A simple and fast two-locus quality control test to detect false positives due to batch effects in genome-wide association studies

The impact of erroneous genotypes having passed standard quality control (QC) can be severe in genome-wide association studies, genotype imputation, and estimation of heritability and prediction of genetic risk based on single nucleotide polymorphisms (SNP). To detect such genotyping errors, a simple two-locus QC method, based on the difference in test statistic of association between single SNPs and pairs of SNPs, was developed and applied. The proposed approach could detect many problematic SNPs with statistical significance even when standard single SNP QC analyses fail to detect them in real data. Depending on the data set used, the number of erroneous SNPs that were not filtered out by standard single SNP QC but detected by the proposed approach varied from a few hundred to thousands. Using simulated data, it was shown that the proposed method was powerful and performed better than other tested existing methods. The power of the proposed approach to detect erroneous genotypes was approximately 80% for a 3% error rate per SNP. This novel QC approach is easy to implement and computationally efficient, and can lead to a better quality of genotypes for subsequent genotype-phenotype investigations.

Genome-wide association study of migraine implicates a common susceptibility variant on 8q22.1

Migraine is a common episodic neurological disorder, typically presenting with recurrent attacks of severe headache and autonomic dysfunction. Apart from rare monogenic subtypes, no genetic or molecular markers for migraine have been convincingly established. We identified the minor allele of rs1835740 on chromosome 8q22.1 to be associated with migraine (P = 5.38 x 10(-)(9), odds ratio = 1.23, 95% CI 1.150-1.324) in a genome-wide association study of 2,731 migraine cases ascertained from three European headache clinics and 10,747 population-matched controls. The association was replicated in 3,202 cases and 40,062 controls for an overall meta-analysis P value of 1.69 x 10(-)(1)(1) (odds ratio = 1.18, 95% CI 1.127-1.244). rs1835740 is located between MTDH (astrocyte elevated gene 1, also known as AEG-1) and PGCP (encoding plasma glutamate carboxypeptidase). In an expression quantitative trait study in lymphoblastoid cell lines, transcript levels of the MTDH were found to have a significant correlation to rs1835740 (P = 3.96 x 10(-)(5), permuted threshold for genome-wide significance 7.7 x 10(-)(5). To our knowledge, our data establish rs1835740 as the first genetic risk factor for migraine.

Genome-wide linkage analysis of multiple measures of neuroticism of 2 large cohorts from Australia and the Netherlands

CONTEXT People meeting diagnostic criteria for anxiety or depressive disorders tend to score high on the personality scale of neuroticism. Studying this personality dimension can give insights into the etiology of these important psychiatric disorders. OBJECTIVES To undertake a comprehensive genome-wide linkage study of neuroticism using large study samples that have been measured multiple times and to compare the results between countries for replication and across time within countries for consistency. DESIGN Genome-wide linkage scan. SETTING Twin individuals and their family members from Australia and the Netherlands. PARTICIPANTS Nineteen thousand six hundred thirty-five sibling pairs completed self-report questionnaires for neuroticism up to 5 times over a period of up to 22 years. Five thousand sixty-nine sibling pairs were genotyped with microsatellite markers. METHODS Nonparametric linkage analyses were conducted in MERLIN-REGRESS for the mean neuroticism scores averaged across time. Additional analyses were conducted for the time-specific measures of neuroticism from each country to investigate consistency of linkage results. RESULTS Three chromosomal regions exceeded empirically derived thresholds for suggestive linkage using mean neuroticism scores: 10p 5 Kosambi cM (cM) (Dutch study sample), 14q 103 cM (Dutch study sample), and 18q 117 cM (combined Australian and Dutch study sample), but only 14q retained significance after correction for multiple testing. These regions all showed evidence for linkage in individual time-specific measures of neuroticism and 1 (18q) showed some evidence for replication between countries. Linkage intervals for these regions all overlap with regions identified in other studies of neuroticism or related traits and/or in studies of anxiety in mice. CONCLUSIONS Our results demonstrate the value of the availability of multiple measures over time and add to the optimism reported in recent reviews for replication of linkage regions for neuroticism. These regions are likely to harbor causal variants for neuroticism and its related psychiatric disorders and can inform prioritization of results from genome-wide association studies.

Genome-wide association studies of quantitative traits with related individuals: Little (power) lost but much to be gained

For complex disease genetics research in human populations, remarkable progress has been made in recent times with the publication of a number of genome-wide association scans (GWAS) and subsequent statistical replications. These studies have identified new genes and pathways implicated in disease, many of which were not known before. Given these early successes, more GWAS are being conducted and planned, both for disease and quantitative phenotypes. Many researchers and clinicians have DNA samples available on collections of families, including both cases and controls. Twin registries around the world have facilitated the collection of large numbers of families, with DNA and multiple quantitative phenotypes collected on twin pairs and their relatives. In the design of a new GWAS with a fixed budget for the number of chips, the question arises whether to include or exclude related individuals. It is commonly believed to be preferable to use unrelated individuals in the first stage of a GWAS because relatives are 'over-matched' for genotypes. In this study, we quantify that for GWAS of a quantitative phenotype, relative to a sample of unrelated individuals surprisingly little power is lost when using relatives. The advantages of using relatives are manifold, including the ability to perform more quality control, the choice to perform within-family tests of association that are robust to population stratification, and the ability to perform joint linkage and association analysis. Therefore, the advantages of using relatives in GWAS for quantitative traits may well outweigh the small disadvantage in terms of statistical power.

A genome-wide linkage scan provides evidence for both new and previously reported loci influencing common migraine

Latent class analysis was performed on migraine symptom data collected in a Dutch population sample (N = 12,210, 59% female) in order to obtain empirical groupings of individuals suffering from symptoms of migraine headache. Based on these heritable groupings (h(2) = 0.49, 95% CI: 0.41-0.57) individuals were classified as affected (migrainous headache) or unaffected. Genome-wide linkage analysis was performed using genotype data from 105 families with at least 2 affected siblings. In addition to this primary phenotype, linkage analyses were performed for the individual migraine symptoms. Significance levels, corrected for the analysis of multiple traits, were determined empirically via a novel simulation approach. Suggestive linkage for migrainous headache was found on chromosomes 1 (LOD = 1.63; pointwise P = 0.0031), 13 (LOD = 1.63; P = 0.0031), and 20 (LOD = 1.85; P = 0.0018). Interestingly, the chromosome 1 peak was located close to the ATP1A2 gene, associated with familial hemiplegic migraine type 2 (FHM2). Individual symptom analysis produced a LOD score of 1.97 (P = 0.0013) on chromosome 5 (photo/phonophobia), a LOD score of 2.13 (P = 0.0009) on chromosome 10 (moderate/severe pain intensity) and a near significant LOD score of 3.31 (P = 0.00005) on chromosome 13 (pulsating headache). These peaks were all located near regions previously reported in migraine linkage studies. Our results provide important replication and support for the presence of migraine susceptibility genes within these regions, and further support the utility of an LCA-based phenotyping approach and analysis of individual symptoms in migraine genetic research. Additionally, our novel "2-step" analysis and simulation approach provides a powerful means to investigate linkage to individual trait components.

Membership cards of Judith Rosenthal, Elma Rosenthal and Arthur Rosenthal to the Jüdischer Kulturbund Berlin Portraits Family

Digital Image

Analysis And Design Of Two Layered Ultra Wide Band Filter

Design of an Ultra Wide Band (UWB) filter over 3.1 GHz to 10.6 GHz using broad side coupled and spur lines in microstrip medium suitable for UWB communications has been presented in this paper. Parameters of broad side coupled lines have been appropriately chosen to achieve ultra wide band response. Spur lines have been incorporated at the input and output feed lines of the filter to improve the stop band rejection characteristics of the filter. Filter has been analyzed based on circuit models and full wave simulations. Experimental results of the filter designed using the proposed structure has been verified against the results obtained from circuit models and full wave simulations. The results match satisfactorily. Stop band rejection of better than 20 dB was obtained over the frequencies of 13 GHz to 18.2 GHz. Overall size of the filter is 40 x 18 x 0.787 mm(3).

Rapid genome wide mapping of phosphine resistance loci by a simple regional averaging analysis in the red flour beetle, Tribolium castaneum

Background Next-generation sequencing technology is an important tool for the rapid, genome-wide identification of genetic variations. However, it is difficult to resolve the ‘signal’ of variations of interest and the ‘noise’ of stochastic sequencing and bioinformatic errors in the large datasets that are generated. We report a simple approach to identify regional linkage to a trait that requires only two pools of DNA to be sequenced from progeny of a defined genetic cross (i.e. bulk segregant analysis) at low coverage (<10×) and without parentage assignment of individual SNPs. The analysis relies on regional averaging of pooled SNP frequencies to rapidly scan polymorphisms across the genome for differential regional homozygosity, which is then displayed graphically. Results Progeny from defined genetic crosses of Tribolium castaneum (F4 and F19) segregating for the phosphine resistance trait were exposed to phosphine to select for the resistance trait while the remainders were left unexposed. Next generation sequencing was then carried out on the genomic DNA from each pool of selected and unselected insects from each generation. The reads were mapped against the annotated T. castaneum genome from NCBI (v3.0) and analysed for SNP variations. Since it is difficult to accurately call individual SNP frequencies when the depth of sequence coverage is low, variant frequencies were averaged across larger regions. Results from regional SNP frequency averaging identified two loci, tc_rph1 on chromosome 8 and tc_rph2 on chromosome 9, which together are responsible for high level resistance. Identification of the two loci was possible with only 5-7× average coverage of the genome per dataset. These loci were subsequently confirmed by direct SNP marker analysis and fine-scale mapping. Individually, homozygosity of tc_rph1 or tc_rph2 results in only weak resistance to phosphine (estimated at up to 1.5-2.5× and 3-5× respectively), whereas in combination they interact synergistically to provide a high-level resistance >200×. The tc_rph2 resistance allele resulted in a significant fitness cost relative to the wild type allele in unselected beetles over eighteen generations. Conclusion We have validated the technique of linkage mapping by low-coverage sequencing of progeny from a simple genetic cross. The approach relied on regional averaging of SNP frequencies and was used to successfully identify candidate gene loci for phosphine resistance in T. castaneum. This is a relatively simple and rapid approach to identifying genomic regions associated with traits in defined genetic crosses that does not require any specialised statistical analysis.

Large-scale characterization of drought pattern: a continent-wide modelling approach applied to the Australian wheatbelt – spatial and temporal trends

* Plant response to drought is complex, so that traits adapted to a specific drought type can confer disadvantage in another drought type. Understanding which type(s) of drought to target is of prime importance for crop improvement. * Modelling was used to quantify seasonal drought patterns for a check variety across the Australian wheatbelt, using 123 yr of weather data for representative locations and managements. Two other genotypes were used to simulate the impact of maturity on drought pattern. * Four major environment types summarized the variability in drought pattern over time and space. Severe stress beginning before flowering was common (44% of occurrences), with (24%) or without (20%) relief during grain filling. High variability occurred from year to year, differing with geographical region. With few exceptions, all four environment types occurred in most seasons, for each location, management system and genotype. * Applications of such environment characterization are proposed to assist breeding and research to focus on germplasm, traits and genes of interest for target environments. The method was applied at a continental scale to highly variable environments and could be extended to other crops, to other drought-prone regions around the world, and to quantify potential changes in drought patterns under future climates.

Temple Emanuel (Andover, Mass.) records, 1939-2001; and Part II (addendum), undated 1952-2004

Temple Emanuel was founded in 1920 in Lawrence, Massachusetts. It began by serving a small immigrant Jewish community that has since grown to an affluent and lively congregation of about 600 families. This growth occurred largely under the tenure of Rabbi Harry A. Roth, who lead the congregation from 1962 until 1990 and oversaw the temple’s move to Andover, Massachusetts. This collection includes correspondence, photographs, and sermons.

Genome-wide association analysis and differential expression analysis of resistance to Sclerotinia stem rot in Brassica napus

Brassica napus is one of the most important oil crops in the world, and stem rot caused by the fungus Sclerotinia sclerotiorum results in major losses in yield and quality. To elucidate resistance genes and pathogenesis-related genes, genome-wide association analysis of 347 accessions was performed using the Illumina 60K Brassica SNP (single nucleotide polymorphism) array. In addition, the detached stem inoculation assay was used to select five highly resistant (R) and susceptible (S) B. napus lines, 48 h postinoculation with S. sclerotiorum for transcriptome sequencing. We identified 17 significant associations for stem resistance on chromosomes A8 and C6, five of which were on A8 and 12 on C6. The SNPs identified on A8 were located in a 409-kb haplotype block, and those on C6 were consistent with previous QTL mapping efforts. Transcriptome analysis suggested that S. sclerotiorum infection activates the immune system, sulphur metabolism, especially glutathione (GSH) and glucosinolates in both R and S genotypes. Genes found to be specific to the R genotype related to the jasmonic acid pathway, lignin biosynthesis, defence response, signal transduction and encoding transcription factors. Twenty-four genes were identified in both the SNP-trait association and transcriptome sequencing analyses, including a tau class glutathione S-transferase (GSTU) gene cluster. This study provides useful insight into the molecular mechanisms underlying the plant's response to S. sclerotiorum.

The neuroscience of inspirational leadership: the importance of collective-oriented language and shared group membership

Effective leaders are believed to inspire followers by providing inclusive visions of the future that followers can identify with. In the present study, we examined the neural mechanisms underlying this process, testing key hypotheses derived from transformational and social identity approaches to leadership. While undergoing functional MRI, supporters from the two major Australian political parties (Liberal vs. Labor) were presented with inspirational collective-oriented and noninspirational personal-oriented statements made by in-group and out-group leaders. Imaging data revealed that inspirational (rather than noninspirational) statements from in-group leaders were associated with increased activation in the bilateral rostral inferior parietal lobule, pars opercularis, and posterior midcingulate cortex: brain areas that are typically implicated in controlling semantic information processing. In contrast, for out-group leaders, greater activation in these areas was associated with noninspirational statements. In addition, noninspirational statements by in-group (but not out-group) leaders resulted in increased activation in the medial prefrontal cortex, an area typically associated with reasoning about a person’s mental state. These results show that followers processed identical statements qualitatively differently as a function of leaders’ group membership, thus demonstrating that shared identity acts as an amplifier for inspirational leadership communication.

Rumen microbial community composition varies with diet and host, but a core microbiome is found across a wide geographical range

Ruminant livestock are important sources of human food and global greenhouse gas emissions. Feed degradation and methane formation by ruminants rely on metabolic interactions between rumen microbes and affect ruminant productivity. Rumen and camelid foregut microbial community composition was determined in 742 samples from 32 animal species and 35 countries, to estimate if this was influenced by diet, host species, or geography. Similar bacteria and archaea dominated in nearly all samples, while protozoal communities were more variable. The dominant bacteria are poorly characterised, but the methanogenic archaea are better known and highly conserved across the world. This universality and limited diversity could make it possible to mitigate methane emissions by developing strategies that target the few dominant methanogens. Differences in microbial community compositions were predominantly attributable to diet, with the host being less influential. There were few strong co-occurrence patterns between microbes, suggesting that major metabolic interactions are non-selective rather than specific. © 2015 Macmillan Publishers Limited.

Area-wide releases and evaluation of the parasitoid Eretmocerus hayati(Hymenoptera:Aphelinidae) for silverleaf whitefly control

Silverleaf whitefly (SLW), Bemisia tabaci biotype B, is a major horticultural pest that costs Queensland vegetable growers millions of dollars in lost production and control measures each year. In the Bowen and Burdekin districts of North Queensland, the major cultivated SLW host crops are tomatoes, melons, green beans, pumpkins, eggplants, and cucumbers, which cover a total production area of approximately 6500 ha. Eretmocerus hayati, an effective SLW parasitoid, was imported into Australia by CSIRO in 2002 and released from quarantine in 2004. In 2006, DAFF established a mass-rearing unit for E. hayati at Bowen Research Station to provide E. hayati for release on vegetable farms within its SLW integrated pest management research program. A total of 1.3 million E. hayati were released over three seasons on 34 vegetable farms in the Bowen and Burdekin districts (October 2006 to December 2008). Post-release samplings were conducted across the release area over this time period with parasitism levels recorded in tomatoes, melons, beans, eggplants, pumpkins, and various SLW weed hosts. Sample data show that E. hayati established at most release sites as well as some non-release sites, indicating natural spread. Overall results from these three years of evaluation clearly demonstrated that E hayati releases played a significant role in SLW control. In most crops sampled, E hayati exerted between 30 and 80% parasitism. Even in regularly sprayed crops, such as tomato and eggplant, E. hayati was able to achieve an overall average parasitism of 45%.

Accounts of K. K. S. I--Membership, Debts, Bonds and Interest

Digital image