Efficient Mixed Model Analysis Research Articles

Retrospective Single Nucleotide Polymorphism Analysis of Host Resistance and Susceptibility to Ovine Johne's Disease Using Restored FFPE DNA.

Johne's disease (JD), also known as paratuberculosis, is a chronic, untreatable gastroenteritis of ruminants caused by Mycobacterium avium subsp. paratuberculosis (MAP) infection. Evidence for host genetic resistance to disease progression exists, although it is limited due to the extended incubation period (years) and diagnostic challenges. To overcome this, previously restored formalin-fixed paraffin embedded tissue (FFPE) DNA from archived FFPE tissue cassettes was utilized for a novel retrospective case-control genome-wide association study (GWAS) on ovine JD. Samples from known MAP-infected flocks with ante- and postmortem diagnostic data were used. Cases (N = 9) had evidence of tissue infection, compared to controls (N = 25) without evidence of tissue infection despite positive antemortem diagnostics. A genome-wide efficient mixed model analysis (GEMMA) to conduct a GWAS using restored FFPE DNA SNP results from the Illumina Ovine SNP50 Bead Chip, identified 10 SNPs reaching genome-wide significance of p < 1 × 10-6 on chromosomes 1, 3, 4, 24, and 26. Pathway analysis using PANTHER and the Kyoto Encyclopedia of Genes and Genomes (KEGG) was completed on 45 genes found within 1 Mb of significant SNPs. Our work provides a framework for the novel use of archived FFPE tissues for animal genetic studies in complex diseases and further evidence for a genetic association in JD.

A Genome-Wide Analysis of the Penumbral Volume in Inbred Mice following Middle Cerebral Artery Occlusion

Following ischemic stroke, the penumbra, at-risk neural tissue surrounding the core infarct, survives for a variable period of time before progressing to infarction. We investigated genetic determinants of the size of penumbra in mice subjected to middle cerebral artery occlusion (MCAO) using a genome-wide approach. 449 male mice from 33 inbred strains underwent MCAO for 6 hours (215 mice) or 24 hours (234 mice). A genome-wide association study using genetic data from the Mouse HapMap project was performed to examine the effects of genetic variants on the penumbra ratio, defined as the ratio of the infarct volume after 6 hours to the infarct volume after 24 hours of MCAO. Efficient mixed model analysis was used to account for strain interrelatedness. Penumbra ratio differed significantly by strain (F = 2.7, P < 0.001) and was associated with 18 significant SNPs, including 6 protein coding genes. We have identified 6 candidate genes for penumbra ratio: Clint1, Nbea, Smtnl2, Rin3, Dclk1, and Slc24a4.

Multiple locus genome-wide association studies for important economic traits of oil palm

Palm oil has a balanced fatty acid composition and has no trans fat. As a result, its use in food has increased as food-labeling laws have changed to specify trans fat content. Increasing oil production is the main goal in oil palm breeding. Genetic mapping and genomic studies in palm trees are necessary to understand the genetic architecture of economic traits of importance for palm oil production. To help achieve this, we sampled 422 oil palms from MPOB (Malaysian Palm Oil Board)­Angola germplasm collection and measured 13 economic traits from these palms. Multi-locus genome-wide association studies (GWAS) were conducted using least absolute shrinkage and selection operator (LASSO) and genome-wide efficient mixed model analysis. We identified 19 quantitative trait loci (QTLs) for 8 traits. Of these, four Angola-specific QTLs associated with bunch components were detected on chromosomes 4, 8, and 11. These QTLs are potentially useful for introgression of desirable genes from the Angola palms to advanced breeding populations for improvement of bunch and oil yield traits. The majority of the QTLs were detected by LASSO-A, in which the p values of individual markers were calculated based on bootstrapped standard errors. Many of the detected QTLs are nearby known QTLs detected from linkage studies reported by other research groups. We also conducted genomic selection (GS) for the 13 traits and concluded that GS can be an effective tool for oil palm breeding. This is the first GWAS and GS study conducted on oil palm germplasm from Angola, and the results can be very useful in oil palm genetic studies and breeding.

Improving power and accuracy of genome-wide association studies via a multi-locus mixed linear model methodology.

Genome-wide association studies (GWAS) have been widely used in genetic dissection of complex traits. However, common methods are all based on a fixed-SNP-effect mixed linear model (MLM) and single marker analysis, such as efficient mixed model analysis (EMMA). These methods require Bonferroni correction for multiple tests, which often is too conservative when the number of markers is extremely large. To address this concern, we proposed a random-SNP-effect MLM (RMLM) and a multi-locus RMLM (MRMLM) for GWAS. The RMLM simply treats the SNP-effect as random, but it allows a modified Bonferroni correction to be used to calculate the threshold p value for significance tests. The MRMLM is a multi-locus model including markers selected from the RMLM method with a less stringent selection criterion. Due to the multi-locus nature, no multiple test correction is needed. Simulation studies show that the MRMLM is more powerful in QTN detection and more accurate in QTN effect estimation than the RMLM, which in turn is more powerful and accurate than the EMMA. To demonstrate the new methods, we analyzed six flowering time related traits in Arabidopsis thaliana and detected more genes than previous reported using the EMMA. Therefore, the MRMLM provides an alternative for multi-locus GWAS.

Rice Diversity Panel Mapping for Identifying Genetics Behind Leaf Vein Density Trait in Rice (&amp;lt;i&amp;gt;Oryza sativa&amp;lt;/i&amp;gt; L.)

A screen of rice genotypes was carried out on a total of 327 genotypes of the rice diversity panel for leaf vein density. Identifying locations of genes that impart to leaf vein density in a quantitative way should capable the using of these genes in plant breeding and accelerate producing C4 rice plant. Finding of genotypes of rice that have less distances between veins is still the challenge of the plant breeders. Screen was shown significant variations in leaf vein density. Quantitative trait loci (QTLs) for the leaf vein density trait were identified by using Efficient Mixed Model Analysis (EMMA). QTLs were considered reportable if they had P values (below 0.0001). The most significant Single nucleotide polymorphisms (SNP) associations (EMMA 1.3, EMMA 1.8 and EMMA 10.1) were in each of the rice chromosomes 1 and 10 respectively. All genes positioned 200 kb around associations were selected. The candidacy of the most promising were NADP-dependent malic enzyme, chloroplast precursor (LOC_Os01g09320; ras-related protein, putative, expressed (LOC_Os01g51700); 60S acidic ribosomal protein (LOC_Os01g09510); Auxin-responsive Aux/IAA gene family member (LOC_Os01g09450; myb-related transcription activator, putative, expressed (LOC_Os01g09280); glycine-rich protein (LOC_Os01g09246); phosphofructokinase (LOC_Os01g09570); oxidoreductase, short chain dehydrogenase/reductase family (SDR) LOC_Os10g31780), which have been expressed in leaf tissue and requisite to be investigated further.

Genome-wide association study identifies nox3 as a critical gene for susceptibility to noise-induced hearing loss.

In the United States, roughly 10% of the population is exposed daily to hazardous levels of noise in the workplace. Twin studies estimate heritability for noise-induced hearing loss (NIHL) of approximately 36%, and strain specific variation in sensitivity has been demonstrated in mice. Based upon the difficulties inherent to the study of NIHL in humans, we have turned to the study of this complex trait in mice. We exposed 5 week-old mice from the Hybrid Mouse Diversity Panel (HMDP) to a 10 kHz octave band noise at 108 dB for 2 hours and assessed the permanent threshold shift 2 weeks post exposure using frequency specific stimuli. These data were then used in a genome-wide association study (GWAS) using the Efficient Mixed Model Analysis (EMMA) to control for population structure. In this manuscript we describe our GWAS, with an emphasis on a significant peak for susceptibility to NIHL on chromosome 17 within a haplotype block containing NADPH oxidase-3 (Nox3). Our peak was detected after an 8 kHz tone burst stimulus. Nox3 mutants and heterozygotes were then tested to validate our GWAS. The mutants and heterozygotes demonstrated a greater susceptibility to NIHL specifically at 8 kHz both on measures of distortion product otoacoustic emissions (DPOAE) and on auditory brainstem response (ABR). We demonstrate that this sensitivity resides within the synaptic ribbons of the cochlea in the mutant animals specifically at 8 kHz. Our work is the first GWAS for NIHL in mice and elucidates the power of our approach to identify tonotopic genetic susceptibility to NIHL.

Interlaminar stress distribution of laminated composites using the mixed-dimensional transition element

This article presents the efficient mixed model analysis, often called global–local approach, to obtain interlaminar stresses at free edges in the laminated composite system under extension and flexure. For the proposed analysis, first, the discrete-layer elements are adopted as three-dimensional elements in the local region. Second, the equivalent single-layer elements are considered as two-dimensional elements in the global region. Finally, the mixed-dimensional transition elements are formulated to connect two different element types used in the global as well as the local regions, respectively. All the elements have higher order shape functions derived from the Lobatto shape function. Modes of the elements are classified into nodal and nodeless modes. The nodal modes have physical meaning, while nodeless modes with respect to the increase of order of the Lobatto shape function do not have physical meaning but improve accuracy of analysis. Therefore, fixing mesh arrangement of present analysis, the quality of the analysis can be enhanced without remeshing work. Some results obtained by the proposed approach are verified with comparison with published references. Also, efficiency of the mixed model analysis using the mixed-dimensional transition element is shown through comparison with numerical results obtained by the single model analysis using only discrete-layer elements.