Functional interpretation of non-coding sequence variation: Concepts and challenges.

Understanding the functional mechanisms underlying genetic signals associated with complex traits and common diseases, such as cancer, diabetes and Alzheimer's disease, is a formidable challenge. Many genetic signals discovered through genome-wide association studies map to non-protein coding sequences, where their molecular consequences are difficult to evaluate. This article summarizes concepts for the systematic interpretation of non-coding genetic signals using genome annotation data sets in different cellular systems. We outline strategies for the global analysis of multiple association intervals and the in-depth molecular investigation of individual intervals. We highlight experimental techniques to validate candidate (potential causal) regulatory variants, with a focus on novel genome-editing techniques including CRISPR/Cas9. These approaches are also applicable to low-frequency and rare variants, which have become increasingly important in genomic studies of complex traits and diseases. There is a pressing need to translate genetic signals into biological mechanisms, leading to prognostic, diagnostic and therapeutic advances

The critical dimension for a 4th order problem with singular nonlinearity

We study the regularity of the extremal solution of the semilinear biharmonic equation \bi u=\f{\lambda}{(1-u)^2}, which models a simple Micro-Electromechanical System (MEMS) device on a ball B\subset\IR^N, under Dirichlet boundary conditions $u=\partial_\nu u=0$ on $\partial B$. We complete here the results of F.H. Lin and Y.S. Yang \cite{LY} regarding the identification of a "pull-in voltage" \la^*>0 such that a stable classical solution u_\la with 0 exists for \la\in (0,\la^*), while there is none of any kind when \la>\la^*. Our main result asserts that the extremal solution $u_{\lambda^*}$ is regular $(\sup_B u_{\lambda^*} <1)$ provided $N \le 8$ while $u_{\lambda^*}$ is singular ($\sup_B u_{\lambda^*} =1$) for $N \ge 9$, in which case $1-C_0|x|^{4/3}\leq u_{\lambda^*} (x) \leq 1-|x|^{4/3}$ on the unit ball, where $C_0:= (\frac{\lambda^*}{\overline{\lambda}})^{1/3}$ and $\bar{\lambda}:= {8/9} (N-{2/3}) (N- {8/3})$.Comment: 19 pages. This paper completes and replaces a paper (with a similar title) which appeared in arXiv:0810.5380. Updated versions --if any-- of this author's papers can be downloaded at this http://www.birs.ca/~nassif

Aequatus: An open-source homology browser

Background: Phylogenetic information inferred from the study of homologous genes helps us to understand the evolution of genes and gene families, including the identification of ancestral gene duplication events as well as regions under positive or purifying selection within lineages. Gene family and orthogroup characterisation enables the identification of syntenic blocks, which can then be visualised with various tools. Unfortunately, currently available tools display only an overview of syntenic regions as a whole, limited to the gene level, and none provide further details about structural changes within genes, such as the conservation of ancestral exon boundaries amongst multiple genomes. Findings: We present Aequatus, a standalone web-based tool that provides an in-depth view of gene structure across gene families, with various options to render and filter visualisations. It relies on pre-calculated alignment and gene feature information typically held in, but not limited to, the Ensembl Compara and Core databases. We also offer Aequatus.js, a reusable JavaScript module that fulfils the visualisation aspects of Aequatus, available within the Galaxy web platform as a visualisation plugin, which can be used to visualise gene trees generated by the GeneSeqToFamily workflow. Availability: Aequatus is an open-source tool freely available to download under the GNU General Public License v3.0 at https://github.com/TGAC/Aequatus. A demo server is available at http://aequatus.earlham.ac.uk/. A publicly available instance of the GeneSeqToFamily workflow to generate gene tree information and visualise it using Aequatus is available on the Galaxy EU server at https://usegalaxy.eu

GARFIELD classifies disease-relevant genomic features through integration of functional annotations with association signals.

Loci discovered by genome-wide association studies predominantly map outside protein-coding genes. The interpretation of the functional consequences of non-coding variants can be greatly enhanced by catalogs of regulatory genomic regions in cell lines and primary tissues. However, robust and readily applicable methods are still lacking by which to systematically evaluate the contribution of these regions to genetic variation implicated in diseases or quantitative traits. Here we propose a novel approach that leverages genome-wide association studies' findings with regulatory or functional annotations to classify features relevant to a phenotype of interest. Within our framework, we account for major sources of confounding not offered by current methods. We further assess enrichment of genome-wide association studies for 19 traits within Encyclopedia of DNA Elements- and Roadmap-derived regulatory regions. We characterize unique enrichment patterns for traits and annotations driving novel biological insights. The method is implemented in standalone software and an R package, to facilitate its application by the research community

Traditional closed-loop sanitation systems in peri-urban and rural Afghanistan: a SWOT analysis

The closed-loop-sanitation-system (CLSS), or sustainable sanitation system, has accelerated in recent years and been successfully implemented in many parts of the world. This study explored the strengths, weaknesses, opportunities, and threats (SWOT) of the traditional CLSS (T-CLSS) in both peri-urban and rural contexts within three different provinces in Afghanistan, the first study of its kind in this country. Participatory research tools such as transect walks, focus group discussions, and interactive workshops have been applied to assess the SWOT components of T- CLSS. The results show that T-CLSS is practiced historically in both peri-urban and rural areas by different generations using local and traditional knowledge, skills and technologies. Socio-cultural acceptance of the system is considered as one of the strengths in both rural and peri-urban areas. It is highly recommended that the feasibility of improved CLSS be assessed and implemented in the light of the T-CLSS system

Genetic Determinants of Variability in Glycated Hemoglobin (HbA1c) in Humans: Review of Recent Progress and Prospects for Use in Diabetes Care

Glycated hemoglobin A1c (HbA1c) indicates the percentage of total hemoglobin that is bound by glucose, produced from the nonenzymatic chemical modification by glucose of hemoglobin molecules carried in erythrocytes. HbA1c represents a surrogate marker of average blood glucose concentration over the previous 8 to 12 weeks, or the average lifespan of the erythrocyte, and thus represents a more stable indicator of glycemic status compared with fasting glucose. HbA1c levels are genetically determined, with heritability of 47% to 59%. Over the past few years, inroads into understanding genetic predisposition by glycemic and nonglycemic factors have been achieved through genome-wide analyses. Here I review current research aimed at discovering genetic determinants of HbA1c levels, discussing insights into biologic factors influencing variability in the general and diabetic population, and across different ethnicities. Furthermore, I discuss briefly the relevance of findings for diabetes monitoring and diagnosis

Improved imputation of low-frequency and rare variants using the UK10K haplotype reference panel

Imputing genotypes from reference panels created by whole-genome sequencing (WGS) provides a cost-effective strategy for augmenting the single-nucleotide polymorphism (SNP) content of genome-wide arrays. The UK10K Cohorts project has generated a data set of 3,781 whole genomes sequenced at low depth (average 7x), aiming to exhaustively characterize genetic variation down to 0.1% minor allele frequency in the British population. Here we demonstrate the value of this resource for improving imputation accuracy at rare and low-frequency variants in both a UK and an Italian population. We show that large increases in imputation accuracy can be achieved by re-phasing WGS reference panels after initial genotype calling. We also present a method for combining WGS panels to improve variant coverage and downstream imputation accuracy, which we illustrate by integrating 7,562 WGS haplotypes from the UK10K project with 2,184 haplotypes from the 1000 Genomes Project. Finally, we introduce a novel approximation that maintains speed without sacrificing imputation accuracy for rare variants

Breed-Specific Hematological Phenotypes in the Dog: A Natural Resource for the Genetic Dissection of Hematological Parameters in a Mammalian Species

Remarkably little has been published on hematological phenotypes of the domestic dog, the most polymorphic species on the planet. Information on the signalment and complete blood cell count of all dogs with normal red and white blood cell parameters judged by existing reference intervals was extracted from a veterinary database. Normal hematological profiles were available for 6046 dogs, 5447 of which also had machine platelet concentrations within the reference interval. Seventy-five pure breeds plus a mixed breed control group were represented by 10 or more dogs. All measured parameters except mean corpuscular hemoglobin concentration (MCHC) varied with age. Concentrations of white blood cells (WBCs), neutrophils, monocytes, lymphocytes, eosinophils and platelets, but not red blood cell parameters, all varied with sex. Neutering status had an impact on hemoglobin concentration, mean corpuscular hemoglobin (MCH), MCHC, and concentrations of WBCs, neutrophils, monocytes, lymphocytes and platelets. Principal component analysis of hematological data revealed 37 pure breeds with distinctive phenotypes. Furthermore, all hematological parameters except MCHC showed significant differences between specific individual breeds and the mixed breed group. Twenty-nine breeds had distinctive phenotypes when assessed in this way, of which 19 had already been identified by principal component analysis. Tentative breed-specific reference intervals were generated for breeds with a distinctive phenotype identified by comparative analysis. This study represents the first large-scale analysis of hematological phenotypes in the dog and underlines the important potential of this species in the elucidation of genetic determinants of hematological traits, triangulating phenotype, breed and genetic predisposition