The hazards of genotype imputation in chromosomal regions under selection: A case study using the Lactase gene region

Although imputation of missing SNP results has been widely used in genetic studies, claims about the quality and usefulness of imputation have outnumbered the few studies that have questioned its limitations. But it is becoming clear that these limitations are real—for example, disease association signals can be missed in regions of LD breakdown. Here, as a case study, using the chromosomal region of the well-known lactase gene, LCT, we address the issue of imputation in the context of variants that have become frequent in a limited number of modern population groups only recently, due to selection. We study SNPs in a 500 bp region covering the enhancer of LCT, and compare imputed genotypes with directly genotyped data. We examine the haplotype pairs of all individuals with discrepant and missing genotypes. We highlight the nonrandom nature of the allelic errors and show that most incorrect imputations and missing data result from long haplotypes that are evolutionarily closely related to those carrying the derived alleles, while some relate to rare and recombinant haplotypes. We conclude that bias of incorrectly imputed and missing genotypes can decrease the accuracy of imputed results substantially

The hazards of genotype imputation when mapping disease susceptibility variants

BACKGROUND: The cost-free increase in statistical power of using imputation to infer missing genotypes is undoubtedly appealing, but is it hazard-free? This case study of three type-2 diabetes (T2D) loci demonstrates that it is not; it sheds light on why this is so and raises concerns as to the shortcomings of imputation at disease loci, where haplotypes differ between cases and reference panel. RESULTS: T2D-associated variants were previously identified using targeted sequencing. We removed these significantly associated SNPs and used neighbouring SNPs to infer them by imputation. We compared imputed with observed genotypes, examined the altered pattern of T2D-SNP association, and investigated the cause of imputation errors by studying haplotype structure. Most T2D variants were incorrectly imputed with a low density of scaffold SNPs, but the majority failed to impute even at high density, despite obtaining high certainty scores. Missing and discordant imputation errors, which were observed disproportionately for the risk alleles, produced monomorphic genotype calls or false-negative associations. We show that haplotypes carrying risk alleles are considerably more common in the T2D cases than the reference panel, for all loci. CONCLUSIONS: Imputation is not a panacea for fine mapping, nor for meta-analysing multiple GWAS based on different arrays and different populations. A total of 80% of the SNPs we have tested are not included in array platforms, explaining why these and other such associated variants may previously have been missed. Regardless of the choice of software and reference haplotypes, imputation drives genotype inference towards the reference panel, introducing errors at disease loci

Magnetron priming by multiple cathodes

A relativistic magnetron priming technique using multiple cathodes is simulated with a three-dimensional, fully electromagnetic, particle-in-cell code. This technique is based on electron emission from N/2N∕2 individual cathodes in an NN-cavity magnetron to prime the ππ mode. In the case of the six-cavity relativistic magnetron, ππ-mode start-oscillation times are reduced up to a factor of 4, and mode competition is suppressed. Most significantly, the highest microwave field power is observed by utilizing three cathodes compared to other recently explored priming techniques.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/87840/2/081501_1.pd

Criteria for Affordable Housing Performance Measurement: A Review

A home is one of the basic human needs, thus a new concept known as Grow Home has risen. This concept was established to encourage more families to buy their own houses. The Grow Home concept is based on the notion of affordable housing. This paper aims to explore a proposal for affordable housing measurement with six assessment components. In other words, this work intends to study factors that can affect affordable housing assessment. In this paper, we investigated the 20 criteria for affordable housing assessment given by Mulliner and Maliene in their study. Then, we rearranged these criteria into five components, and added the Grow Home component. Each component has different criteria. Finally, six affordable housing measurement components are identified, namely, income ratios, loans and accommodations, facilities and services, safety and comfort, quality management, and Grow Home. These components are also considered as main factors that directly affect affordable housing. This study aspires to contribute to existing literature by proposing six assessment components as a measurement of affordable housing

Preparation and Characterization of the Extracellular Domain of Human Sid-1

In C. elegans, the cell surface protein Sid-1 imports extracellular dsRNA into the cytosol of most non-neuronal cells, enabling systemic spread of RNA interference (RNAi) throughout the worm. Sid-1 homologs are found in many other animals, although for most a function for the protein has not yet been established. Sid-1 proteins are composed of an N-terminal extracellular domain (ECD) followed by 9–12 predicted transmembrane regions. We developed a baculovirus system to express and purify the ECD of the human Sid-1 protein SidT1. Recombinant SidT1 ECD is glycosylated and spontaneously assembles into a stable and discrete tetrameric structure. Electron microscopy (EM) and small angle x-ray scattering (SAXS) studies reveal that the SidT1 ECD tetramer is a compact, puck-shaped globular particle, which we hypothesize may control access of dsRNA to the transmembrane pore. These characterizations provide inroads towards understanding the mechanism of this unique RNA transport system from structural prospective

Identification and Replication of Three Novel Myopia Common Susceptibility Gene Loci on Chromosome 3q26 using Linkage and Linkage Disequilibrium Mapping

Refractive error is a highly heritable quantitative trait responsible for considerable morbidity. Following an initial genome-wide linkage study using microsatellite markers, we confirmed evidence for linkage to chromosome 3q26 and then conducted fine-scale association mapping using high-resolution linkage disequilibrium unit (LDU) maps. We used a preliminary discovery marker set across the 30-Mb region with an average SNP density of 1 SNP/15 kb (Map 1). Map 1 was divided into 51 LDU windows and additional SNPs were genotyped for six regions (Map 2) that showed preliminary evidence of multi-marker association using composite likelihood. A total of 575 cases and controls selected from the tails of the trait distribution were genotyped for the discovery sample. Malecot model estimates indicate three loci with putative common functional variants centred on MFN1 (180,566 kb; 95% confidence interval 180,505–180, 655 kb), approximately 156 kb upstream from alternate-splicing SOX2OT (182,595 kb; 95% CI 182,533–182,688 kb) and PSARL (184,386 kb; 95% CI 184,356–184,411 kb), with the loci showing modest to strong evidence of association for the Map 2 discovery samples (p<10−7, p<10−10, and p = 0.01, respectively). Using an unselected independent sample of 1,430 individuals, results replicated for the MFN1 (p = 0.006), SOX2OT (p = 0.0002), and PSARL (p = 0.0005) gene regions. MFN1 and PSARL both interact with OPA1 to regulate mitochondrial fusion and the inhibition of mitochondrial-led apoptosis, respectively. That two mitochondrial regulatory processes in the retina are implicated in the aetiology of myopia is surprising and is likely to provide novel insight into the molecular genetic basis of common myopia

Health-Promoting Properties of Common Herbs

Herbs have been used as food and for medicinal purposes for centuries. Research interest has focused on various herbs that possess hypolipidemic, antiplatelet, antitumor, or immune-stimulating properties that may be useful adjuncts in helping reduce the risk of cardiovascular disease and cancer. In different herbs, a wide variety of active phytochemicals, including the flavonoids, terpenoids, lignans, sulfides, polyphenolics, carotenoids, coumarins, saponins, plant sterols, curcumins, and phthalides have been identified. Several of these phytochemicals either inhibit nitrosation or the formation of DNA adducts or stimulate the activity of protective enzymes such as the Phase II enzyme glutathione transferase (EC 2.5.1.18). Research has centered around the biochemical activity of the Allium sp: and the Labiatae, Umbelliferae, and Zingiberaceae families, as well as flaxseed, licorice root, and green tea. Many of these herbs contain potent antioxidant compounds that provide significant protection against chronic diseases. These compounds may protect LDL cholesterol from oxidation, inhibit cyclooxygenase and lipoxygenase enzymes, inhibit lipid peroxidation, or have antiviral or antitumor activity. The volatile essential oils of commonly used culinary herbs, spices, and herbal teas inhibit mevalonate synthesis and thereby suppress cholesterol synthesis and tumor growth