| 1. |
- Ameur, Adam, et al.
(författare)
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SweGen : a whole-genome data resource of genetic variability in a cross-section of the Swedish population
- 2017
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Ingår i: European Journal of Human Genetics. - : NATURE PUBLISHING GROUP. - 1018-4813 .- 1476-5438. ; 25:11, s. 1253-1260
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Tidskriftsartikel (refereegranskat)abstract
- Here we describe the SweGen data set, a comprehensive map of genetic variation in the Swedish population. These data represent a basic resource for clinical genetics laboratories as well as for sequencing-based association studies by providing information on genetic variant frequencies in a cohort that is well matched to national patient cohorts. To select samples for this study, we first examined the genetic structure of the Swedish population using high-density SNP-array data from a nation-wide cohort of over 10 000 Swedish-born individuals included in the Swedish Twin Registry. A total of 1000 individuals, reflecting a cross-section of the population and capturing the main genetic structure, were selected for whole-genome sequencing. Analysis pipelines were developed for automated alignment, variant calling and quality control of the sequencing data. This resulted in a genome-wide collection of aggregated variant frequencies in the Swedish population that we have made available to the scientific community through the website https://swefreq.nbis.se. A total of 29.2 million single-nucleotide variants and 3.8 million indels were detected in the 1000 samples, with 9.9 million of these variants not present in current databases. Each sample contributed with an average of 7199 individual-specific variants. In addition, an average of 8645 larger structural variants (SVs) were detected per individual, and we demonstrate that the population frequencies of these SVs can be used for efficient filtering analyses. Finally, our results show that the genetic diversity within Sweden is substantial compared with the diversity among continental European populations, underscoring the relevance of establishing a local reference data set.
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| 2. |
- Fasterius, Erik, et al.
(författare)
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A novel RNA sequencing data analysis method for cell line authentication
- 2017
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Ingår i: PLOS ONE. - : PUBLIC LIBRARY SCIENCE. - 1932-6203. ; 12:2
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Tidskriftsartikel (refereegranskat)abstract
- We have developed a novel analysis method that can interrogate the authenticity of biological samples used for generation of transcriptome profiles in public data repositories. The method uses RNA sequencing information to reveal mutations in expressed transcripts and subsequently confirms the identity of analysed cells by comparison with publicly available cell-specific mutational profiles. Cell lines constitute key model systems widely used within cancer research, but their identity needs to be confirmed in order to minimise the influence of cell contaminations and genetic drift on the analysis. Using both public and novel data, we demonstrate the use of RNA-sequencing data analysis for cell line authentication by examining the validity of COLO205, DLD1, HCT15, HCT116, HKE3, HT29 and RKO colorectal cancer cell lines. We successfully authenticate the studied cell lines and validate previous reports indicating that DLD1 and HCT15 are synonymous. We also show that the analysed HKE3 cells harbour an unexpected KRAS-G13D mutation and confirm that this cell line is a genuine KRAS dosage mutant, rather than a true isogenic derivative of HCT116 expressing only the wild type KRAS. This authentication method could be used to revisit the numerous cell line based RNA sequencing experiments available in public data repositories, analyse new experiments where whole genome sequencing is not available, as well as facilitate comparisons of data from different experiments, platforms and laboratories.
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| 3. |
- Franco, Irene, et al.
(författare)
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Somatic mutagenesis in satellite cells associates with human skeletal muscle aging
- 2018
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Human aging is associated with a decline in skeletal muscle (SkM) function and a reduction in the number and activity of satellite cells (SCs), the resident stem cells. To study the connection between SC aging and muscle impairment, we analyze the whole genome of single SC clones of the leg muscle vastus lateralis from healthy individuals of different ages (21-78 years). We find an accumulation rate of 13 somatic mutations per genome per year, consistent with proliferation of SCs in the healthy adult muscle. SkM-expressed genes are protected from mutations, but aging results in an increase in mutations in exons and promoters, targeting genes involved in SC activity and muscle function. In agreement with SC mutations affecting the whole tissue, we detect a missense mutation in a SC propagating to the muscle. Our results suggest somatic mutagenesis in SCs as a driving force in the age-related decline of SkM function.
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| 4. |
- Franco, Irene, et al.
(författare)
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Whole genome DNA sequencing provides an atlas of somatic mutagenesis in healthy human cells and identifies a tumor-prone cell type
- 2019
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Ingår i: Genome Biology. - : Springer Science and Business Media LLC. - 1465-6906 .- 1474-760X. ; 20:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: The lifelong accumulation of somatic mutations underlies age-related phenotypes and cancer. Mutagenic forces are thought to shape the genome of aging cells in a tissue-specific way. Whole genome analyses of somatic mutation patterns, based on both types and genomic distribution of variants, can shed light on specific processes active in different human tissues and their effect on the transition to cancer. Results: To analyze somatic mutation patterns, we compile a comprehensive genetic atlas of somatic mutations in healthy human cells. High-confidence variants are obtained from newly generated and publicly available whole genome DNA sequencing data from single non-cancer cells, clonally expanded in vitro. To enable a well-controlled comparison of different cell types, we obtain single genome data (92% mean coverage) from multi-organ biopsies from the same donors. These data show multiple cell types that are protected from mutagens and display a stereotyped mutation profile, despite their origin from different tissues. Conversely, the same tissue harbors cells with distinct mutation profiles associated to different differentiation states. Analyses of mutation rate in the coding and non-coding portions of the genome identify a cell type bearing a unique mutation pattern characterized by mutation enrichment in active chromatin, regulatory, and transcribed regions. Conclusions: Our analysis of normal cells from healthy donors identifies a somatic mutation landscape that enhances the risk of tumor transformation in a specific cell population from the kidney proximal tubule. This unique pattern is characterized by high rate of mutation accumulation during adult life and specific targeting of expressed genes and regulatory regions.
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| 5. |
- Franklin, Oskar, et al.
(författare)
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Plasma micro-RNA alterations appear late in pancreatic cancer
- 2018
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Ingår i: Annals of Surgery. - 0003-4932 .- 1528-1140. ; 267:4, s. 775-781
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: The aim of this research was to study whether plasma microRNAs (miRNA) can be used for early detection of pancreatic cancer (PC) by analyzing prediagnostic plasma samples collected before a PC diagnosis. Background: PC has a poor prognosis due to late presenting symptoms and early metastasis. Circulating miRNAs are altered in PC at diagnosis but have not been evaluated in a prediagnostic setting. Methods: We first performed an initial screen using a panel of 372 miRNAs in a retrospective case-control cohort that included early-stage PC patients and healthy controls. Significantly altered miRNAs at diagnosis were then measured in an early detection case-control cohort wherein plasma samples in the cases are collected before a PC diagnosis. Carbohydrate antigen 19–9 (Ca 19–9) levels were measured in all samples for comparison. Results: Our initial screen, including 23 stage I-II PC cases and 22 controls, revealed 15 candidate miRNAs that were differentially expressed in plasma samples at PC diagnosis. We combined all 15 miRNAs into a multivariate statistical model, which outperformed Ca 19–9 in receiver-operating characteristics analysis. However, none of the candidate miRNAs, individually or in combination, were significantly altered in prediagnostic plasma samples from 67 future PC patients compared with 132 matched controls. In comparison, Ca 19–9 levels were significantly higher in the cases at <5 years before diagnosis. Conclusion: Plasma miRNAs are altered in PC patients at diagnosis, but the candidate miRNAs found in this study appear late in the course of the disease and cannot be used for early detection of the disease.
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| 6. |
- Helgadottir, Hafdis, et al.
(författare)
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Somatic mutation that affects transcription factor binding upstream of CD55 in the temporal cortex of a late-onset Alzheimer disease patient
- 2019
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 28:16, s. 2675-2685
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease (AD) is the most common neurodegenerative disease worldwide. Familial cases suggest genetic components; however, monogenetic causes are few, and the vast majority of incidences have unknown cause. Sequencing efforts have focused on germline mutations, but improved technology has opened up for studies on somatic mutations in affected brain tissue samples. Here we use ultra-deep sequencing on brain and blood from early-onset AD (EOAD) and late-onset AD (LOAD) patients and non-AD individuals (n = 16). In total, 2.86 Mb of genomic regions, previously associated with AD, were targeted included 28 genes and upstream and downstream regulatory regions. Tailored downstream bioinformatics filtering identified 11 somatic single nucleotide variants in the temporal cortex in AD patients and none in the controls. One variant was validated to be present at 0.4% allele frequency in temporal cortex of a LOAD patient. This variant was predicted to affect transcription factor binding sites upstream of the CD55 gene, contributing to AD pathogenesis by affecting the complement system. Our results suggest that future studies targeting larger portions of the genome for somatic mutation analysis are important to obtain an increased understanding for the molecular basis of both EOAD and LOAD.
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| 7. |
- Li, M., et al.
(författare)
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Model validation and uncertainty analysis in the wear prediction of a wet clutch
- 2016
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Ingår i: Wear. - : Elsevier BV. - 0043-1648 .- 1873-2577. ; 364-365, s. 112-121
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Tidskriftsartikel (refereegranskat)abstract
- An uncertainty quantification analysis is performed to further investigate the nature of the “two-stage” wear process of the paper-based friction lining in a wet clutch. In this approach, the results of a computerized wear prediction model are examined through sensitivity analysis and a model validation that utilizes the Monte Carlo (MC) method. Extensive computational results that take into account the uncertainty and variability in the input data are presented to gain insight into the evolution of temperature and wear during the engagement process.
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| 8. |
- Lundin Kleberg, Johan, et al.
(författare)
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Sex Differences in Social Attention in Infants at Risk for Autism
- 2019
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Ingår i: Journal of autism and developmental disorders. - : Springer Science and Business Media LLC. - 0162-3257 .- 1573-3432. ; 49:4, s. 1342-1351
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Tidskriftsartikel (refereegranskat)abstract
- We studied visual attention to emotional faces in 10-month-old infant siblings of children with ASD (ASD-sibs; N = 70) and a siblings of typically developing children (N = 29) using static stimuli. Contrary to our predictions, we found no evidence for atypical gaze behavior in ASD-sibs when boys and girls were analyzed together. However, a sex difference was found in ASD-sibs' visual attention to the mouth. Male ASD-sibs looked more at the mouth across emotions compared to male controls and female ASD-sibs. In contrast, female ASD-sibs looked less at the mouth compared to female controls. These findings suggest that some aspects of early emerging atypical social attention in ASD-sibs may be sex specific.
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| 9. |
- Lundin, Martin, 1975-, et al.
(författare)
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Kåren och karriären : studentpolitiken som språngbräda
- 2016
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Bok (refereegranskat)abstract
- I den här rapporten undersöker vi om arbetsmarknadsinträdet för studenter vid universitet och högskolor underlättas av att de deltar aktivt i studentkårspolitik. Vi studerar också om sannolikheten att ställa upp som kandidat i allmänna val ökar som en effekt av studentkårsengagemang. Data består av 5 000 kandidater till studentkårsfullmäktige vid universiteten i Uppsala, Lund och Stockholm mellan 1982 och 2005. Med hjälp av en "kvasi-experimentell" forskningsmetod visar vi att deltagande i kårfullmäktiges aktiviteter i hög grad påskyndar inträdet på arbetsmarknaden. Vi finner även att sannolikheten att på tre års sikt få ett välbetalt jobb ökar väsentligt. Däremot tycks alla arbetsmarknadseffekter vara kortlivade. Vidare visar analysen att sannolikheten att kandidera i allmänna val ökar av att väljas in i kårfullmäktige. De politiska effekterna tycks till skillnad från arbetsmarknadseffekterna vara stabila många år efter valet till studentkårsfullmäktige.
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| 10. |
- Lundin, Martin, et al.
(författare)
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Leadership Experiences within Civil Organizations and Candidacy in Public Elections : Causal Evidence from a Quasi-Experimental Approach
- 2016
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Ingår i: Political Behavior. - : Springer Science and Business Media LLC. - 0190-9320 .- 1573-6687. ; 38:2, s. 433-454
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Tidskriftsartikel (refereegranskat)abstract
- Standing as a candidate in public elections has been characterized as the ultimate act of political participation. We test the hypothesis that acquiring office within civil organizations increases the probability of becoming a candidate in public elections. In order to take self-selection problems into account, we provide quasi-experimental evidence using election discontinuities, in which we compare the likelihood of being nominated for public office between closely ranked winners and losers in Swedish student union (SU) elections. Our original data cover 5,000 SU candidates and register data on their candidacies in public elections (1991–2010). The analysis provides support to the hypothesis: Students elected to SU councils were about 34 percent (6 percentage points) more likely to become a candidate in a public election than SU council candidates who were not elected. The causal impact is fairly stable over time. The analysis makes important contributions to two interrelated bodies of literature: First, it provides political recruitment literature with causal evidence that acquiring leadership experiences at arenas outside of representative democratic institutions facilitate entry into election processes. Second, it provides strong evidence to an increasingly contested issue within political participation research by showing that certain organizational activities increase individuals’ political involvement.
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