Loss-of-function mutations cause many mendelian diseases. Here we aimed to create a catalog of autosomal genes that are completely knocked out in humans by rare loss-of-function mutations. We ...sequenced the whole genomes of 2,636 Icelanders and imputed the sequence variants identified in this set into 101,584 additional chip-genotyped and phased Icelanders. We found a total of 6,795 autosomal loss-of-function SNPs and indels in 4,924 genes. Of the genotyped Icelanders, 7.7% are homozygotes or compound heterozygotes for loss-of-function mutations with a minor allele frequency (MAF) below 2% in 1,171 genes (complete knockouts). Genes that are highly expressed in the brain are less often completely knocked out than other genes. Homozygous loss-of-function offspring of two heterozygous parents occurred less frequently than expected (deficit of 136 per 10,000 transmissions for variants with MAF <2%, 95% confidence interval (CI) = 10-261).
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
Meiotic recombination involves a combination of gene conversion and crossover events that, along with mutations, produce germline genetic diversity. Here we report the discovery of 3,176 SNP and 61 ...indel gene conversions. Our estimate of the non-crossover (NCO) gene conversion rate (G) is 7.0 for SNPs and 5.8 for indels per megabase per generation, and the GC bias is 67.6%. For indels, we demonstrate a 65.6% preference for the shorter allele. NCO gene conversions from mothers are longer than those from fathers, and G is 2.17 times greater in mothers. Notably, G increases with the age of mothers, but not the age of fathers. A disproportionate number of NCO gene conversions in older mothers occur outside double-strand break (DSB) regions and in regions with relatively low GC content. This points to age-related changes in the mechanisms of meiotic gene conversion in oocytes.
Long-read sequencing can enable the detection of base modifications, such as CpG methylation, in single molecules of DNA. The most commonly used methods for long-read sequencing are nanopore ...developed by Oxford Nanopore Technologies (ONT) and single molecule real-time (SMRT) sequencing developed by Pacific Bioscience (PacBio). In this study, we systematically compare the performance of CpG methylation detection from long-read sequencing.
We demonstrate that CpG methylation detection from 7179 nanopore-sequenced DNA samples is highly accurate and consistent with 132 oxidative bisulfite-sequenced (oxBS) samples, isolated from the same blood draws. We introduce quality filters for CpGs that further enhance the accuracy of CpG methylation detection from nanopore-sequenced DNA, while removing at most 30% of CpGs. We evaluate the per-site performance of CpG methylation detection across different genomic features and CpG methylation rates and demonstrate how the latest R10.4 flowcell chemistry and base-calling algorithms improve methylation detection from nanopore sequencing. Additionally, we show how the methylation detection of 50 SMRT-sequenced genomes compares to nanopore sequencing and oxBS.
This study provides the first systematic comparison of CpG methylation detection tools for long-read sequencing methods. We compare two commonly used computational methods for the detection of CpG methylation in a large number of nanopore genomes, including samples sequenced using the latest R10.4 nanopore flowcell chemistry and 50 SMRT sequenced samples. We provide insights into the strengths and limitations of each sequencing method as well as recommendations for standardization and evaluation of tools designed for genome-scale modified base detection using long-read sequencing.
We conducted a genome-wide association scan (GWAS) of endometriosis using 25.5 million sequence variants detected through whole-genome sequencing (WGS) of 8,453 Icelanders and imputed into 1,840 ...cases and 129,016 control women, followed by testing of associated variants in Danish samples. Here we report the discovery of a new endometriosis susceptibility locus on 4q12 (rs17773813G, OR=1.28; P=3.8 × 10(-11)), upstream of KDR encoding vascular endothelial growth factor receptor 2 (VEGFR2). The variant correlates with disease severity (P=0.0046) when moderate/severe endometriosis cases are tested against minimal/mild cases. We further report association of rs519664T in TTC39B on 9p22 with endometriosis (P=4.8 × 10(-10); OR=1.29). The involvement of KDR in endometriosis risk highlights the importance of the VEGF pathway in the pathogenesis of the disease.
Gene expression profiles were examined in freshly isolated peripheral blood mononuclear cells (PBMC) from two independent cohorts (training and test sets) of glucocorticoid (GC)-sensitive (n = 64) ...and GC-resistant (n = 42) asthma patients in search of genes that accurately predict responders and nonresponders to inhaled corticosteroids. A total of 11,812 genes were examined with high-density oligonucleotide microarrays in both resting PBMC (106 patients) and cells treated in vitro with IL-1β and TNF-α combined (88 patients), with or without GC. A total of 5,011 genes were expressed at significant levels in the PBMC, and 1,334 of those were notably up-regulated or down-regulated by IL-1β/TNF-α treatment. The expression changes of 923 genes were significantly reversed in GC responders in the presence of GC. The expression pattern of 15 of these 923 genes that most accurately separated GC responders (n = 26) from the nonresponders (n = 18) in the training set, based on the weighted voting algorithm, predicted the independent test set of equal size with 84% accuracy. The expression accuracy of these genes was confirmed by real-time-quantitative PCR, wherein 11 of the 15 genes predicted GC sensitivity at baseline with 84% accuracy, with one gene predicting at 81% in an independent cohort of 79 patients. We conclude that we have uncovered gene expression profiles in PBMC that predict clinical response to inhaled GC therapy with meaningful accuracy. Upon validation in an independent study, these results support the development of a diagnostic test to guide GC therapy in asthma patients.
Since modern refrigeration technologies were introduced in the early
19
th
century, their use has significantly increased. In fact it is now almost impossible imagine life without refrigeration and ...air conditioning. Currently, cooling is primarily achieved with vapor compression machines that use a specific refrigerant that can be tailored to any required temperature level. To achieve these properties, blends of hydrogen, carbon, fluorine and chlorine in various mixing ratios are utilized. Depending on those ratios, the refrigerant exhibits a specific set of properties in regard to refrigeration, but also a global warming potential and an ozone depletion potential. Since the adverse effects of those substances have been discovered, the field of refrigeration is moving away from conventional refrigerants, constantly searching for better alternatives. Thermoacoustic refrigeration is such an alternative that can provide cooling to essentially any required temperature level without using any environmentally harmful substances. It is a niche technology that can be expanded into a broader market, primarily if the sizing problem can be solved. Currently, the most efficient thermoacoustic refrigerators are used in industrial settings. As an example, this work illustrates the benefits of this technology with a consideration of its Total Equivalent Warming Impact (TEWI) compared to conventional cooling in vehicles, which is shown to be a potential target application. Also, additional target applications are suggested.
We describe a technique to detect gravity wave packets in high‐resolution radiosonde soundings of horizontal wind and temperature. The vertical profiles of meridional and zonal wind speeds are ...transformed using the Morlet wavelet, and regions of high wind variance in height‐wavenumber space are identified as gravity wave packets. Application of the Stokes parameter analysis to horizontal wind and temperature profiles of the reconstructed wave packets yields the wave parameters. The technique was applied to twice‐daily radiosonde launches at Macquarie Island (55°S, 159°E) between 1993 and 1995. A strong seasonal cycle in the total wave variance was found, with a maximum in winter. The amount of wave energy propagating downward from the upper stratosphere also maximized in winter. Waves propagated predominately toward the southwest in winter, but in summer propagation directions were approximately isotropic. The intrinsic frequencies were close to the inertial frequency, and the waves had inferred horizontal wavelengths of several hundred kilometers.
Clonal hematopoiesis (CH) arises when a substantial proportion of mature blood cells is derived from a single dominant hematopoietic stem cell lineage. Somatic mutations in candidate driver (CD) ...genes are thought to be responsible for at least some cases of CH. Using whole-genome sequencing of 11 262 Icelanders, we found 1403 cases of CH by using barcodes of mosaic somatic mutations in peripheral blood, whether or not they have a mutation in a CD gene. We find that CH is very common in the elderly, trending toward inevitability. We show that somatic mutations in TET2, DNMT3A, ASXL1, and PPM1D are associated with CH at high significance. However, known CD mutations were evident in only a fraction of CH cases. Nevertheless, the highly prevalent CH we detect associates with increased mortality rates, risk for hematological malignancy, smoking behavior, telomere length, Y-chromosome loss, and other phenotypic characteristics. Modeling suggests some CH cases could arise in the absence of CD mutations as a result of neutral drift acting on a small population of active hematopoietic stem cells. Finally, we find a germline deletion in intron 3 of the telomerase reverse transcriptase (TERT) gene that predisposes to CH (rs34002450; P = 7.4 × 10−12; odds ratio, 1.37).
•Whole-genome sequencing of 11 262 Icelanders reveals that clonal hematopoiesis is very common in the elderly.•Somatic mutation of some genes is strongly associated with clonal hematopoiesis, but in most cases, no driver mutations were evident.
CFD simulation of thermoacoustic cooling Zink, Florian; Vipperman, Jeffrey; Schaefer, Laura
International journal of heat and mass transfer,
09/2010, Letnik:
53, Številka:
19
Journal Article
Recenzirano
In the field of thermoacoustic energy conversion, the application of numerical analysis techniques, specifically computational fluid dynamics (CFD) simulations, have gained ground in recent years. ...Previous efforts have focused on single thermoacoustic couples that were subjected to the thermoacoustic effect through an oscillatory boundary condition. CFD simulations of an entire thermoacoustic device are computationally expensive and few examples exist. The present work presents an extension of a simulation of a whole thermoacoustic engine that also includes a refrigeration stack. Through interaction of thermally generated sound waves, cooling of the working gas in this stack is demonstrated.
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