A Genome-Wide Association Study Reveals Loci Influencing Height and Other Conformation Traits in Horses

The molecular analysis of genes influencing human height has been notoriously difficult. Genome-wide association studies (GWAS) for height in humans based on tens of thousands to hundreds of thousands of samples so far revealed ∼200 loci for human height explaining only 20% of the heritability. In domestic animals isolated populations with a greatly reduced genetic heterogeneity facilitate a more efficient analysis of complex traits. We performed a genome-wide association study on 1,077 Franches-Montagnes (FM) horses using ∼40,000 SNPs. Our study revealed two QTL for height at withers on chromosomes 3 and 9. The association signal on chromosome 3 is close to the LCORL/NCAPG genes. The association signal on chromosome 9 is close to the ZFAT gene. Both loci have already been shown to influence height in humans. Interestingly, there are very large intergenic regions at the association signals. The two detected QTL together explain ∼18.2% of the heritable variation of height in horses. However, another large fraction of the variance for height in horses results from ECA 1 (11.0%), although the association analysis did not reveal significantly associated SNPs on this chromosome. The QTL region on ECA 3 associated with height at withers was also significantly associated with wither height, conformation of legs, ventral border of mandible, correctness of gaits, and expression of the head. The region on ECA 9 associated with height at withers was also associated with wither height, length of croup and length of back. In addition to these two QTL regions on ECA 3 and ECA 9 we detected another QTL on ECA 6 for correctness of gaits. Our study highlights the value of domestic animal populations for the genetic analysis of complex traits

Nanostructuring perovskite oxides: The impact of SrTiO3 nanocubes 3D self-assembly on thermal conductivity.

Nanostructuring the perovskite oxide SrTiO3 via 3D assemblage of nanocubes is shown to lower the thermal conductivity over a broad range of temperatures. This is particularly valuable in thermoelectric material applications. The assemblages are composed of pristine perovskite grain interiors confined by SrO or TiO2-rich interfaces resembling Ruddlesden Popper and Magneli phases. The optimum performance in terms of the thermoelectric device applications are predicted to come from SrTiO3 nanocubes synthesised in a Sr-rich environment, although TiO2-rich nanocubes would have an increased strength. The vibrational fingerprint of the assemblages, characterized by a combination of lattice and molecular dynamics, display the characteristic modes of the perovskite structure and significant interface vibrational modes, some at very low frequency. TiO2-rich assemblages display splitting of the active modes similar to anatase providing a way to distinguish them from SrO-rich assemblages. Finally, we show that the IR active low vibrational frequencies are sensitive to the structure and stacking of the nanocubes indicating that it could be an efficient experimental route for identifying and characterizing the material with very low thermal conductivity

Prediction of Extracellular Proteases of the Human Pathogen Helicobacter pylori Reveals Proteolytic Activity of the Hp1018/19 Protein HtrA

Exported proteases of Helicobacter pylori (H. pylori) are potentially involved in pathogen-associated disorders leading to gastric inflammation and neoplasia. By comprehensive sequence screening of the H. pylori proteome for predicted secreted proteases, we retrieved several candidate genes. We detected caseinolytic activities of several such proteases, which are released independently from the H. pylori type IV secretion system encoded by the cag pathogenicity island (cagPAI). Among these, we found the predicted serine protease HtrA (Hp1019), which was previously identified in the bacterial secretome of H. pylori. Importantly, we further found that the H. pylori genes hp1018 and hp1019 represent a single gene likely coding for an exported protein. Here, we directly verified proteolytic activity of HtrA in vitro and identified the HtrA protease in zymograms by mass spectrometry. Overexpressed and purified HtrA exhibited pronounced proteolytic activity, which is inactivated after mutation of Ser205 to alanine in the predicted active center of HtrA. These data demonstrate that H. pylori secretes HtrA as an active protease, which might represent a novel candidate target for therapeutic intervention strategies

Tracing the origins of centrioles, cilia, and flagella

Centrioles/basal bodies (CBBs) are microtubule-based cylindrical organelles that nucleate the formation of centrosomes, cilia, and flagella. CBBs, cilia, and flagella are ancestral structures; they are present in all major eukaryotic groups. Despite the conservation of their core structure, there is variability in their architecture, function, and biogenesis. Recent genomic and functional studies have provided insight into the evolution of the structure and function of these organelles

Lysosome Biogenesis and Autophagy

Lysosomes degrade biological components acquired by endocytosis, the major cellular pathway for internalization of extracellular material, and macroautophagy. This chapter presents an overview of these two major degradative intracellular pathways, and highlights the emerging cross talks between them, in healthy and diseased conditions. The pathways to lysosomes include the biosynthetic transport routes, endocytic pathways, and the autophagy pathways. The central actors of the autophagy process are the ATG genes. Based on their organization in complexes and interactions, the ATG genes have been divided into many functional clusters that compose the core autophagy machinery. Cross talk between the endocytic and autophagic pathways occurs at many levels: transcriptional regulation, protein sharing, and compartmental connections. The chapter focuses on the fusion and fission events between compartments of the endolysosomal system and autophagic membranes, respectively. Lysosome-related disorders are caused by mutations in genes encoding for proteins that directly affect lysosomal functioning, including lysosomal hydrolases and lysosomal membrane proteins

IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes.

GWAS have identified >200 risk loci for Inflammatory Bowel Disease (IBD). The majority of disease associations are known to be driven by regulatory variants. To identify the putative causative genes that are perturbed by these variants, we generate a large transcriptome data set (nine disease-relevant cell types) and identify 23,650 cis-eQTL. We show that these are determined by ∼9720 regulatory modules, of which ∼3000 operate in multiple tissues and ∼970 on multiple genes. We identify regulatory modules that drive the disease association for 63 of the 200 risk loci, and show that these are enriched in multigenic modules. Based on these analyses, we resequence 45 of the corresponding 100 candidate genes in 6600 Crohn disease (CD) cases and 5500 controls, and show with burden tests that they include likely causative genes. Our analyses indicate that ≥10-fold larger sample sizes will be required to demonstrate the causality of individual genes using this approach

Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association study

Crohn's disease and ulcerative colitis are the two major forms of inflammatory bowel disease; treatment strategies have historically been determined by this binary categorisation. Genetic studies have identified 163 susceptibility loci for inflammatory bowel disease, mostly shared between Crohn's disease and ulcerative colitis. We undertook the largest genotype association study, to date, in widely used clinical subphenotypes of inflammatory bowel disease with the goal of further understanding the biological relations between diseases

Ostracod fauna of the Bell shale formation of Michigan

Master of ScienceGeology and MineralogyUniversity of Michiganhttp://deepblue.lib.umich.edu/bitstream/2027.42/115272/1/39015003263558.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/115272/2/39015003263558.pd

Fibrosis: from mechanisms to medicines

Fibrosis can affect any organ and is responsible for up to 45% of all deaths in the industrialized world. Long thought to be relentlessly progressive and irreversible, both pre-clinical models and clinical trials in various organ systems have shown that fibrosis is a highly dynamic process. This has clear implications for therapeutic interventions designed to capitalize on this inherent plasticity. However, despite significant progress in our understanding of the pathobiology of fibrosis, a translational gap remains between identification of putative antifibrotic targets and conversion into effective patient therapies. Here we discuss the transformative experimental strategies that are being leveraged to dissect the key cellular and molecular mechanisms regulating fibrosis, and the translational approaches which are enabling the emergence of precision medicine-based therapies for patients with fibrosis