We're thrilled to announce that we have now transitioned to exclusively using the data delivery system Data Delivery System (DDS) for all our data deliveries. DDS will now be our default system, streamlining our processes and enhancing our service.
We’re thrilled to announce that we have now transitioned to exclusively using the data delivery system Data Delivery System (DDS) for all our data deliveries. Starting today, DDS will be our default system, streamlining our processes and enhancing our service.
Since November 1 we’ve been experiencing technical issues with the NGI order page. There is a major service disruption affecting several IT-systems hosted by the SciLifeLab Data Centre and they are currently working on solving the problem.
We’re really sorry for any trouble this may cause you!
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A novel unstable duplication upstream of HAS2 predisposes to a breed-defining skin phenotype and a periodic fever syndrome in Chinese Shar-Pei dogs.
M Olsson, JRS Meadows, K Truvé, G Rosengren Pielberg, F Puppo, E Mauceli, J Quilez, N Tonomura, G Zanna, MJ Docampo, A Bassols, AC Avery, EK Karlsson, A Thomas, DL Kastner, E Bongcam-Rudloff, MT Webster, A Sanchez, A Hedhammar, EF Remmers, L Andersson, L Ferrer, L Tintle, K Lindblad-Toh
PLoS Genet., 7 (3) 1553-7404 (2011)
Hereditary periodic fever syndromes are characterized by recurrent episodes of fever and inflammation with no known pathogenic or autoimmune cause. In humans, several genes have been implicated in this group of diseases, but the majority of cases remain unexplained. A similar periodic fever syndrome is relatively frequent in the Chinese Shar-Pei breed of dogs. In the western world, Shar-Pei have been strongly selected for a distinctive thick and heavily folded skin. In this study, a mutation affecting both these traits was identified. Using genome-wide SNP analysis of Shar-Pei and other breeds, the strongest signal of a breed-specific selective sweep was located on chromosome 13. The same region also harbored the strongest genome-wide association (GWA) signal for susceptibility to the periodic fever syndrome (p(raw) = 2.3 × 10⁻⁶, p(genome) = 0.01). Dense targeted resequencing revealed two partially overlapping duplications, 14.3 Kb and 16.1 Kb in size, unique to Shar-Pei and upstream of the Hyaluronic Acid Synthase 2 (HAS2) gene. HAS2 encodes the rate-limiting enzyme synthesizing hyaluronan (HA), a major component of the skin. HA is up-regulated and accumulates in the thickened skin of Shar-Pei. A high copy number of the 16.1 Kb duplication was associated with an increased expression of HAS2 as well as the periodic fever syndrome (p < 0.0001). When fragmented, HA can act as a trigger of the innate immune system and stimulate sterile fever and inflammation. The strong selection for the skin phenotype therefore appears to enrich for a pleiotropic mutation predisposing these dogs to a periodic fever syndrome. The identification of HA as a major risk factor for this canine disease raises the potential of this glycosaminoglycan as a risk factor for human periodic fevers and as an important driver of chronic inflammation.
Clonostachysrosea is a mycoparasitic fungal species that is an efficient biocontrol agent against many plant diseases. During mycoparasitic interactions, one of the most crucial steps is the hydrolysis of the prey's fungal cell wall, which mainly consists of glucans, glycoproteins and chitin. Chitinases are hydrolytic enzymes responsible for chitin degradation and it is suggested that they play an important role in fungal-fungal interactions. Fungal chitinases belong exclusively to the glycoside hydrolase (GH) family 18.These GH18 proteins are categorized into three distinct phylogenetic groups (A, B and C), subdivided into several subgroups. In this study, we identified 14 GH18 genes in the C. rosea genome, which is remarkably low compared with the high numbers found in mycoparasitic Trichoderma species. Phylogenetic analysis revealed that C. rosea contains eight genes in group A, two genes in group B, two genes in group C, one gene encoding a putative ENGase (endo-β-N-acetylglucosaminidase) and the ech37 gene, which is of bacterial origin. Gene expression analysis showed that only two genes had higher transcription levels during fungal-fungal interactions, while eight out of 14 GH18 genes were triggered by chitin. Furthermore, deletion of the C group chiC2 gene decreased the growth inhibitory activity of C. rosea culture filtrates against Botrytis cinerea and Rhizoctonia solani, although the biocontrol ability of C. rosea against B. cinerea was not affected. In addition, a potential role of the CHIC2 chitinase in the sporulation process was revealed. These results provide new information about the role of GH18 proteins in mycoparasitic interactions.
Rare variant analysis in eczema identifies exonic variants in DUSP1, NOTCH4 and SLC9A4.
S Grosche, I Marenholz, J Esparza-Gordillo, A Arnau-Soler, E Pairo-Castineira, F Rüschendorf, TS Ahluwalia, C Almqvist, A Arnold, Australian Asthma Genetics Consortium (AAGC), H Baurecht, H Bisgaard, K Bønnelykke, SJ Brown, M Bustamante, JA Curtin, A Custovic, SC Dharmage, A Esplugues, M Falchi, D Fernandez-Orth, MAR Ferreira, A Franke, S Gerdes, C Gieger, H Hakonarson, PG Holt, G Homuth, N Hubner, PG Hysi, M Jarvelin, R Karlsson, GH Koppelman, S Lau, M Lutz, PKE Magnusson, GB Marks, M Müller-Nurasyid, MM Nöthen, L Paternoster, CE Pennell, A Peters, K Rawlik, CF Robertson, E Rodriguez, S Sebert, A Simpson, PMA Sleiman, M Standl, D Stölzl, K Strauch, A Szwajda, A Tenesa, PJ Thompson, V Ullemar, A Visconti, JM Vonk, CA Wang, S Weidinger, M Wielscher, CL Worth, C Xu, Y Lee
Nat Commun, 12 (1) 2041-1723 (2021)
Previous genome-wide association studies revealed multiple common variants involved in eczema but the role of rare variants remains to be elucidated. Here, we investigate the role of rare variants in eczema susceptibility. We meta-analyze 21 study populations including 20,016 eczema cases and 380,433 controls. Rare variants are imputed with high accuracy using large population-based reference panels. We identify rare exonic variants in DUSP1, NOTCH4, and SLC9A4 to be associated with eczema. In DUSP1 and NOTCH4 missense variants are predicted to impact conserved functional domains. In addition, five novel common variants at SATB1-AS1/KCNH8, TRIB1/LINC00861, ZBTB1, TBX21/OSBPL7, and CSF2RB are discovered. While genes prioritized based on rare variants are significantly up-regulated in the skin, common variants point to immune cell function. Over 20% of the single nucleotide variant-based heritability is attributable to rare and low-frequency variants. The identified rare/low-frequency variants located in functional protein domains point to promising targets for novel therapeutic approaches to eczema.
Ageing desexualizes the Drosophila brain transcriptome.
A Malacrinò, MI Brengdahl, CM Kimber, A Mital, VN Shenoi, C Mirabello, U Friberg
Proc. Biol. Sci., 289 (1980) 1471-2954 (2022)
General evolutionary theory predicts that individuals in low condition should invest less in sexual traits compared to individuals in high condition. Whether this positive association between condition and investment also holds between young (high condition) and senesced (low condition) individuals is however less clear, since elevated investment into reproduction may be beneficial when individuals approach the end of their life. To address how investment into sexual traits changes with age, we study genes with sex-biased expression in the brain, the tissue from which sexual behaviours are directed. Across two distinct populations of Drosophila melanogaster, we find that old brains display fewer sex-biased genes, and that expression of both male-biased and female-biased genes converges towards a sexually intermediate phenotype owing to changes in both sexes with age. We further find that sex-biased genes in general show heightened age-dependent expression in comparison to unbiased genes and that age-related changes in the sexual brain transcriptome are commonly larger in males than females. Our results hence show that ageing causes a desexualization of the fruit fly brain transcriptome and that this change mirrors the general prediction that low condition individuals should invest less in sexual phenotypes.
Transcriptional responses in Parascaris univalens after in vitro exposure to ivermectin, pyrantel citrate and thiabendazole.
F Martin, F Dube, O Karlsson Lindsjö, M Eydal, J Höglund, TF Bergström, E Tydén
Parasit Vectors, 13 (1) 1756-3305 (2020)
Parascaris univalens is a pathogenic parasite of foals and yearlings worldwide. In recent years, Parascaris spp. worms have developed resistance to several of the commonly used anthelmintics, though currently the mechanisms behind this development are unknown. The aim of this study was to investigate the transcriptional responses in adult P. univalens worms after in vitro exposure to different concentrations of three anthelmintic drugs, focusing on drug targets and drug metabolising pathways.
Adult worms were collected from the intestines of two foals at slaughter. The foals were naturally infected and had never been treated with anthelmintics. Worms were incubated in cell culture media containing different concentrations of either ivermectin (10-9 M, 10-11 M, 10-13 M), pyrantel citrate (10-6 M, 10-8 M, 10-10 M), thiabendazole (10-5 M, 10-7 M, 10-9 M) or without anthelmintics (control) at 37 °C for 24 h. After incubation, the viability of the worms was assessed and RNA extracted from the anterior region of 36 worms and sequenced on an Illumina NovaSeq 6000 system.
All worms were alive at the end of the incubation but showed varying degrees of viability depending on the drug and concentration used. Differential expression (Padj < 0.05 and log2 fold change ≥ 1 or ≤ - 1) analysis showed similarities and differences in the transcriptional response after exposure to the different drug classes. Candidate genes upregulated or downregulated in drug exposed worms include members of the phase I metabolic pathway short-chain dehydrogenase/reductase superfamily (SDR), flavin containing monooxygenase superfamily (FMO) and cytochrome P450-family (CYP), as well as members of the membrane transporters major facilitator superfamily (MFS) and solute carrier superfamily (SLC). Generally, different targets of the anthelmintics used were found to be upregulated and downregulated in an unspecific pattern after drug exposure, apart from the GABA receptor subunit lgc-37, which was upregulated only in worms exposed to 10-9 M of ivermectin.
To our knowledge, this is the first time the expression of lgc-37 and members of the FMO, SDR, MFS and SLC superfamilies have been described in P. univalens and future work should be focused on characterising these candidate genes to further explore their potential involvement in drug metabolism and anthelmintic resistance.
Increasing evidence suggests an epigenetic contribution to the pathogenesis of autoimmune diseases, including primary Sjögren's Syndrome (pSS). The aim of this study was to investigate the role of DNA methylation in pSS by analysing multiple tissues from patients and controls.
Genome-wide DNA methylation profiles were generated using HumanMethylation450K BeadChips for whole blood, CD19+ B cells and minor salivary gland biopsies. Gene expression was analysed in CD19+ B cells by RNA-sequencing. Analysis of genetic regulatory effects on DNA methylation at known pSS risk loci was performed.
We identified prominent hypomethylation of interferon (IFN)-regulated genes in whole blood and CD19+ B cells, including at the genes MX1, IFI44L and PARP9, replicating previous reports in pSS, as well as identifying a large number of novel associations. Enrichment for genomic overlap with histone marks for enhancer and promoter regions was observed. We showed for the first time that hypomethylation of IFN-regulated genes in pSS B cells was associated with their increased expression. In minor salivary gland biopsies we observed hypomethylation of the IFN-induced gene OAS2. Pathway and disease analysis resulted in enrichment of antigen presentation, IFN signalling and lymphoproliferative disorders. Evidence for genetic control of methylation levels at known pSS risk loci was observed.
Our study highlights the role of epigenetic regulation of IFN-induced genes in pSS where replication is needed for novel findings. The association with altered gene expression suggests a functional mechanism for differentially methylated CpG sites in pSS aetiology.
Toward best practice in cancer mutation detection with whole-genome and whole-exome sequencing.
W Xiao, L Ren, Z Chen, LT Fang, Y Zhao, J Lack, M Guan, B Zhu, E Jaeger, L Kerrigan, TM Blomquist, T Hung, M Sultan, K Idler, C Lu, A Scherer, R Kusko, M Moos, C Xiao, ST Sherry, OD Abaan, W Chen, X Chen, J Nordlund, U Liljedahl, R Maestro, M Polano, J Drabek, P Vojta, S Kõks, E Reimann, BS Madala, T Mercer, C Miller, H Jacob, T Truong, A Moshrefi, A Natarajan, A Granat, GP Schroth, R Kalamegham, E Peters, V Petitjean, A Walton, TW Shen, K Talsania, CJ Vera, K Langenbach, M de Mars, JA Hipp, JC Willey, J Wang, J Shetty, Y Kriga, A Raziuddin, B Tran, Y Zheng, Y Yu, M Cam, P Jailwala, C Nguyen, D Meerzaman, Q Chen, C Yan, B Ernest, U Mehra, RV Jensen, W Jones, JL Li, BN Papas, M Pirooznia, YC Chen, F Seifuddin, Z Li, X Liu, W Resch, J Wang, L Wu, G Yavas, C Miles, B Ning, W Tong, CE Mason, E Donaldson, S Lababidi, LM Staudt, Z Tezak, H Hong, C Wang, L Shi
Clinical applications of precision oncology require accurate tests that can distinguish true cancer-specific mutations from errors introduced at each step of next-generation sequencing (NGS). To date, no bulk sequencing study has addressed the effects of cross-site reproducibility, nor the biological, technical and computational factors that influence variant identification. Here we report a systematic interrogation of somatic mutations in paired tumor-normal cell lines to identify factors affecting detection reproducibility and accuracy at six different centers. Using whole-genome sequencing (WGS) and whole-exome sequencing (WES), we evaluated the reproducibility of different sample types with varying input amount and tumor purity, and multiple library construction protocols, followed by processing with nine bioinformatics pipelines. We found that read coverage and callers affected both WGS and WES reproducibility, but WES performance was influenced by insert fragment size, genomic copy content and the global imbalance score (GIV; G > T/C > A). Finally, taking into account library preparation protocol, tumor content, read coverage and bioinformatics processes concomitantly, we recommend actionable practices to improve the reproducibility and accuracy of NGS experiments for cancer mutation detection.
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