Publications by authors named "Lasse Maretty"

14 Publications

  • Page 1 of 1

Replicative aging is associated with loss of genetic heterogeneity from extrachromosomal circular DNA in Saccharomyces cerevisiae.

Nucleic Acids Res 2020 08;48(14):7883-7898

Ecology and Evolution, Department of Biology, University of Copenhagen, Copenhagen DK-2100, Denmark.

Circular DNA can arise from all parts of eukaryotic chromosomes. In yeast, circular ribosomal DNA (rDNA) accumulates dramatically as cells age, however little is known about the accumulation of other chromosome-derived circles or the contribution of such circles to genetic variation in aged cells. We profiled circular DNA in Saccharomyces cerevisiae populations sampled when young and after extensive aging. Young cells possessed highly diverse circular DNA populations but 94% of the circular DNA were lost after ∼15 divisions, whereas rDNA circles underwent massive accumulation to >95% of circular DNA. Circles present in both young and old cells were characterized by replication origins including circles from unique regions of the genome and repetitive regions: rDNA and telomeric Y' regions. We further observed that circles can have flexible inheritance patterns: [HXT6/7circle] normally segregates to mother cells but in low glucose is present in up to 50% of cells, the majority of which must have inherited this circle from their mother. Interestingly, [HXT6/7circle] cells are eventually replaced by cells carrying stable chromosomal HXT6 HXT6/7 HXT7 amplifications, suggesting circular DNAs are intermediates in chromosomal amplifications. In conclusion, the heterogeneity of circular DNA offers flexibility in adaptation, but this heterogeneity is remarkably diminished with age.
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http://dx.doi.org/10.1093/nar/gkaa545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430651PMC
August 2020

Sensitive detection of circular DNAs at single-nucleotide resolution using guided realignment of partially aligned reads.

BMC Bioinformatics 2019 Dec 12;20(1):663. Epub 2019 Dec 12.

Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, DK-2200, København N, Denmark.

Background: Circular DNA has recently been identified across different species including human normal and cancerous tissue, but short-read mappers are unable to align many of the reads crossing circle junctions hence limiting their detection from short-read sequencing data.

Results: Here, we propose a new method, Circle-Map that guides the realignment of partially aligned reads using information from discordantly mapped reads to map the short unaligned portions using a probabilistic model. We compared Circle-Map to similar up-to-date methods for circular DNA and RNA detection and we demonstrate how the approach implemented in Circle-Map dramatically increases sensitivity for detection of circular DNA on both simulated and real data while retaining high precision.

Conclusion: Circle-Map is an easy-to-use command line tool that implements the required pipeline to accurately detect circular DNA from circle enriched next generation sequencing experiments. Circle-Map is implemented in python3.6 and it is freely available at https://github.com/iprada/Circle-Map.
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http://dx.doi.org/10.1186/s12859-019-3160-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6909605PMC
December 2019

Accurate genotyping across variant classes and lengths using variant graphs.

Nat Genet 2018 07 18;50(7):1054-1059. Epub 2018 Jun 18.

The Bioinformatics Centre, Department of Biology, University of Copenhagen, Copenhagen, Denmark.

Genotype estimates from short-read sequencing data are typically based on the alignment of reads to a linear reference, but reads originating from more complex variants (for example, structural variants) often align poorly, resulting in biased genotype estimates. This bias can be mitigated by first collecting a set of candidate variants across discovery methods, individuals and databases, and then realigning the reads to the variants and reference simultaneously. However, this realignment problem has proved computationally difficult. Here, we present a new method (BayesTyper) that uses exact alignment of read k-mers to a graph representation of the reference and variants to efficiently perform unbiased, probabilistic genotyping across the variation spectrum. We demonstrate that BayesTyper generally provides superior variant sensitivity and genotyping accuracy relative to existing methods when used to integrate variants across discovery approaches and individuals. Finally, we demonstrate that including a 'variation-prior' database containing already known variants significantly improves sensitivity.
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http://dx.doi.org/10.1038/s41588-018-0145-5DOI Listing
July 2018

Circular DNA elements of chromosomal origin are common in healthy human somatic tissue.

Nat Commun 2018 03 14;9(1):1069. Epub 2018 Mar 14.

Department of Biology, University of Copenhagen, Copenhagen, DK-2100, Denmark.

The human genome is generally organized into stable chromosomes, and only tumor cells are known to accumulate kilobase (kb)-sized extrachromosomal circular DNA elements (eccDNAs). However, it must be expected that kb eccDNAs exist in normal cells as a result of mutations. Here, we purify and sequence eccDNAs from muscle and blood samples from 16 healthy men, detecting ~100,000 unique eccDNA types from 16 million nuclei. Half of these structures carry genes or gene fragments and the majority are smaller than 25 kb. Transcription from eccDNAs suggests that eccDNAs reside in nuclei and recurrence of certain eccDNAs in several individuals implies DNA circularization hotspots. Gene-rich chromosomes contribute to more eccDNAs per megabase and the most transcribed protein-coding gene in muscle, TTN (titin), provides the most eccDNAs per gene. Thus, somatic genomes are rich in chromosome-derived eccDNAs that may influence phenotypes through altered gene copy numbers and transcription of full-length or truncated genes.
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http://dx.doi.org/10.1038/s41467-018-03369-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5852086PMC
March 2018

Increased Plasmodium chabaudi malaria mortality in mice with nutritional iron deficiency can be reduced by short-term adjunctive iron supplementation.

Malar J 2018 Jan 16;17(1):34. Epub 2018 Jan 16.

Centre for Medical Parasitology, Department of Clinical Microbiology, Copenhagen University Hospital (Rigshospitalet), Copenhagen, Denmark.

Background: Iron deficiency is the most widespread nutrient deficiency and an important cause of developmental impairment in children. However, some studies have indicated that iron deficiency can also protect against malaria, which is a leading cause of childhood morbidity and mortality in large parts of the world. This has rendered interventions against iron deficiency in malaria-endemic areas controversial.

Methods: The effect of nutritional iron deficiency on the clinical outcome of Plasmodium chabaudi AS infection in A/J mice and the impact of intravenous iron supplementation with ferric carboxymaltose were studied before and after parasite infection. Plasma levels of the iron status markers hepcidin and fibroblast growth factor 23 were measured in animals surviving and succumbing to malaria, and accompanying tissue pathology in the liver and the spleen was assessed.

Results: Nutritional iron deficiency was associated with increased mortality from P. chabaudi malaria. This increased mortality could be partially offset by carefully timed, short-duration adjunctive iron supplementation. Moribund animals were characterized by low levels of hepcidin and high levels of fibroblast growth factor 23. All infected mice had extramedullary splenic haematopoiesis, and iron-supplemented mice had visually detectable intracellular iron stores.

Conclusions: Blood transfusions are the only currently available means to correct severe anaemia in children with malaria. The potential of carefully timed, short-duration adjunctive iron supplementation as a safe alternative should be considered.
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http://dx.doi.org/10.1186/s12936-018-2186-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5771219PMC
January 2018

Sequencing and de novo assembly of 150 genomes from Denmark as a population reference.

Nature 2017 08 26;548(7665):87-91. Epub 2017 Jul 26.

Bioinformatics Research Centre, Aarhus University, 8000 Aarhus, Denmark.

Hundreds of thousands of human genomes are now being sequenced to characterize genetic variation and use this information to augment association mapping studies of complex disorders and other phenotypic traits. Genetic variation is identified mainly by mapping short reads to the reference genome or by performing local assembly. However, these approaches are biased against discovery of structural variants and variation in the more complex parts of the genome. Hence, large-scale de novo assembly is needed. Here we show that it is possible to construct excellent de novo assemblies from high-coverage sequencing with mate-pair libraries extending up to 20 kilobases. We report de novo assemblies of 150 individuals (50 trios) from the GenomeDenmark project. The quality of these assemblies is similar to those obtained using the more expensive long-read technology. We use the assemblies to identify a rich set of structural variants including many novel insertions and demonstrate how this variant catalogue enables further deciphering of known association mapping signals. We leverage the assemblies to provide 100 completely resolved major histocompatibility complex haplotypes and to resolve major parts of the Y chromosome. Our study provides a regional reference genome that we expect will improve the power of future association mapping studies and hence pave the way for precision medicine initiatives, which now are being launched in many countries including Denmark.
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http://dx.doi.org/10.1038/nature23264DOI Listing
August 2017

RNA Sequencing of Trigeminal Ganglia in Rattus Norvegicus after Glyceryl Trinitrate Infusion with Relevance to Migraine.

PLoS One 2016 23;11(5):e0155039. Epub 2016 May 23.

Danish Headache Center, Department of Neurology, Glostrup Research Institute, Rigshospitalet, and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Introduction: Infusion of glyceryl trinitrate (GTN), a donor of nitric oxide, induces immediate headache in humans that in migraineurs is followed by a delayed migraine attack. In order to achieve increased knowledge of mechanisms activated during GTN-infusion this present study aims to investigate transcriptional responses to GTN-infusion in the rat trigeminal ganglia.

Methods: Rats were infused with GTN or vehicle and trigeminal ganglia were isolated either 30 or 90 minutes post infusion. RNA sequencing was used to investigate transcriptomic changes in response to the treatment. Furthermore, we developed a novel method for Gene Set Analysis Of Variance (GSANOVA) to identify gene sets associated with transcriptional changes across time.

Results: 15 genes displayed significant changes in transcription levels in response to GTN-infusion. Ten of these genes showed either sustained up- or down-regulation in the 90-minute period after infusion. The GSANOVA analysis demonstrate enrichment of pathways pointing towards an increase in immune response, signal transduction, and neuroplasticity in response to GTN-infusion. Future functional in-depth studies of these mechanisms are expected to increase our understanding of migraine pathogenesis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0155039PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4877077PMC
July 2017

Next-generation biology: Sequencing and data analysis approaches for non-model organisms.

Mar Genomics 2016 Dec 13;30:3-13. Epub 2016 May 13.

Centre for GeoGenetics, Natural History Museum of Denmark, University of Copenhagen, Copenhagen, Denmark.

As sequencing technologies become more affordable, it is now realistic to propose studying the evolutionary history of virtually any organism on a genomic scale. However, when dealing with non-model organisms it is not always easy to choose the best approach given a specific biological question, a limited budget, and challenging sample material. Furthermore, although recent advances in technology offer unprecedented opportunities for research in non-model organisms, they also demand unprecedented awareness from the researcher regarding the assumptions and limitations of each method. In this review we present an overview of the current sequencing technologies and the methods used in typical high-throughput data analysis pipelines. Subsequently, we contextualize high-throughput DNA sequencing technologies within their applications in non-model organism biology. We include tips regarding managing unconventional sample material, comparative and population genetic approaches that do not require fully assembled genomes, and advice on how to deal with low depth sequencing data.
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http://dx.doi.org/10.1016/j.margen.2016.04.012DOI Listing
December 2016

Coalescent Inference Using Serially Sampled, High-Throughput Sequencing Data from Intrahost HIV Infection.

Genetics 2016 Apr 8;202(4):1449-72. Epub 2016 Feb 8.

Department of Statistics, University of Warwick, Coventry, United Kingdom Department of Computer Science, University of Warwick, Coventry, United Kingdom

Human immunodeficiency virus (HIV) is a rapidly evolving pathogen that causes chronic infections, so genetic diversity within a single infection can be very high. High-throughput "deep" sequencing can now measure this diversity in unprecedented detail, particularly since it can be performed at different time points during an infection, and this offers a potentially powerful way to infer the evolutionary dynamics of the intrahost viral population. However, population genomic inference from HIV sequence data is challenging because of high rates of mutation and recombination, rapid demographic changes, and ongoing selective pressures. In this article we develop a new method for inference using HIV deep sequencing data, using an approach based on importance sampling of ancestral recombination graphs under a multilocus coalescent model. The approach further extends recent progress in the approximation of so-called conditional sampling distributions, a quantity of key interest when approximating coalescent likelihoods. The chief novelties of our method are that it is able to infer rates of recombination and mutation, as well as the effective population size, while handling sampling over different time points and missing data without extra computational difficulty. We apply our method to a data set of HIV-1, in which several hundred sequences were obtained from an infected individual at seven time points over 2 years. We find mutation rate and effective population size estimates to be comparable to those produced by the software BEAST. Additionally, our method is able to produce local recombination rate estimates. The software underlying our method, Coalescenator, is freely available.
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http://dx.doi.org/10.1534/genetics.115.177931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4905535PMC
April 2016

Polymorphisms in the Haem Oxygenase-1 promoter are not associated with severity of Plasmodium falciparum malaria in Ghanaian children.

Malar J 2015 Apr 11;14:153. Epub 2015 Apr 11.

Centre for Medical Parasitology at Department of Immunology & Microbiology, University of Copenhagen, Østerfarimagsgade 5, Building 22-23, 1014, Copenhagen K., Denmark.

Background: Haem oxygenase-1 (HO-1) catabolizes haem and has both cytotoxic and cytoprotective effects. Polymorphisms in the promoter of the Haem oxygenase-1 (HMOX1) gene encoding HO-1 have been associated with several diseases including severe malaria. The objective of this study was to determine the allele and genotype frequencies of two single nucleotide polymorphisms; A(-413)T and G(-1135)A, and a (GT)n repeat length polymorphism in the HMOX1 promoter in paediatric malaria patients and controls to determine possible associations with malaria disease severity.

Methods: Study participants were Ghanaian children (n=296) admitted to the emergency room at the Department of Child Health, Korle-Bu Teaching Hospital, Accra, Ghana during the malaria season from June to August in 1995, 1996 and 1997, classified as having uncomplicated malaria (n=101) or severe malaria (n=195; defined as severe anaemia (n=63) or cerebral malaria (n=132)). Furthermore, 287 individuals without a detectable Plasmodium infection or asymptomatic carriers of the parasite were enrolled as controls. Blood samples from participants were extracted for DNA and allele and genotype frequencies were determined with allele-specific PCR, restriction fragment length analysis and microsatellite analysis.

Results: The number of (GT)n repeats in the study participants varied between 21 and 46 with the majority of alleles having lengths of 26 (8.1%), 29/30 (13.2/17.9%) and 39/40 (8.0/13.8%) repeats, and was categorized into short, medium and long repeats. The (-413)T allele was very common (69.8%), while the (-1135)A allele was present in only 17.4% of the Ghanaian population. The G(-1135)A locus was excluded from further analysis after failing the Hardy-Weinberg equilibrium test. No significant differences in allele or genotype distribution of the A(-413)T and (GT)n repeat polymorphisms were found between the controls and the malaria patients, or between the disease groups, for any of the analysed polymorphisms and no associations with malaria severity were found.

Conclusion: These results contribute to the understanding of the role of HMOX1/HO-1. This current study did not find any evidence of association between HMOX1 promoter polymorphisms and malaria susceptibility or severe malaria and hence contradicts previous findings. Further studies are needed to fully elucidate the relationship between HMOX1 polymorphisms and malarial disease.
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http://dx.doi.org/10.1186/s12936-015-0668-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4396170PMC
April 2015

Plasmodium falciparum avoids change in erythrocytic surface expression of phagocytosis markers during inhibition of nitric oxide synthase activity.

Mol Biochem Parasitol 2014 Nov 29;198(1):29-36. Epub 2014 Nov 29.

Centre for Medical Parasitology, Department for Clinical Microbiology, Copenhagen University Hospital and Department of International Health, Immunology and Microbiology, University of Copenhagen, Denmark. Electronic address:

Nitric oxide (NO) accumulates in Plasmodium falciparum-infected erythrocytes. It may be produced by a parasite NO synthase (NOS) or by nitrate reduction. The parasite's benefit of NO accumulation is not understood. We investigated if inhibiting the P. falciparum NOS with specific and unspecific NOS inhibitors led to a decrease in intraerythrocytic NO accumulation and if this was associated with a change in surface expression of the phagocytosis markers CD47 and phosphatidyl serine. The specific inducible NOS inhibitors l-canavanine and GW274150 dose-dependently decreased intraerythrocytic NO while l-NMMA (an unspecific NOS inhibitor) and caveolin-1 scaffolding domain peptide (a specific endothelial NOS inhibitor) did not affect NO levels. Phosphatidyl serine externalization markedly increased upon P. falciparum infection. l-canavanine did not modify this whereas caveolin-1 scaffolding domain peptide increased the fraction of phosphatidyl serine exposing cells significantly. The infection did not change the level of expression of neither total CD47 nor its oxidized form. Unrelated to NOS inhibition, incubation with caveolin-1 scaffolding domain peptide lead to a decrease in oxidized CD47. In conclusion, the data imply that NOS inhibitors decrease NO accumulation in P. falciparum-infected erythrocytes but this does not correlate with the level of two major erythrocytic phagocytosis markers.
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http://dx.doi.org/10.1016/j.molbiopara.2014.11.003DOI Listing
November 2014

Bayesian transcriptome assembly.

Genome Biol 2014 ;15(10):501

The Bioinformatics Centre, Department of Biology and Biotech Research andInnovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, 2200, Copenhagen, Denmark.

RNA sequencing allows for simultaneous transcript discovery and quantification, but reconstructing complete transcripts from such data remains difficult. Here, we introduce Bayesembler, a novel probabilistic method for transcriptome assembly built on a Bayesian model of the RNA sequencing process. Under this model, samples from the posterior distribution over transcripts and their abundance values are obtained using Gibbs sampling. By using the frequency at which transcripts are observed during sampling to select the final assembly, we demonstrate marked improvements in sensitivity and precision over state-of-the-art assemblers on both simulated and real data. Bayesembler is available at https://github.com/bioinformatics-centre/bayesembler.
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http://dx.doi.org/10.1186/s13059-014-0501-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4397945PMC
October 2015

Intravenous ferric carboxymaltose accelerates erythropoietic recovery from experimental malarial anemia.

J Infect Dis 2012 Apr 21;205(7):1173-7. Epub 2012 Feb 21.

Centre for Medical Parasitology, Department of Clinical Microbiology, Copenhagen University Hospital (Rigshospitalet), University of Copenhagen, Copenhagen, Denmark.

Iron restriction has been proposed as a cause of erythropoietic suppression in malarial anemia; however, the role of iron in malaria remains controversial, because it may increase parasitemia. To investigate the role of iron-restricted erythropoiesis, A/J mice were infected with Plasmodium chabaudi AS, treated with intravenous ferric carboxymaltose at different times, and compared with untreated controls. Iron treatment significantly increased weight and hemoglobin nadirs and provided enhanced reticulocytosis and faster recovery, compared with controls. Our findings challenge the restrictive use of iron therapy in malaria and show the need for trials of intravenous ferric carboxymaltose as an adjunctive treatment for severe malarial anemia.
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http://dx.doi.org/10.1093/infdis/jis020DOI Listing
April 2012

Metallothionein-I+II in neuroprotection.

Biofactors 2009 Jul-Aug;35(4):315-25

Section of Neuroprotection, Institute of Neuroscience and Pharmacology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.

Metallothionein (MT)-I+II synthesis is induced in the central nervous system (CNS) in response to practically any pathogen or disorder, where it is increased mainly in reactive glia. MT-I+II are involved in host defence reactions and neuroprotection during neuropathological conditions, in which MT-I+II decrease inflammation and secondary tissue damage (oxidative stress, neurodegeneration, and apoptosis) and promote post-injury repair and regeneration (angiogenesis, neurogenesis, neuronal sprouting and tissue remodelling). Intracellularly the molecular MT-I+II actions involve metal ion control and scavenging of reactive oxygen species (ROS) leading to cellular redox control. By regulating metal ions, MT-I+II can control metal-containing transcription factors, zinc-finger proteins and p53. However, the neuroprotective functions of MT-I+II also involve an extracellular component. MT-I+II protects the neurons by signal transduction through the low-density lipoprotein family of receptors on the cell surface involving lipoprotein receptor-1 (LRP1) and megalin (LRP2). In this review we discuss the newest data on cerebral MT-I+II functions following brain injury and experimental autoimmune encephalomyelitis.
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http://dx.doi.org/10.1002/biof.44DOI Listing
November 2009