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- 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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- Screaton, E., et al.
(författare)
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Interactions between deformation and fluids in the frontal thrust region of the NanTroSEIZE transect offshore the Kii Peninsula, Japan : Results from IODP Expedition 316 Sites C0006 and C0007
- 2009
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Ingår i: Geochemistry Geophysics Geosystems. - 1525-2027. ; 10, s. Q0AD01-
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Tidskriftsartikel (refereegranskat)abstract
- Integrated Ocean Drilling Program (IODP) Expedition 316 Sites C0006 and C0007 examined the deformation front of the Nankai accretionary prism offshore the Kii Peninsula, Japan. In the drilling area, the frontal thrust shows unusual behavior as compared to other regions of the Nankai Trough. Drilling results, integrated with observations from seismic reflection profiles, suggest that the frontal thrust has been active since similar to 0.78-0.436 Ma and accommodated similar to 13 to 34% of the estimated plate convergence during that time. The remainder has likely been distributed among out-of-sequence thrusts further landward and/or accommodated through diffuse shortening. Unlike results of previous drilling on the Nankai margin, porosity data provide no indication of undercompaction beneath thrust faults. Furthermore, pore water geochemistry data lack clear indicators of fluid flow from depth. These differences may be related to coarser material with higher permeability or more complex patterns of faulting that could potentially provide more avenues for fluid escape. In turn, fluid pressures may affect deformation. Well-drained, sand-rich material under the frontal thrust could have increased fault strength and helped to maintain a large taper angle near the toe. Recent resumption of normal frontal imbrication is inferred from seismic reflection data. Associated decollement propagation into weaker sediments at depth may help explain evidence for recent slope failures within the frontal thrust region. This evidence consists of seafloor bathymetry, normal faults documented in cores, and low porosities in near surface sediments that suggest removal of overlying material. Overall, results provide insight into the complex interactions between incoming materials, deformation, and fluids in the frontal thrust region.
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- Skelton, A., et al.
(författare)
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Hydrochemical Changes Before and After Earthquakes Based on Long-Term Measurements of Multiple Parameters at Two Sites in Northern IcelandA Review
- 2019
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Ingår i: Journal of Geophysical Research-Solid Earth. - : American Geophysical Union (AGU). - 2169-9313 .- 2169-9356. ; 124:3, s. 2702-2720
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Tidskriftsartikel (refereegranskat)abstract
- Hydrochemical changes before and after earthquakes have been reported for over 50years. However, few reports provide sufficient data for an association to be verified statistically. Also, no mechanism has been proposed to explain why hydrochemical changes are observed far from earthquake foci where associated strains are small (<10(-8)). Here we address these challenges based on time series of multiple hydrochemical parameters from two sites in northern Iceland. We report hydrochemical changes before and after M >5 earthquakes in 2002, 2012, and 2013. The longevity of the time series (10 and 16years) permits statistical verification of coupling between hydrochemical changes and earthquakes. We used a Student t test to find significant hydrochemical changes and a binomial test to confirm association with earthquakes. Probable association was confirmed for preseismic changes based on five parameters (Na, Si, K, O-18, and H-2) and postseismic changes based on eight parameters (Ca, Na, Si, Cl, F, SO4, O-18, and H-2). Using concentration ratios and stable isotope values, we showed that (1) gradual preseismic changes were caused by source mixing, which resulted in a shift from equilibrium and triggered water-rock interaction; (2) postseismic changes were caused by rapid source mixing; and (3) longer-term hydrochemical changes were caused by source mixing and mineral growth. Because hydrochemical changes occur at small earthquake-related strains, we attribute source mixing and water-rock interaction to microscale fracturing. Because fracture density and size scale inversely, we infer that mixing of nearby sources and water-rock interaction are feasible responses to small earthquake-related strains. Plain Language Summary Changes in groundwater chemistry before and after earthquakes have been reported for over 50years. However, few studies have been able to prove that the earthquakes caused these changes. Also, no study has explained why these changes are often reported far from where the earthquake occurred. Here we address these challenges based on measurements of groundwater chemistry made at two sites in northern Iceland over time periods of 10 and 16years. We used statistical methods to prove that the earthquakes caused changes of ground water chemistry both before and after the earthquakes. We showed that changes of groundwater chemistry before earthquakes were caused by slow mixing between different groundwaters, which triggered reactions with the wall rock that changed groundwater chemistry, and that changes of groundwater chemistry after earthquakes were causes by rapid mixing between different groundwaters. That these changes were detected far from where the earthquakes occurred suggests that cracking of the wall rock at a very small scale was all that was needed for mixing of different groundwaters and reactions with the wall rock to occur.
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- Xiao, Wenming, et al.
(författare)
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Toward best practice in cancer mutation detection with whole-genome and whole-exome sequencing
- 2021
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Ingår i: Nature Biotechnology. - : Springer Nature. - 1087-0156 .- 1546-1696. ; 39:9, s. 1141-1150
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Tidskriftsartikel (refereegranskat)abstract
- Recommendations are given on optimal read coverage and selection of calling algorithm to maximize the reproducibility of cancer mutation detection in whole-genome or whole-exome sequencing. 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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