| 31. |
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| 32. |
- Lundmark, Per E, et al.
(författare)
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Evaluation of HapMap data in six populations of European descent
- 2008
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Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 16:9, s. 1142-1150
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Tidskriftsartikel (refereegranskat)abstract
- We studied how well the European CEU samples used in the Haplotype Mapping Project (HapMap) represent five European populations by analyzing nuclear family samples from the Swedish, Finnish, Dutch, British and Australian (European ancestry) populations. The number of samples from each population (about 30 parent-offspring trios) was similar to that in the HapMap sample sets. A panel of 186 single nucleotide polymorphisms (SNPs) distributed over the 1.5 Mb region of the GRID2 gene on chromosome 4 was genotyped. The genotype data were compared pair-wise between the HapMap sample and the other population samples. Principal component analysis (PCA) was used to cluster the data from different populations with respect to allele frequencies and to define the markers responsible for observed variance. The only sample with detectable differences in allele frequencies was that from Kuusamo, Finland. This sample also separated from the others, including the other Finnish sample, in the PCA analysis. A set of tagSNPs was defined based on the HapMap data and applied to the samples. The tagSNPs were found to capture the genetic variation in the analyzed region at r(2)>0.8 at levels ranging from 95% in the Kuusamo sample to 87% in the Australian sample. To capture the maximal genetic variation in the region, the Kuusamo, HapMap and Australian samples required 58, 63 and 73 native tagSNPs, respectively. The HapMap CEU sample represents the European samples well for tagSNP selection, with some caution regarding estimation of allele frequencies in the Finnish Kuusamo sample, and a slight reduction in tagging efficiency in the Australian sample.
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| 33. |
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| 34. |
- Lysenkova Wiklander, Mariya, et al.
(författare)
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Genomic, transcriptomic and epigenomic sequencing data of the B-cell leukemia cell line REH
- 2023
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Ingår i: BMC Research Notes. - : BioMed Central (BMC). - 1756-0500. ; 16:1
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Tidskriftsartikel (refereegranskat)abstract
- ObjectivesThe aim of this data paper is to describe a collection of 33 genomic, transcriptomic and epigenomic sequencing datasets of the B-cell acute lymphoblastic leukemia (ALL) cell line REH. REH is one of the most frequently used cell lines for functional studies of pediatric ALL, and these data provide a multi-faceted characterization of its molecular features. The datasets described herein, generated with short- and long-read sequencing technologies, can both provide insights into the complex aberrant karyotype of REH, and be used as reference datasets for sequencing data quality assessment or for methods development.Data descriptionThis paper describes 33 datasets corresponding to 867 gigabases of raw sequencing data generated from the REH cell line. These datasets include five different approaches for whole genome sequencing (WGS) on four sequencing platforms, two RNA sequencing (RNA-seq) techniques on two different sequencing platforms, DNA methylation sequencing, and single-cell ATAC-sequencing.
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| 35. |
- McEvoy, Brian P., et al.
(författare)
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Geographical structure and differential natural selection among North European populations
- 2009
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Ingår i: Genome Research. - : Cold Spring Harbor Laboratory. - 1088-9051 .- 1549-5469. ; 19:5, s. 804-814
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Tidskriftsartikel (refereegranskat)abstract
- Population structure can provide novel insight into the human past, and recognizing and correcting for such stratification is a practical concern in gene mapping by many association methodologies. We investigate these patterns, primarily through principal component (PC) analysis of whole genome SNP polymorphism, in 2099 individuals from populations of Northern European origin (Ireland, United Kingdom, Netherlands, Denmark, Sweden, Finland, Australia, and HapMap European-American). The major trends (PC1 and PC2) demonstrate an ability to detect geographic substructure, even over a small area like the British Isles, and this information can then be applied to finely dissect the ancestry of the European-Australian and European-American samples. They simultaneously point to the importance of considering population stratification in what might be considered a small homogeneous region. There is evidence from FST-based analysis of genic and nongenic SNPs that differential positive selection has operated across these populations despite their short divergence time and relatively similar geographic and environmental range. The pressure appears to have been focused on genes involved in immunity, perhaps reflecting response to infectious disease epidemic. Such an event may explain a striking selective sweep centered on the rs2508049-G allele, close to the HLA-G gene on chromosome 6. Evidence of the sweep extends over a 8-Mb/3.5-cM region. Overall, the results illustrate the power of dense genotype and sample data to explore regional population variation, the events that have crafted it, and their implications in both explaining disease prevalence and mapping these genes by association.
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| 36. |
- Pullabhatla, Venu, et al.
(författare)
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De novo mutations implicate novel genes in systemic lupus erythematosus
- 2018
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Ingår i: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 27:3, s. 421-429
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Tidskriftsartikel (refereegranskat)abstract
- The omnigenic model of complex disease stipulates that the majority of the heritability will be explained by the effects of common variation on genes in the periphery of core disease pathways. Rare variant associations, expected to explain far less of the heritability, may be enriched in core disease genes and thus will be instrumental in the understanding of complex disease pathogenesis and their potential therapeutic targets. Here, using complementary whole-exome sequencing, high-density imputation, and in vitro cellular assays, we identify candidate core genes in the pathogenesis of systemic lupus erythematosus (SLE). Using extreme-phenotype sampling, we sequenced the exomes of 30 SLE parent-affected-offspring trios and identified 14 genes with missense de novo mutations (DNM), none of which are within the >80 SLE susceptibility loci implicated through genome-wide association studies. In a follow-up cohort of 10, 995 individuals of matched European ancestry, we imputed genotype data to the density of the combined UK10K-1000 genomes Phase III reference panel across the 14 candidate genes. Gene-level analyses indicate three functional candidates: DNMT3A, PRKCD, and C1QTNF4. We identify a burden of rare variants across PRKCD associated with SLE risk (P = 0.0028), and across DNMT3A associated with two severe disease prognosis sub-phenotypes (P = 0.0005 and P = 0.0033). We further characterise the TNF-dependent functions of the third candidate gene C1QTNF4 on NF-kappa B activation and apoptosis, which are inhibited by the p.His198Gln DNM. Our results identify three novel genes in SLE susceptibility and support extreme-phenotype sampling and DNM gene discovery to aid the search for core disease genes implicated through rare variation.
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| 37. |
- Raine, Amanda, et al.
(författare)
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Data quality of whole genome bisulfite sequencing on Illumina platforms
- 2018
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 13:4
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Tidskriftsartikel (refereegranskat)abstract
- The powerful HiSeq X sequencers with their patterned flowcell technology and fast turnaround times are instrumental for many large-scale genomic and epigenomic studies. However, assessment of DNA methylation by sodium bisulfite treatment results in sequencing libraries of low diversity, which may impact data quality and yield. In this report we assess the quality of WGBS data generated on the HiSeq X system in comparison with data generated on the HiSeq 2500 system and the newly released NovaSeq system. We report a systematic issue with low basecall quality scores assigned to guanines in the second read of WGBS when using certain Real Time Analysis (RTA) software versions on the HiSeq X sequencer, reminiscent of an issue that was previously reported with certain HiSeq 2500 software versions. However, with the HD.3.4.0 /RTA 2.7.7 software upgrade for the HiSeq X system, we observed an overall improved quality and yield of the WGBS data generated, which in turn empowers cost-effective and high quality DNA methylation studies.
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| 38. |
- Sawcer, Stephen, et al.
(författare)
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Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis
- 2011
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 476:7359, s. 214-219
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Tidskriftsartikel (refereegranskat)abstract
- Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
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| 39. |
- Sehat, Bita, et al.
(författare)
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SUMOylation Mediates the Nuclear Translocation and Signaling of the IGF-1 Receptor
- 2010
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Ingår i: Science Signaling. - : American Association for the Advancement of Science (AAAS). - 1945-0877 .- 1937-9145. ; 3:108
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Tidskriftsartikel (refereegranskat)abstract
- The insulin-like growth factor 1 receptor (IGF-1R) plays crucial roles in developmental and cancer biology. Most of its biological effects have been ascribed to its tyrosine kinase activity, which propagates signaling through the phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways. Here, we report that IGF-1 promotes the modification of IGF-1R by small ubiquitin-like modifier protein-1 (SUMO-1) and its translocation to the nucleus. Nuclear IGF-1R associated with enhancer-like elements and increased transcription in reporter assays. The SUMOylation sites of IGF-1R were identified as three evolutionarily conserved lysine residues-Lys(1025), Lys(1100), and Lys(1120)-in the beta subunit of the receptor. Mutation of these SUMO-1 sites abolished the ability of IGF-1R to translocate to the nucleus and activate transcription, but did not alter its kinase-dependent signaling. Thus, we demonstrate a SUMOylation-mediated mechanism of IGF-1R signaling that has potential implications for gene regulation.
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| 40. |
- Sigurdsson, Snaevar, et al.
(författare)
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Association of a Haplotype in the Promoter Region of the Interferon Regulatory Factor 5 Gene With Rheumatoid Arthritis
- 2007
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 56:7, s. 2202-2210
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Tidskriftsartikel (refereegranskat)abstract
- Objective. To determine whether genetic variants of the interferon regulatory factor 5 (IRF-5) and Tyk-2 genes are associated with rheumatoid arthritis (RA). Methods. Five single-nucleotide polymorphisms (SNPs) in IRF5 and 3 SNPs in Tyk2 were analyzed in a Swedish cohort of 1,530 patients with RA and 881 controls. A replication study was performed in a Dutch cohort of 387 patients with RA and 181 controls. All patient sera were tested for the presence of autoantibodies against cyclic citrullinated peptides (anti-CCP). Results. Four of the 5 SNPs located in the 5' region of IRF5 were associated with RA, while no association was observed with the Tyk2 SNPs. The minor alleles of 3 of the IRF5 SNPs, which were in linkage disequilibrium and formed a relatively common haplotype with a frequency of ∼0.33, appeared to confer protection against RA. Although these disease associations were seen in the entire patient group, they were mainly found in RA patients who were negative for anti-CCP. A suggestive association of IRF5 SNPs with anti-CCP-negative RA was also observed in the Dutch cohort. Conclusion. Given the fact that anti-CCP-negative RA differs from anti-CCP-positive RA with respect to genetic and environmental risk factor profiles, our results indicate that genetic variants of IRF5 contribute to a unique disease etiology and pathogenesis in anti-CCP-negative RA.
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