A fast method for computing high-significance disease association in large population-based studies

Because of rapid progress in genotyping techniques, many large-scale, genomewide disease-association studies are now under way. Typically, the disorders examined are multifactorial, and, therefore, researchers seeking association must consider interactions among loci and between loci and other factors. One of the challenges of large disease-association studies is obtaining accurate estimates of the significance of discovered associations. The linkage disequilibrium between SNPs makes the tests highly dependent, and dependency worsens when interactions are tested. The standard way of assigning significance (P value) is by a permutation test. Unfortunately, in large studies, it is prohibitively slow to compute low P values by this method. We present here a faster algorithm for accurately calculating low P values in case-control association studies. Unlike with several previous methods, we do not assume a specific distribution of the traits, given the genotypes. Our method is based on importance sampling and on accounting for the decay in linkage disequilibrium along the chromosome. The algorithm is dramatically faster than the standard permutation test. On data sets mimicking medium-to-large association studies, it speeds up computation by a factor of 5,000-100,000, sometimes reducing running times from years to minutes. Thus, our method significantly increases the problem-size range for which accurate, meaningful association results are attainable.     

Subversion of actin dynamics by EPEC and EHEC

During the course of infection, enteropathogenic and enterohaemorrhagic Escherichia coli (EPEC and EHEC, respectively) subvert the host cell signalling machinery and hijack the actin cytoskeleton to tighten their interaction with the gut epithelium, while avoiding phagocytosis by professional phagocytes. Much progress has been made recently in our understanding of how EPEC and EHEC regulate the pathways leading to local activation of two regulators of actin cytoskeleton dynamics, the Wiskott-Aldrich syndrome protein (N-WASP) and the Arp2/3 complex. A recent highlight is the unravelling of functions for effector proteins (particularly Tir, TccP, Map and EspG/EspG2) that are injected into the host cell by a type III secretion system.     

EspF of enteropathogenic Escherichia coli binds sorting nexin 9

EspF of enteropathogenic Escherichia coli targets mitochondria and subverts a number of cellular functions. EspF consists of six putative Src homology 3 (SH3) domain binding motifs. In this study we identified sorting nexin 9 (SNX9) as a host cell EspF binding partner protein, which binds EspF via its amino-terminal SH3 region. Coimmunoprecipitation and confocal microscopy showed specific EspF-SNX9 interaction and non-mitochondrial protein colocalization in infected epithelial cells.     

On the complexity of sparse exon assembly.

Gene structure prediction is one of the most important problems in computational molecular biology. It involves two steps: the first is finding the evidence (e.g., predicting splice sites) and the second is interpreting the evidence, that is, trying to determine the whole gene structure by assembling its pieces. In this paper, we suggest a combinatorial solution to the second step, which is also referred to as the "Exon Assembly Problem." We use a similarity-based approach that aims to produce a single gene structure based on similarities to a known homologous sequence. We target the sparse case, where filtering has been applied to the data, resulting in a set of O(n) candidate exon blocks. Our algorithm yields an O(n(2) square root of n) solution.     

A novel category of enteropathogenic Escherichia coli simultaneously utilizes the Nck and TccP pathways to induce actin remodelling

Enterohaemorrhagic Escherichia coli (EHEC) and enteropathogenic E. coli (EPEC) induce drastic reorganization of the microfilament cytoskeleton. EHEC and EPEC translocate Tir (translocated intimin receptor) which, once inserted into the host plasma membrane, binds the bacterial outer membrane adhesin intimin. Tir(EPEC) then becomes tyrosine phosphorylated facilitating the recruitment and site-specific binding of the eukaryotic adaptor Nck, which in turn binds and activates the Wiskott-Aldrich syndrome protein (N-WASP), leading to actin-related protein 2/3 (Arp2/3) complex-mediated actin polymerization. In contrast, Tir(EHEC) has no Nck binding site; instead, EHEC utilizes the translocated effector TccP (Tir-cytoskeleton coupling protein) to bind and activate N-WASP. Here we report a novel class of EPEC that translocates both TccP and Tir(EPEC)-like effector molecules. Consistent with these characteristics, we show that both the Tir-Nck and Tir:TccP actin remodelling pathways function simultaneously during infection, making this a novel and versatile EPEC category.     

Variations on a theme: plant autophagy in comparison to yeast and mammals

Autophagy is an evolutionary conserved process of bulk degradation and nutrient sequestration that occurs in all eukaryotic cells. Yet, in recent years, autophagy has also been shown to play a role in the specific degradation of individual proteins or protein aggregates as well as of damaged organelles. The process was initially discovered in yeast and has also been very well studied in mammals and, to a lesser extent, in plants. In this review, we summarize what is known regarding the various functions of autopahgy in plants but also attempt to address some specific issues concerning plant autophagy, such as the insufficient knowledge regarding autophagy in various plant species other than Arabidopsis, the fact that some genes belonging to the core autophagy machinery in various organisms are still missing in plants, the existence of autophagy multigene families in plants and the possible operation of selective autophagy in plants, a study that is still in its infancy. In addition, we point to plant-specific autophagy processes, such as the participation of autophagy during development and germination of the seed, a unique plant organ. Throughout this review, we demonstrate that the use of innovative bioinformatic resources, together with recent biological discoveries (such as the ATG8-interacting motif), should pave the way to a more comprehensive understanding of the multiple functions of plant autophagy.     

Absolute quantification of somatic DNA alterations in human cancer

We describe a computational method that infers tumor purity and malignant cell ploidy directly from analysis of somatic DNA alterations. The method, named ABSOLUTE, can detect subclonal heterogeneity and somatic homozygosity, and it can calculate statistical sensitivity for detection of specific aberrations. We used ABSOLUTE to analyze exome sequencing data from 214 ovarian carcinoma tumor-normal pairs. This analysis identified both pervasive subclonal somatic point-mutations and a small subset of predominantly clonal and homozygous mutations, which were overrepresented in the tumor suppressor genes TP53 and NF1 and in a candidate tumor suppressor gene CDK12. We also used ABSOLUTE to infer absolute allelic copy-number profiles from 3,155 diverse cancer specimens, revealing that genome-doubling events are common in human cancer, likely occur in cells that are already aneuploid, and influence pathways of tumor progression (for example, with recessive inactivation of NF1 being less common after genome doubling). ABSOLUTE will facilitate the design of clinical sequencing studies and studies of cancer genome evolution and intra-tumor heterogeneity.     

Systematic Identification of Rhythmic Genes Reveals camk1gb as a New Element in the Circadian Clockwork

A wide variety of biochemical, physiological, and molecular processes are known to have daily rhythms driven by an endogenous circadian clock. While extensive research has greatly improved our understanding of the molecular mechanisms that constitute the circadian clock, the links between this clock and dependent processes have remained elusive. To address this gap in our knowledge, we have used RNA sequencing (RNA–seq) and DNA microarrays to systematically identify clock-controlled genes in the zebrafish pineal gland. In addition to a comprehensive view of the expression pattern of known clock components within this master clock tissue, this approach has revealed novel potential elements of the circadian timing system. We have implicated one rhythmically expressed gene, camk1gb, in connecting the clock with downstream physiology of the pineal gland. Remarkably, knockdown of camk1gb disrupts locomotor activity in the whole larva, even though it is predominantly expressed within the pineal gland. Therefore, it appears that camk1gb plays a role in linking the pineal master clock with the periphery.