Publications by authors named "Iñigo Prada-Luengo"

6 Publications

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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

Near-Random Distribution of Chromosome-Derived Circular DNA in the Condensed Genome of Pigeons and the Larger, More Repeat-Rich Human Genome.

Genome Biol Evol 2020 01;12(1):3762-3777

Department of Biology, University of Copenhagen, Denmark.

Extrachromosomal circular DNA (eccDNA) elements of chromosomal origin are known to be common in a number of eukaryotic species. However, it remains to be addressed whether genomic features such as genome size, the load of repetitive elements within a genome, and/or animal physiology affect the number of eccDNAs. Here, we investigate the distribution and numbers of eccDNAs in a condensed and less repeat-rich genome compared with the human genome, using Columba livia domestica (domestic rock pigeon) as a model organism. By sequencing eccDNA in blood and breast muscle from three pigeon breeds at various ages and with different flight behavior, we characterize 30,000 unique eccDNAs. We identify genomic regions that are likely hotspots for DNA circularization in breast muscle, including genes involved in muscle development. We find that although eccDNA counts do not correlate with the biological age in pigeons, the number of unique eccDNAs in a nonflying breed (king pigeons) is significantly higher (9-fold) than homing pigeons. Furthermore, a comparison between eccDNA from skeletal muscle in pigeons and humans reveals ∼9-10 times more unique eccDNAs per human nucleus. The fraction of eccDNA sequences, derived from repetitive elements, exist in proportions to genome content, that is, human 72.4% (expected 52.5%) and pigeon 8.7% (expected 5.5%). Overall, our results support that eccDNAs are common in pigeons, that the amount of unique eccDNA types per nucleus can differ between species as well as subspecies, and suggest that eccDNAs from repeats are found in proportions relative to the content of repetitive elements in a genome.
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http://dx.doi.org/10.1093/gbe/evz281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993614PMC
January 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

To Be or Not to Be: Circular RNAs or mRNAs From Circular DNAs?

Front Genet 2019 11;10:940. Epub 2019 Oct 11.

Neurosciences Area, Biodonostia Health Research Institute, San Sebastián, Spain.

In recent years, there has been a growing interest in circular RNAs (circRNAs) since they are involved in a wide spectrum of cellular functions that might have a large impact on phenotype and disease. CircRNAs are mainly recorded by RNA-Seq and computational methods focused on the detection of back-splicing junction sequences considered the diagnostic feature of circRNAs. While some protocols remove linear RNA prior to sequencing, many have characterized circRNAs by sorting through total RNA sequencing data without excluding the possibility that some linear RNA can provide the same signal as a circRNA. Recent studies have revealed that circular DNAs of chromosomal origin are common in eukaryotic genomes and that they can be transcribed. Transcription events across the junction of circular DNAs would result in a transcript with a junction similar to those present in circRNAs. Therefore, in this report, we want to draw attention to transcripts from such circular DNAs both as an interesting new player in the transcriptome and also as a confounding factor that must be taken into account when studying circRNAs.
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http://dx.doi.org/10.3389/fgene.2019.00940DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6797608PMC
October 2019

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

Circular RNA profiling reveals that circular RNAs from ANXA2 can be used as new biomarkers for multiple sclerosis.

Hum Mol Genet 2017 09;26(18):3564-3572

Multiple Sclerosis Unit, Neurosciences Area, Biodonostia Health Research Institute, 20014, San Sebastián, Spain.

Multiple sclerosis is an autoimmune disease, with higher prevalence in women, in whom the immune system is dysregulated. This dysregulation has been shown to correlate with changes in transcriptome expression as well as in gene-expression regulators, such as non-coding RNAs (e.g. microRNAs). Indeed, some of these have been suggested as biomarkers for multiple sclerosis even though few biomarkers have reached the clinical practice. Recently, a novel family of non-coding RNAs, circular RNAs, has emerged as a new player in the complex network of gene-expression regulation. MicroRNA regulation function through a 'sponge system' and a RNA splicing regulation function have been proposed for the circular RNAs. This regulating role together with their high stability in biofluids makes them seemingly good candidates as biomarkers. Given the dysregulation of both protein-coding and non-coding transcriptome that have been reported in multiple sclerosis patients, we hypothesised that circular RNA expression may also be altered. Therefore, we carried out expression profiling of 13.617 circular RNAs in peripheral blood leucocytes from multiple sclerosis patients and healthy controls finding 406 differentially expressed (P-value < 0.05, Fold change > 1.5) and demonstrate after validation that, circ_0005402 and circ_0035560 are underexpressed in multiple sclerosis patients and could be used as biomarkers of the disease.
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http://dx.doi.org/10.1093/hmg/ddx243DOI Listing
September 2017