Integrated genotype calling and association analysis of SNPs, common copy number polymorphisms and rare CNVs

Accurate and complete measurement of single nucleotide (SNP) and copy number (CNV) variants, both common and rare, will be required to understand the role of genetic variation in disease. We present Birdsuite, a four-stage analytical framework instantiated in software for deriving integrated and mutually consistent copy number and SNP genotypes. The method sequentially assigns copy number across regions of common copy number polymorphisms (CNPs), calls genotypes of SNPs, identifies rare CNVs via a hidden Markov model (HMM), and generates an integrated sequence and copy number genotype at every locus (for example, including genotypes such as A-null, AAB and BBB in addition to AA, AB and BB calls). Such genotypes more accurately depict the underlying sequence of each individual, reducing the rate of apparent mendelian inconsistencies. The Birdsuite software is applied here to data from the Affymetrix SNP 6.0 array. Additionally, we describe a method, implemented in PLINK, to utilize these combined SNP and CNV genotypes for association testing with a phenotype.     

Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci

Systemic lupus erythematosus (SLE) is a common systemic autoimmune disease with complex etiology but strong clustering in families (lambda(S) = approximately 30). We performed a genome-wide association scan using 317,501 SNPs in 720 women of European ancestry with SLE and in 2,337 controls, and we genotyped consistently associated SNPs in two additional independent sample sets totaling 1,846 affected women and 1,825 controls. Aside from the expected strong association between SLE and the HLA region on chromosome 6p21 and the previously confirmed non-HLA locus IRF5 on chromosome 7q32, we found evidence of association with replication (1.1 x 10(-7) < P(overall) < 1.6 x 10(-23); odds ratio = 0.82-1.62) in four regions: 16p11.2 (ITGAM), 11p15.5 (KIAA1542), 3p14.3 (PXK) and 1q25.1 (rs10798269). We also found evidence for association (P < 1 x 10(-5)) at FCGR2A, PTPN22 and STAT4, regions previously associated with SLE and other autoimmune diseases, as well as at > or =9 other loci (P < 2 x 10(-7)). Our results show that numerous genes, some with known immune-related functions, predispose to SLE.     

Enterotypes of the human gut microbiome

Our knowledge of species and functional composition of the human gut microbiome is rapidly increasing, but it is still based on very few cohorts and little is known about variation across the world. By combining 22 newly sequenced faecal metagenomes of individuals from four countries with previously published data sets, here we identify three robust clusters (referred to as enterotypes hereafter) that are not nation or continent specific. We also confirmed the enterotypes in two published, larger cohorts, indicating that intestinal microbiota variation is generally stratified, not continuous. This indicates further the existence of a limited number of well-balanced host-microbial symbiotic states that might respond differently to diet and drug intake. The enterotypes are mostly driven by species composition, but abundant molecular functions are not necessarily provided by abundant species, highlighting the importance of a functional analysis to understand microbial communities. Although individual host properties such as body mass index, age, or gender cannot explain the observed enterotypes, data-driven marker genes or functional modules can be identified for each of these host properties. For example, twelve genes significantly correlate with age and three functional modules with the body mass index, hinting at a diagnostic potential of microbial markers.     

Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3

Missense mutations in the CIAS1 gene cause three autoinflammatory disorders: familial cold autoinflammatory syndrome, Muckle-Wells syndrome and neonatal-onset multiple-system inflammatory disease. Cryopyrin (also called Nalp3), the product of CIAS1, is a member of the NOD-LRR protein family that has been linked to the activation of intracellular host defence signalling pathways. Cryopyrin forms a multi-protein complex termed 'the inflammasome', which contains the apoptosis-associated speck-like protein (ASC) and caspase-1, and promotes caspase-1 activation and processing of pro-interleukin (IL)-1beta (ref. 4). Here we show the effect of cryopyrin deficiency on inflammasome function and immune responses. Cryopyrin and ASC are essential for caspase-1 activation and IL-1beta and IL-18 production in response to bacterial RNA and the imidazoquinoline compounds R837 and R848. In contrast, secretion of tumour-necrosis factor-alpha and IL-6, as well as activation of NF-kappaB and mitogen-activated protein kinases (MAPKs) were unaffected by cryopyrin deficiency. Furthermore, we show that Toll-like receptors and cryopyrin control the secretion of IL-1beta and IL-18 through different intracellular pathways. These results reveal a critical role for cryopyrin in host defence through bacterial RNA-mediated activation of caspase-1, and provide insights regarding the pathogenesis of autoinflammatory syndromes.     

Compositional asynchronous membrane systems

This paper presents an algorithmic way of building complex membrane systems by coupling elementary membranes. Its application seems particularly valuable in the case of asynchronous membrane systems, since the resulting membrane system remains asynchronous. The composition method is based on a handshake mechanism implemented by using antiport rules and promoters.     

Feasibility-Oriented Application of System Analysis in SMEs-The Cybernetic Approach of VSM Applied to Horticultural Retail Companies in Germany

Many approaches of business analysis focus on single disciplines or specific problems but ignore complex and dynamic interrelations between small and medium-sized enterprises (SMEs), their stakeholders, and their business environment. In order to meet these challenges, the system analysis tool Vester sensitivity model (VSM) is applied on a reference company representative of the German horticultural retail sector. Based on the principles of system theory and (bio-) cybernetics, the VSM system building tool uses net thinking, heuristics, and a participatory approach to illustrate and evaluate the systemic role of relevant key variables, and their interrelations in the example company. In this article, the analytical steps of the VSM are applied up to the finalized effect system model of the reference company. As an innovative aspect, the article emphasizes how the multilevel process of the system analysis can be put into practice more effectively by using interactive media tools to enable the required communication and consensus by the participating stakeholder panel. Elements such as the manager’s ability of strategic planning, the organizational climate, and the company’s image were uncovered as critical, but also stabilizing key factors for such companies. Although the study focuses on the specific situation of German horticultural retail companies as the research subject, the suggested procedure of integrated knowledge generation is transferrable to any business, industry branch, and country. Especially scholars, advisors, and business analysts working in the field of SME management can use the concept to evaluate such systems in the overall context of the companies under investigation.     

Detecting recent positive selection in the human genome from haplotype structure

The ability to detect recent natural selection in the human population would have profound implications for the study of human history and for medicine. Here, we introduce a framework for detecting the genetic imprint of recent positive selection by analysing long-range haplotypes in human populations. We first identify haplotypes at a locus of interest (core haplotypes). We then assess the age of each core haplotype by the decay of its association to alleles at various distances from the locus, as measured by extended haplotype homozygosity (EHH). Core haplotypes that have unusually high EHH and a high population frequency indicate the presence of a mutation that rose to prominence in the human gene pool faster than expected under neutral evolution. We applied this approach to investigate selection at two genes carrying common variants implicated in resistance to malaria: G6PD and CD40 ligand. At both loci, the core haplotypes carrying the proposed protective mutation stand out and show significant evidence of selection. More generally, the method could be used to scan the entire genome for evidence of recent positive selection.     

Swollen liquid-crystalline lamellar phase based on extended solid-like sheets

Ordering particles at the nanometre length scale is a challenging and active research area in materials science. Several approaches have so far been developed, ranging from the manipulation of individual particles to the exploitation of self-assembly in colloids. Nanometre-scale ordering is well known to appear spontaneously when anisotropic organic moieties form liquid-crystalline phases; this behaviour is also observed for anisotropic mineral nanoparticles resulting in the formation of nematic, smectic and hexagonal mesophases. Here we describe a lyotropic liquid-crystalline lamellar phase comprising an aqueous dispersion of planar solid-like sheets in which all the atoms involved in a layer are covalently bonded. The spacing of these phosphatoantimonate single layers can be increased 100-fold, resulting in one-dimensional structures whose periodicity can be tuned from 1.5 to 225 nanometres. These highly organized materials can be mechanically or magnetically aligned over large pH and temperature ranges, and this property can be used to measure residual dipolar couplings for the structure determination of biomolecules by liquid-state NMR. We also expect that our approach will result in the discovery of other classes of mineral lyotropic lamellar phases.     

Mise en évidence par dichroïsme circulaire d'une association intermoléculaire pour les complexes NADP(H)-Cu2+

Summary The presence of a conservative excitonic term in the ultraviolet circular dichroism spectra of NADP(H)-Cu²⁺ complexes in equimolar solution (5·10^–4M/l) shows the existence of an intermolecular association by formation of a stable Cu²⁺-bridged stacked adduct between the purine moieties of 2 neighbouring dinucleotides.     

Extension of southern range and new specimens of the western gray squirrel, Sciurus griseus anthonyi (Mammalia: Sciuridae), in Baja California, México

We documented a southern range extension and new specimens of western gray squirrel ( Sciurus griseus anthonyi ) for the state of Baja California, M&eacute;xico. The most recent specimen was collected in the town Catavi&ntilde;a and represents the southernmost record for the species and subspecies. Repeated observations of individuals in this new location suggest the presence of a marginal population in Mediterranean chaparral&ndash;desert scrub transition vegetation. Documentamos la extension de &aacute;mbito m&aacute;s sure&ntilde;o y nuevos espec&iacute;menes de a ardilla gris occidental ( Sciurus griseus anthonyi ) para el Estado de Baja California, M&eacute;xico. El esp&eacute;cimen m&aacute;s reciente fue recolectado en el poblado de Catavi&ntilde;a y representa el registro m&aacute;s sure&ntilde;o para la especie y subespecie. Observaciones repetidas de individuos en esta &uacute;ltima localidad sure&ntilde;a sugiere la presencia de una poblaci&oacute;n marginal en vegetaci&oacute;n de transici&oacute;n de chaparral mediterr&aacute;neo&ndash;matorral des&eacute;rtico.