Function2Gene: A gene selection tool to increase the power of genetic association studies by utilizing public databases and expert knowledge

<p>Abstract</p> <p>Background</p> <p>Many common disorders have multiple genetic components which convey increased susceptibility. SNPs have been used to identify genetic components which are associated with a disease. Unfortunately, many studies using these methods suffer from low reproducibility due to lack of power.</p> <p>Results</p> <p>We present a set of programs which implement a novel method for searching for disease-associated genes using prior information to select and order genes from publicly available databases by their prior likelihood of association with the disease. These programs were used in a published study of childhood-onset SLE which yielded novel associations with modest sample size.</p> <p>Conclusion</p> <p>Using prior information to decrease the size of the problem space to an amount commensurate with available samples and resources while maintaining appropriate power enables researchers to increase their likelihood of discovering reproducible associations.</p

A Comprehensive Analysis of Shared Loci between Systemic Lupus Erythematosus (SLE) and Sixteen Autoimmune Diseases Reveals Limited Genetic Overlap

In spite of the well-known clustering of multiple autoimmune disorders in families, analyses of specific shared genes and polymorphisms between systemic lupus erythematosus (SLE) and other autoimmune diseases (ADs) have been limited. Therefore, we comprehensively tested autoimmune variants for association with SLE, aiming to identify pleiotropic genetic associations between these diseases. We compiled a list of 446 non–Major Histocompatibility Complex (MHC) variants identified in genome-wide association studies (GWAS) of populations of European ancestry across 17 ADs. We then tested these variants in our combined Caucasian SLE cohorts of 1,500 cases and 5,706 controls. We tested a subset of these polymorphisms in an independent Caucasian replication cohort of 2,085 SLE cases and 2,854 controls, allowing the computation of a meta-analysis between all cohorts. We have uncovered novel shared SLE loci that passed multiple comparisons adjustment, including the VTCN1 (rs12046117, P = 2.02×10−06) region. We observed that the loci shared among the most ADs include IL23R, OLIG3/TNFAIP3, and IL2RA. Given the lack of a universal autoimmune risk locus outside of the MHC and variable specificities for different diseases, our data suggests partial pleiotropy among ADs. Hierarchical clustering of ADs suggested that the most genetically related ADs appear to be type 1 diabetes with rheumatoid arthritis and Crohn's disease with ulcerative colitis. These findings support a relatively distinct genetic susceptibility for SLE. For many of the shared GWAS autoimmune loci, we found no evidence for association with SLE, including IL23R. Also, several established SLE loci are apparently not associated with other ADs, including the ITGAM-ITGAX and TNFSF4 regions. This study represents the most comprehensive evaluation of shared autoimmune loci to date, supports a relatively distinct non–MHC genetic susceptibility for SLE, provides further evidence for previously and newly identified shared genes in SLE, and highlights the value of studies of potentially pleiotropic genes in autoimmune diseases

Systems protobiology:Origin of life in lipid catalytic networks

Life is that which replicates and evolves, but there is no consensus on how life emerged. We advocate a systems protobiology view, whereby the first replicators were assemblies of spontaneously accreting, heterogeneous and mostly non-canonical amphiphiles. This view is substantiated by rigorous chemical kinetics simulations of the graded autocatalysis replication domain (GARD) model, based on the notion that the replication or reproduction of compositional information predated that of sequence information. GARD reveals the emergence of privileged non-equilibrium assemblies (composomes), which portray catalysis-based homeostatic (concentration-preserving) growth. Such a process, along with occasional assembly fission, embodies cell-like reproduction. GARD pre-RNA evolution is evidenced in the selection of different composomes within a sparse fitness landscape, in response to environmental chemical changes. These observations refute claims that GARD assemblies (or other mutually catalytic networks in the metabolism first scenario) cannot evolve. Composomes represent both a genotype and a selectable phenotype, anteceding present-day biology in which the two are mostly separated. Detailed GARD analyses show attractor-like transitions from random assemblies to self-organized composomes, with negative entropy change, thus establishing composomes as dissipative systemstextemdashhallmarks of life. We show a preliminary new version of our model, metabolic GARD (M-GARD), in which lipid covalent modifications are orchestrated by non-enzymatic lipid catalysts, themselves compositionally reproduced. M-GARD fills the gap of the lack of true metabolism in basic GARD, and is rewardingly supported by a published experimental instance of a lipid-based mutually catalytic network. Anticipating near-future far-reaching progress of molecular dynamics, M-GARD is slated to quantitatively depict elaborate protocells, with orchestrated reproduction of both lipid bilayer and lumenal content. Finally, a GARD analysis in a whole-planet context offers the potential for estimating the probability of life's emergence. The invigorated GARD scrutiny presented in this review enhances the validity of autocatalytic sets as a bona fide early evolution scenario and provides essential infrastructure for a paradigm shift towards a systems protobiology view of life's origin

Role of transmembrane domains in the functions of B- and T-cell receptors

The antigen receptors on the surface of B- and T-lymphocytes are complexes of several integral membrane proteins, essential for their proper expression and function. Recent studies demonstrated that transmembrane (TM) domains of the components of these receptors play a critical role in their association and function. It was specifically demonstrated that in many cases point mutations in the TM domains can partially or completely disrupt the receptor surface expression and function. Here we review studies of the TM domains of B- and T-cell receptors. Furthermore, we use a novel method, PHDtopology, to provide estimates of the exact locations and lengths of the TM domains of the subunit components of these receptors. Most previous studies used single residue hydrophobicity as a criterion for determining the position and length of the TM domains. In contrast, PHDtopology utilizes a system of neural networks and the evolutionary information contained in multiple alignments of related sequences to predict the location, length, and orientation of transmembrane helices. Present results significantly differ from most published estimates of the TM domains of the B- and T-cell receptor components, primarily in the length of the TM domains. These results may lead to modification of putative TM motifs and re-interpretation of the results of studies using mutated TM domains. The availability of PHDtopology on the Internet would make it a valuable tool in the future studies of the TM domains of integral membrane proteins. 1998 Elsevier Science B.V. All rights reserved

Revised Assignment of Energy Storage in the Primary Photochemical Event in Bacteriorhodopsin

Bactcriorhodopsin is the light-transducing protein in the purple membrane of Halobacterium halobium. Irradiation of the light-adapted form (bR) initiates a photocycle that pumps protons across the membrane. An accurate assignment of the energy storage associated with the primary event of bR is important to an understanding of the molecular mechanism and the stoichiometry of proton pumping. Previous photocalorimetric studies have concluded that ~16 kcal mol-1 is stored in the K photoproduct, an energy sufficient to pump two protons per photocycle

Thrombospondin-1 Modulates the Angiogenic Phenotype of Human Cerebral Arteriovenous Malformation Endothelial Cells

Background: The management of cerebral arteriovenous malformation (AVM) is challenging, and invasive therapies place vital intracranial structures at risk of injury. The development of noninvasive, pharmacologic approaches relies on identifying factors that mediate key angiogenic processes. Previous studies indicate that endothelial cells (ECs) derived from cerebral AVM (AVM-ECs) are distinct from control brain ECs with regard to important angiogenic characteristics. Objective: To determine whether thrombospondin-1 (TSP-1), a potent angiostatic factor, regulates critical angiogenic features of AVM-ECs and to identify factors that modulate TSP-1 production in AVM-ECs. Methods: EC proliferation, migration, and tubule formation were evaluated with bromodeoxyuridine incorporation, Boyden chamber, and Matrigel studies, respectively. TSP-1 and inhibitor of DNA binding/differentiation 1 (Id1) mRNA levels were quantified with microarray and quantitative real-time polymerase chain reaction analyses. TSP-1 protein expression was measured using Western blotting, immunohistochemical, and enzyme-linked immunosorbent assay techniques. The mechanistic link between Id1 and TSP-1 was established through small interfering RNA-mediated knockdown of Id1 in AVM-ECs followed by Western blot and enzyme-linked immunosorbent assay experiments assessing TSP-1 production. Results: AVM-ECs proliferate faster, migrate more quickly, and form disorganized tubules compared with brain ECs. TSP-1 is significantly down-regulated in AVM-ECs. The addition of TSP-1 to AVM-EC cultures normalizes the rate of proliferation and migration and the efficiency of tubule formation, whereas brain ECs are unaffected. Id1 negatively regulates TSP-1 expression in AVM-ECs. Conclusion: These data highlight a novel role for TSP-1 in the pathobiology of AVM angiogenesis and provide a context for its use in the clinical management of brain AVMs