing evidence for a fast-Z effect. We further found clear signatures of hybrid misexpression in brain, heart, kidney, and liver. However, while testis showed the highest divergence of gene expression among tissues, it showed no clear signature of misexpression in F1 hybrids, even though these hybrids were found to be sterile. It is therefore unlikely that incompatibilities between cis-trans regulatory changes explain the observed sterility. Instead, we found evidence that cis-regulatory changes play a significant role in the evolution of gene expression in testis, which illustrates the tissue-specific nature of cis-regulatory evolution bypassing constraints associated with pleiotropic effects of genes. 

  • 7.
    Mármol-Sánchez, Emilio
    et al.
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Centre for Palaeogenetics, Sweden.
    Fromm, Bastian
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab). UiT - The Arctic University of Norway, Norway.
    Oskolkov, Nikolay
    Pochon, Zoé
    Stockholm University, Faculty of Humanities, Department of Archaeology and Classical Studies. Centre for Palaeogenetics, Sweden.
    Kalogeropoulos, Panagiotis
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Eriksson, Eli
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Biryukova, Inna
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Sekar, Vaishnovi
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Ersmark, Erik
    Andersson, Björn
    Dalén, Love
    Stockholm University, Faculty of Science, Department of Zoology. Centre for Palaeogenetics, Sweden; Swedish Museum of Natural History, Sweden.
    Friedländer, Marc R.
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Historical RNA expression profiles from the extinct Tasmanian tiger2023In: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 33, no 8, p. 1299-1316Article in journal (Refereed)
    Abstract [en]

    Paleogenomics continues to yield valuable insights into the evolution, population dynamics, and ecology of our ancestors and other extinct species. However, DNA sequencing cannot reveal tissue-specific gene expression, cellular identity, or gene regulation, which are only attainable at the transcriptional level. Pioneering studies have shown that useful RNA can be extracted from ancient specimens preserved in permafrost and historical skins from extant canids, but no attempts have been made so far on extinct species. We extract, sequence, and analyze historical RNA from muscle and skin tissue of a ∼130-year-old Tasmanian tiger (Thylacinus cynocephalus) preserved in desiccation at room temperature in a museum collection. The transcriptional profiles closely resemble those of extant species, revealing specific anatomical features such as slow muscle fibers or blood infiltration. Metatranscriptomic analysis, RNA damage, tissue-specific RNA profiles, and expression hotspots genome-wide further confirm the thylacine origin of the sequences. RNA sequences are used to improve protein-coding and noncoding annotations, evidencing missing exonic loci and the location of ribosomal RNA genes while increasing the number of annotated thylacine microRNAs from 62 to 325. We discover a thylacine-specific microRNA isoform that could not have been confirmed without RNA evidence. Finally, we detect traces of RNA viruses, suggesting the possibility of profiling viral evolution. Our results represent the first successful attempt to obtain transcriptional profiles from an extinct animal species, providing thought-to-be-lost information on gene expression dynamics. These findings hold promising implications for the study of RNA molecules across the vast collections of natural history museums and from well-preserved permafrost remains.

  • 8. Palahi i Torres, Aleix
    et al.
    Hook, Lars
    Nasvall, Karin
    Shipilina, Daria
    Wiklund, Christer
    Stockholm University, Faculty of Science, Department of Zoology, Animal Ecology. Stockholm University, Faculty of Science, Department of Zoology, Population Genetics. Stockholm University, Faculty of Science, The Bolin Centre for Climate Research (together with KTH & SMHI).
    Vila, Roger
    Pruisscher, Peter
    Backstrom, Niclas
    The fine-scale recombination rate variation and associations with genomic features in a butterfly2023In: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 33, no 5, p. 810-823Article in journal (Refereed)
    Abstract [en]

    Recombination is a key molecular mechanism that has profound implications on both micro- and macroevolutionary processes. However, the determinants of recombination rate variation in holocentric organisms are poorly understood, in particular in Lepidoptera (moths and butterflies). The wood white butterfly (Leptidea sinapis) shows considerable intraspecific variation in chromosome numbers and is a suitable system for studying regional recombination rate variation and its potential molecular underpinnings. Here, we developed a large whole-genome resequencing data set from a population of wood whites to obtain high-resolution recombination maps using linkage disequilibrium information. The analyses revealed that larger chromosomes had a bimodal recombination landscape, potentially caused by interference between simultaneous chiasmata. The recombination rate was significantly lower in subtelomeric regions, with exceptions associated with segregating chromosome rearrangements, showing that fissions and fusions can have considerable effects on the recombination landscape. There was no association between the inferred recombination rate and base composition, supporting a limited influence of GC-biased gene conversion in butterflies. We found significant but variable associations between the recombination rate and the density of different classes of transposable elements, most notably a significant enrichment of short interspersed nucleotide elements in genomic regions with higher recombination rate. Finally, the analyses unveiled significant enrichment of genes involved in farnesyltranstransferase activity in recombination coldspots, potentially indicating that expression of transferases can inhibit formation of chiasmata during meiotic division. Our results provide novel information about recombination rate variation in holocentric organisms and have particular implications for forthcoming research in population genetics, molecular/genome evolution, and speciation.

  • 9.
    Sahlin, Kristoffer
    Stockholm University, Faculty of Science, Department of Mathematics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Effective sequence similarity detection with strobemers2021In: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 31, no 11, p. 2080-2094Article in journal (Refereed)
    Abstract [en]

    k-mer-based methods are widely used in bioinformatics for various types of sequence comparisons. However, a single mutation will mutate k consecutive k-mers and make most k-mer-based applications for sequence comparison sensitive to variable mutation rates. Many techniques have been studied to overcome this sensitivity, for example, spaced k-mers and k-mer permutation techniques, but these techniques do not handle indels well. For indels, pairs or groups of small k-mers are commonly used, but these methods first produce k-mer matches, and only in a second step, a pairing or grouping of k-mers is performed. Such techniques produce many redundant k-mer matches owing to the size of k Here, we propose strobemers as an alternative to k-mers for sequence comparison. Intuitively, strobemers consist of two or more linked shorter k-mers, where the combination of linked k-mers is decided by a hash function. We use simulated data to show that strobemers provide more evenly distributed sequence matches and are less sensitive to different mutation rates than k-mers and spaced k-mers. Strobemers also produce higher match coverage across sequences. We further implement a proof-of-concept sequence-matching tool StrobeMap and use synthetic and biological Oxford Nanopore sequencing data to show the utility of using strobemers for sequence comparison in different contexts such as sequence clustering and alignment scenarios.

  • 10. Song, Lingyun
    et al.
    Zhang, Zhancheng
    Grasfeder, Linda L.
    Boyle, Alan P.
    Giresi, Paul G.
    Lee, Bum-Kyu
    Sheffield, Nathan C.
    Graef, Stefan
    Huss, Mikael
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Keefe, Damian
    Liu, Zheng
    London, Darin
    McDaniell, Ryan M.
    Shibata, Yoichiro
    Showers, Kimberly A.
    Simon, Jeremy M.
    Vales, Teresa
    Wang, Tianyuan
    Winter, Deborah
    Zhang, Zhuzhu
    Clarke, Neil D.
    Birney, Ewan
    Iyer, Vishwanath R.
    Crawford, Gregory E.
    Lieb, Jason D.
    Furey, Terrence S.
    Open chromatin defined by DNaseI and FAIRE identifies regulatory elements that shape cell-type identity2011In: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 21, no 10, p. 1757-1767Article in journal (Refereed)
    Abstract [en]

    The human body contains thousands of unique cell types, each with specialized functions. Cell identity is governed in large part by gene transcription programs, which are determined by regulatory elements encoded in DNA. To identify regulatory elements active in seven cell lines representative of diverse human cell types, we used DNase-seq and FAIRE-seq (Formaldehyde Assisted Isolation of Regulatory Elements) to map open chromatin.'' Over 870,000 DNaseI or FAIRE sites, which correspond tightly to nucleosome-depleted regions, were identified across the seven cell lines, covering nearly 9% of the genome. The combination of DNaseI and FAIRE is more effective than either assay alone in identifying likely regulatory elements, as judged by coincidence with transcription factor binding locations determined in the same cells. Open chromatin common to all seven cell types tended to be at or near transcription start sites and to be coincident with CTCF binding sites, while open chromatin sites found in only one cell type were typically located away from transcription start sites and contained DNA motifs recognized by regulators of cell-type identity. We show that open chromatin regions bound by CTCF are potent insulators. We identified clusters of open regulatory elements (COREs) that were physically near each other and whose appearance was coordinated among one or more cell types. Gene expression and RNA Pol II binding data support the hypothesis that COREs control gene activity required for the maintenance of cell-type identity. This publicly available atlas of regulatory elements may prove valuable in identifying noncoding DNA sequence variants that are causally linked to human disease.

  • 11.
    Wahlstedt, Helene
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Daniel, Chammiran
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Ensterö, Mats
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Öhman, Marie
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Large-scale mRNA sequencing determines global regulation of RNA editing during brain development2009In: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 19, p. 978-986Article in journal (Refereed)
    Abstract [en]

    RNA editing by adenosine deamination has been shown to generate multiple isoforms of several neural receptors, often with profound effects on receptor function. However, little is known about the regulation of editing activity during development. We have developed a large-scale RNA sequencing protocol to determine adenosine-to-inosine (A-to-I) editing frequencies in the coding region of genes in the mammalian brain. Using the 454 Life Sciences (Roche) Amplicon Sequencing technology, we were able to determine even low levels of editing with high accuracy. The efficiency of editing for 28 different sites was analyzed during the development of the mouse brain from embryogenesis to adulthood. We show that, with few exceptions, the editing efficiency is low during embryogenesis, increasing gradually at different rates up to the adult mouse. The variation in editing gave receptors like HTR2C and GABAA (gamma-aminobutyric acid type A) a different set of protein isoforms during development from those in the adult animal. Furthermore, we show that this regulation of editing activity cannot be explained by an altered expression of the ADAR proteins but, rather, by the presence of a regulatory network that controls the editing activity during development.

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