| 1. |
- Stenberg, Per, 1974-, et al.
(författare)
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Buffering of segmental and chromosomal aneuploidies in Drosophila melanogaster
- 2009
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Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 5:5
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Tidskriftsartikel (refereegranskat)abstract
- Chromosomal instability, which involves the deletion and duplication of chromosomes or chromosome parts, is a common feature of cancers, and deficiency screens are commonly used to detect genes involved in various biological pathways. However, despite their importance, the effects of deficiencies, duplications, and chromosome losses on the regulation of whole chromosomes and large chromosome domains are largely unknown. Therefore, to explore these effects, we examined expression patterns of genes in several Drosophila deficiency hemizygotes and a duplication hemizygote using microarrays. The results indicate that genes expressed in deficiency hemizygotes are significantly buffered, and that the buffering effect is general rather than being mainly mediated by feedback regulation of individual genes. In addition, differentially expressed genes in haploid condition appear to be generally more strongly buffered than ubiquitously expressed genes in haploid condition, but, among genes present in triploid condition, ubiquitously expressed genes are generally more strongly buffered than differentially expressed genes. Furthermore, we show that the 4th chromosome is compensated in response to dose differences. Our results suggest general mechanisms have evolved that stimulate or repress gene expression of aneuploid regions as appropriate, and on the 4th chromosome of Drosophila this compensation is mediated by Painting of Fourth (POF).
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| 2. |
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| 3. |
- Faucillion, Marie-Line, 1989-, et al.
(författare)
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Modulation of RNA stability regulates gene expression in two opposite ways : through buffering of RNA levels upon global perturbations and by supporting adapted differential expression
- 2022
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Ingår i: Nucleic Acids Research. - : Oxford University Press. - 0305-1048 .- 1362-4962. ; 50:8, s. 4372-4388
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Tidskriftsartikel (refereegranskat)abstract
- The steady state levels of RNAs, often referred to as expression levels, result from a well-balanced combination of RNA transcription and decay. Alterations in RNA levels will therefore result from tight regulation of transcription rates, decay rates or both. Here, we explore the role of RNA stability in achieving balanced gene expression and present genome-wide RNA stabilities in Drosophila melanogaster male and female cells as well as male cells depleted of proteins essential for dosage compensation. We identify two distinct RNA-stability mediated responses involved in regulation of gene expression. The first of these responds to acute and global changes in transcription and thus counteracts potentially harmful gene mis-expression by shifting the RNA stability in the direction opposite to the transcriptional change. The second response enhances inter-individual differential gene expression by adjusting the RNA stability in the same direction as a transcriptional change. Both mechanisms are global, act on housekeeping as well as non-housekeeping genes and were observed in both flies and mammals. Additionally, we show that, in contrast to mammals, modulation of RNA stability does not detectably contribute to dosage compensation of the sex-chromosomes in D. melanogaster.
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| 4. |
- Johansson, Anna-Mia, 1978-
(författare)
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Chromosome-wide gene regulatory mechanisms in Drosophila melanogaster
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In Drosophila there are two different chromosome-wide targeting systems, the dosage compensation system that equalizes the transcriptional output from X-linked genes between males and females, and the regulation of the 4th chromosome mediated by the POF protein. The best studied of these two mechanisms is the dosage compensation system. To attain dosage compensation in Drosophila at least five different proteins, encoded by the male-specific lethal genes msl1, msl2, msl3, mle and mof, are required. These proteins together with two non-coding RNAs (roX1 and roX2) form a dosage compensation complex (MSL complex), which binds exclusively to the X chromosome in Drosophila males and up-regulates the transcription approximately two times. In this thesis I show that roX1 and roX2 are most likely the only non-coding RNAs within the MSL complex. As expected, the roX transcripts were enriched within the MSL complex. Interestingly, one additional transcript was identified within the MSL complex. This transcript did not associate with the X chromosome and is therefore not believed to be involved in up-regulation of the X-linked genes. This transcript encodes for the rate limiting component in the MSL complex, the MSL2 protein. A model is proposed in which free, partial or complete, MSL complex feed-back regulates the amount of msl2 transcript, and thereby limits the MSL complex production. The second chromosome-wide regulatory system in flies acts on an autosome, the heterochromatic 4th chromosome. This regulation is a balancing mechanism between at least two different proteins, the chromosome 4 specific protein painting of fourth (POF) and heterochromatin protein 1 (HP1). POF binds to nascent RNAs transcribed from the 4th chromosome and HP1 target the same set of genes at the chromatin level. POF stimulates the transcribed genes, while HP1 represses them; together they create the most optimal condition for these genes. This type of balancing mechanism may be a more general way to fine-tune transcription at a chromosome-wide level and raises the question about autosomal gene regulation as a general mechanism.
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| 5. |
- Johansson, Anna-Mia, 1978-, et al.
(författare)
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Genome-wide mapping of Painting of fourth on Drosophila melanogaster salivary gland polytene chromosomes
- 2014
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Ingår i: Genomics Data. - : Elsevier BV. - 2213-5960. ; 2, s. 63-65
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Tidskriftsartikel (refereegranskat)abstract
- The protein Painting of fourth (POF) in Drosophila melanogaster specifically targets and stimulates expression output from the heterochromatic 4th chromosome, thereby representing an autosome specific protein [1,2]. Despite the high specificity for chromosome 4 genes, POF is occasionally observed binding to the cytological region 2L:31 in males and females [3] and two loci on the X-chromosome, PoX1 and PoX2 only in females [4]. Here we provide a detailed description of the experimental design and analysis of the tiling array data presented by Lundberg and colleagues in G3: Genes, Genomes, Genetics 2013 [4], where the female specific POF binding to PoX1 and PoX2 loci on the X chromosome was reported. We show the genome-wide high resolution binding profile of the POF protein where these different POF binding sites are detected. The complete data set is available at http://www.ncbi.nlm.nih.gov/geo/ (accession: GSE45402).
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| 6. |
- Johansson, Anna-Mia, 1978-, et al.
(författare)
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POF Regulates the Expression of Genes on the Fourth Chromosome in Drosophila melanogaster by Binding to Nascent RNA
- 2012
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Ingår i: Molecular and Cellular Biology. - : American Society for Microbiology. - 0270-7306 .- 1098-5549. ; 32:11, s. 2121-2134
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- In Drosophila, two chromosome-wide compensatory systems have been characterized: the dosage compensation system that acts on the male X chromosome and the chromosome-specific regulation of genes located on the heterochromatic fourth chromosome. Dosage compensation in Drosophila is accomplished by hypertranscription of the single male X chromosome mediated by the male-specific lethal (MSL) complex. The mechanism of this compensation is suggested to involve enhanced transcriptional elongation mediated by the MSL complex, while the mechanism of compensation mediated by the painting of fourth (POF) protein on the fourth chromosome has remained elusive. Here, we show that POF binds to nascent RNA, and this binding is associated with increased transcription output from chromosome 4. We also show that genes located in heterochromatic regions spend less time in transition from the site of transcription to the nuclear envelope. These results provide useful insights into the means by which genes in heterochromatic regions can overcome the repressive influence of their hostile environment.
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| 7. |
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| 8. |
- Karlsson, Edvin, et al.
(författare)
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Airborne microbial biodiversity and seasonality in Northern and Southern Sweden
- 2020
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Ingår i: PeerJ. - : PeerJ. - 2167-8359. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Microorganisms are essential constituents of ecosystems. To improve our understanding of how various factors shape microbial diversity and composition in nature it is important to study how microorganisms vary in space and time. Factors shaping microbial communities in ground level air have been surveyed in a limited number of studies, indicating that geographic location, season and local climate influence the microbial communities. However, few have surveyed more than one location, at high latitude or continuously over more than a year. We surveyed the airborne microbial communities over two full consecutive years in Kiruna, in the Arctic boreal zone, and Ljungbyhed, in the Southern nemoral zone of Sweden, by using a unique collection of archived air filters. We mapped both geographic and seasonal differences in bacterial and fungal communities and evaluated environmental factors that may contribute to these differences and found that location, season and weather influence the airborne communities. Location had stronger influence on the bacterial community composition compared to season, while location and season had equal influence on the fungal community composition. However, the airborne bacterial and fungal diversity showed overall the same trend over the seasons, regardless of location, with a peak during the warmer parts of the year, except for the fungal seasonal trend in Ljungbyhed, which fluctuated more within season. Interestingly, the diversity and evenness of the airborne communities were generally lower in Ljungbyhed. In addition, both bacterial and fungal communities varied significantly within and between locations, where orders like Rhizobiales, Rhodospirillales and Agaricales dominated in Kiruna, whereas Bacillales, Clostridiales and Sordariales dominated in Ljungbyhed. These differences are a likely reflection of the landscape surrounding the sampling sites where the landscape in Ljungbyhed is more homogenous and predominantly characterized by artificial and agricultural surroundings. Our results further indicate that local landscape, as well as seasonal variation, shapes microbial communities in air.
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| 9. |
- Lewerentz, Jacob, 1992-, et al.
(författare)
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The path to immortalization of cells starts by managing stress through gene duplications
- 2023
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Ingår i: Experimental Cell Research. - : Elsevier. - 0014-4827 .- 1090-2422. ; 422:1
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Tidskriftsartikel (refereegranskat)abstract
- The genomes of immortalized cell lines (and cancer cells) are characterized by multiple types of aberrations, ranging from single nucleotide polymorphisms (SNPs) to structural rearrangements that have accumulated over time. Consequently, it is difficult to estimate the relative impact of different aberrations, the order of events, and which gene functions were under selective pressure at the early stage towards cellular immortalization. Here, we have established novel cell cultures derived from Drosophila melanogaster embryos that were sampled at multiple time points over a one-year period. Using short-read DNA sequencing, we show that copy-number gain in preferentially stress-related genes were acquired in a dominant fraction of cells in 300-days old cultures. Furthermore, transposable elements were active in cells of all cultures. Only a few (<1%) SNPs could be followed over time, and these showed no trend to increase or decrease. We conclude that the early cellular responses of a novel culture comprise sequence duplication and transposable element activity. During immortalization, positive selection first occurs on genes that are related to stress response before shifting to genes that are related to growth.
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| 10. |
- Lewerentz, Jacob, et al.
(författare)
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Transposon activity, local duplications and propagation of structural variants across haplotypes drive the evolution of the Drosophila S2 cell line
- 2022
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Ingår i: BMC Genomics. - : BioMed Central. - 1471-2164. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Immortalized cell lines are widely used model systems whose genomes are often highly rearranged and polyploid. However, their genome structure is seldom deciphered and is thus not accounted for during analyses. We therefore used linked short- and long-read sequencing to perform haplotype-level reconstruction of the genome of a Drosophila melanogaster cell line (S2-DRSC) with a complex genome structure.Results: Using a custom implementation (that is designed to use ultra-long reads in complex genomes with nested rearrangements) to call structural variants (SVs), we found that the most common SV was repetitive sequence insertion or deletion (> 80% of SVs), with Gypsy retrotransposon insertions dominating. The second most common SV was local sequence duplication. SNPs and other SVs were rarer, but several large chromosomal translocations and mitochondrial genome insertions were observed. Haplotypes were highly similar at the nucleotide level but structurally very different. Insertion SVs existed at various haplotype frequencies and were unlinked on chromosomes, demonstrating that haplotypes have different structures and suggesting the existence of a mechanism that allows SVs to propagate across haplotypes. Finally, using public short-read data, we found that transposable element insertions and local duplications are common in other D. melanogaster cell lines.Conclusions: The S2-DRSC cell line evolved through retrotransposon activity and vast local sequence duplications, that we hypothesize were the products of DNA re-replication events. Additionally, mutations can propagate across haplotypes (possibly explained by mitotic recombination), which enables fine-tuning of mutational impact and prevents accumulation of deleterious events, an inherent problem of clonal reproduction. We conclude that traditional linear homozygous genome representation conceals the complexity when dealing with rearranged and heterozygous clonal cells.
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| 11. |
- Lindell, Ellen, 1979, et al.
(författare)
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Benign paroxysmal positional vertigo, dizziness, and health-related quality of life among older adults in a population-based setting
- 2021
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Ingår i: European Archives of Oto-Rhino-Laryngology. - : Springer Science and Business Media LLC. - 0937-4477 .- 1434-4726. ; 278:5, s. 1637-1644
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Tidskriftsartikel (refereegranskat)abstract
- Purpose Dizziness may affect quality of life in a negative way and contribute to falls. The aim of this study was to investigate and compare 75 years old with dizziness caused by benign paroxysmal positional vertigo (BPPV) to those with general dizziness/impaired balance (non-BPPV related) and to those reporting no dizziness, regarding health-related quality of life (HRQL), falls, tiredness, and walking speed in a population-based setting. Method A cross-sectional population-based sample, including 671 75 years old (398 women, 273 men), was investigated for BPPV, dizziness symptoms, falls, and walking speed. HRQL was assessed using the 36-item Short Form-36 Health Survey (SF-36). Result A total of 67 persons (10%) had symptoms of BPPV with 11 (1.6%) having nystagmus when tested for BPPV. Having BPPV as well as general dizziness/impaired balance was associated with reduced HRQL, more tiredness, enhanced number of falls, and lower walking speed. Furthermore, the risk of having BPPV increased fourfold if symptoms of dizziness when turning in bed was reported. Conclusion Having problems with dizziness is common among senior citizens where BPPV can be an unrecognized cause of dizziness that may impact HRQL and overall well-being. As BPPV is common among older adults, and is potentially curable through reposition maneuvers, it is important to liberally test for, and treat the condition. Information about dizziness when turning in bed can help to pinpoint persons with enhanced risk for BPPV also on a population-based level.
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| 12. |
- Lindell, Ellen, 1979, et al.
(författare)
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Dizziness and its association with walking speed and falls efficacy among older men and women in an urban population
- 2020
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Ingår i: Aging Clinical and Experimental Research. - : Springer Science and Business Media LLC. - 1594-0667 .- 1720-8319. ; 32, s. 1049-1056
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Tidskriftsartikel (refereegranskat)abstract
- © 2019, The Author(s). Background: Dizziness is common among older people and falling is a feared complication. Aim: The purpose of this study was to investigate the presence of dizziness and its association with falls, walking speed and fear of falling, including sex differences, among 79-year-olds. Secondary purposes were to describe the relationship between dizziness and falls to number of medications and diseases. Method: The study consisted of the fifth cohort of Gothenburg’s H70 birth cohort studies. A sample of 662 79-year-olds (404 women, 258 men) were investigated with questions regarding dizziness, previous falls and falls efficacy [estimated according to the falls efficacy scale Swedish version (FES (S))]. Functional tests included self-selected and maximal walking speed over 20m. Results: Dizziness was reported among 51% of the women and by 58% of the men (p = 0.12). Approximately, 40% had fallen during the past 12months (41% women, 38% of the men, p = 0.48). Dizziness was related to a higher risk of falls among women (OR 2.63 (95% CI 1.67−4.14, p < 0.0001), but not among men (OR 1.07, 95% CI 0.63−1.82, p = 0.8). Dizzy individuals had lower scores on FES (S) (p < 0.01), more medications (p < 0.001) and diseases (p < 0.001) than those without dizziness. Participants who reported dizziness walked 10% slower than participants without dizziness (p < 0.001). Conclusion: Women with dizziness more often reported falls compared to women without dizziness—a trend that was not seen among men. Persons with dizziness walked slower. Many medications increased risk of falling; hence, number of medications alone might help pinpoint risk groups for falling.
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| 13. |
- Lundberg, Lina E, 1982-, et al.
(författare)
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Targeting of painting of fourth to roX1 and roX2 proximal sites suggests evolutionary links between dosage compensation and the regulation of the 4th chromosome in Drosophila melanogaster
- 2013
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Ingår i: G3. - : Oxford University Press (OUP). - 2160-1836. ; 3:8, s. 1325-1334
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Tidskriftsartikel (refereegranskat)abstract
- In Drosophila melanogaster, two chromosome-specific targeting and regulatory systems have been described. The male-specific lethal (MSL) complex supports dosage compensation by stimulating gene expression from the male X-chromosome and the protein Painting of fourth (POF) specifically targets and stimulates expression from the heterochromatic 4(th) chromosome. The targeting sites of both systems are well characterized, but the principles underlying the targeting mechanisms have remained elusive. Here we present an original observation, namely that POF specifically targets two loci on the X-chromosome, PoX1 and PoX2 (POF-on-X). PoX1 and PoX2 are located close to the roX1 and roX2 genes, which encode ncRNAs important for the correct targeting and spreading of the MSL-complex. We also found that the targeting of POF to PoX1 and PoX2 is largely dependent on roX expression and identified a high-affinity target region which ectopically recruits POF. The results presented support a model linking the MSL-complex to POF and dosage compensation to regulation of heterochromatin.
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| 14. |
- Zare, Aman, et al.
(författare)
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The gut microbiome participates in transgenerational inheritance of low temperature responses in Drosophila melanogaster
- 2018
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Ingår i: FEBS Letters. - : John Wiley & Sons. - 0014-5793 .- 1873-3468. ; 592:24, s. 4078-4086
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Tidskriftsartikel (refereegranskat)abstract
- Environmental perturbations induce transcriptional changes, some of which may be inherited even in the absence of the initial stimulus. Previous studies have focused on transfers through the germ-line although microbiota is also passed on to the offspring. Thus, we inspected the involvement of the gut microbiome in transgenerational inheritance of environmental exposures in Drosophila melanogaster. We grew flies in the cold versus control temperatures and compared their transcriptional patterns in both conditions as well as in their offspring. F2 flies grew in control temperature while we controlled their microbiota acquisition from either F1 sets. Transcriptional status of some genes was conserved transgenerationally, and a subset of these genes, mainly expressed in the gut, was transcriptionally dependent on the acquired microbiome. This article is protected by copyright. All rights reserved.
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| 15. |
- Ås, Joel, et al.
(författare)
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Whole genome case-control study of central nervous system toxicity due to antimicrobial drugs
- 2024
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 19:2
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Tidskriftsartikel (refereegranskat)abstract
- A genetic predisposition to central nervous system (CNS) toxicity induced by antimicrobial drugs (antibiotics, antivirals, antifungals, and antiparasitic drugs) has been suspected. Whole genome sequencing of 66 cases and 833 controls was performed to investigate whether antimicrobial drug-induced CNS toxicity was associated with genetic variation. The primary objective was to test whether antimicrobial-induced CNS toxicity was associated with seventeen efflux transporters at the blood-brain barrier. In this study, variants or structural elements in efflux transporters were not significantly associated with CNS toxicity. Secondary objectives were to test whether antimicrobial-induced CNS toxicity was associated with genes over the whole genome, with HLA, or with structural genetic variation. Uncommon variants in and close to three genes were significantly associated with CNS toxicity according to a sequence kernel association test combined with an optimal unified test (SKAT-O). These genes were LCP1 (q = 0.013), RETSAT (q = 0.013) and SFMBT2 (q = 0.035). Two variants were driving the LCP1 association: rs6561297 (p = 1.15x10-6, OR: 4.60 [95% CI: 2.51–8.46]) and the regulatory variant rs10492451 (p = 1.15x10-6, OR: 4.60 [95% CI: 2.51–8.46]). No common genetic variant, HLA-type or structural variation was associated with CNS toxicity. In conclusion, CNS toxicity due to antimicrobial drugs was associated with uncommon variants in LCP1, RETSAT and SFMBT2.
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| 16. |
- Ås, Joel, et al.
(författare)
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Whole genome case-control study of central nervous system toxicity due to antimicrobial drugs
- 2024
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Ingår i: PLOS ONE. - : PUBLIC LIBRARY SCIENCE. - 1932-6203. ; 19:2
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Tidskriftsartikel (refereegranskat)abstract
- A genetic predisposition to central nervous system (CNS) toxicity induced by antimicrobial drugs (antibiotics, antivirals, antifungals, and antiparasitic drugs) has been suspected. Whole genome sequencing of 66 cases and 833 controls was performed to investigate whether antimicrobial drug-induced CNS toxicity was associated with genetic variation. The primary objective was to test whether antimicrobial-induced CNS toxicity was associated with seventeen efflux transporters at the blood-brain barrier. In this study, variants or structural elements in efflux transporters were not significantly associated with CNS toxicity. Secondary objectives were to test whether antimicrobial-induced CNS toxicity was associated with genes over the whole genome, with HLA, or with structural genetic variation. Uncommon variants in and close to three genes were significantly associated with CNS toxicity according to a sequence kernel association test combined with an optimal unified test (SKAT-O). These genes were LCP1 (q = 0.013), RETSAT (q = 0.013) and SFMBT2 (q = 0.035). Two variants were driving the LCP1 association: rs6561297 (p = 1.15x10-6, OR: 4.60 [95% CI: 2.51-8.46]) and the regulatory variant rs10492451 (p = 1.15x10-6, OR: 4.60 [95% CI: 2.51-8.46]). No common genetic variant, HLA-type or structural variation was associated with CNS toxicity. In conclusion, CNS toxicity due to antimicrobial drugs was associated with uncommon variants in LCP1, RETSAT and SFMBT2.
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