Positional cloning of a novel gene influencing asthma from chromosome 2q14

Asthma is a common disease in children and young adults. Four separate reports have linked asthma and related phenotypes to an ill-defined interval between 2q14 and 2q32 (refs. 1-4), and two mouse genome screens have linked bronchial hyper-responsiveness to the region homologous to 2q14 (refs. 5,6). We found and replicated association between asthma and the D2S308 microsatellite, 800 kb distal to the IL1 cluster on 2q14. We sequenced the surrounding region and constructed a comprehensive, high-density, single-nucleotide polymorphism (SNP) linkage disequilibrium (LD) map. SNP association was limited to the initial exons of a solitary gene of 3.6 kb (DPP10), which extends over 1 Mb of genomic DNA. DPP10 encodes a homolog of dipeptidyl peptidases (DPPs) that cleave terminal dipeptides from cytokines and chemokines, and it presents a potential new target for asthma therapy.     

Compartments revealed in food-web structure

Compartments in food webs are subgroups of taxa in which many strong interactions occur within the subgroups and few weak interactions occur between the subgroups. Theoretically, compartments increase the stability in networks, such as food webs. Compartments have been difficult to detect in empirical food webs because of incompatible approaches or insufficient methodological rigour. Here we show that a method for detecting compartments from the social networking science identified significant compartments in three of five complex, empirical food webs. Detection of compartments was influenced by food web resolution, such as interactions with weights. Because the method identifies compartmental boundaries in which interactions are concentrated, it is compatible with the definition of compartments. The method is rigorous because it maximizes an explicit function, identifies the number of non-overlapping compartments, assigns membership to compartments, and tests the statistical significance of the results. A graphical presentation reveals systemic relationships and taxa-specific positions as structured by compartments. From this graphic, we explore two scenarios of disturbance to develop a hypothesis for testing how compartmentalized interactions increase stability in food webs.     

The vector alignments of asteroid spins by thermal torques

Collisions have been thought to be the dominant process altering asteroid rotations, but recent observations of the Koronis family of asteroids suggest that this may be incorrect. This group of asteroids was formed in a catastrophic collision several billion years ago; in the intervening period their rotational axes should have become nearly random because of subsequent collisions, with spin rates that follow a maxwellian distribution. What is seen, however, is that the observed family members with prograde spins have nearly identical periods (7.5-9.5 h) and obliquities between 42 and 50 degrees, while those with retrograde spins have obliquities between 154 and 169 degrees with periods either <5 h or >13 h. Here we show that these non-random orientations and spin rates can be explained by 'thermal torques' (arising from differential solar heating), which modify the spin states over time. In some cases, the asteroids become trapped in spin-orbit resonances. Our results suggest that thermal torques may be more important than collisions in changing the spin states (and possibly shapes) of asteroids with diameters <40 km.     

Nalp1b controls mouse macrophage susceptibility to anthrax lethal toxin

The pathogenesis of Bacillus anthracis, the bacterium that causes anthrax, depends on secretion of three factors that combine to form two bipartite toxins. Edema toxin, consisting of protective antigen (PA) and edema factor (EF), causes the edema associated with cutaneous anthrax infections, whereas lethal toxin (LeTx), consisting of PA and lethal factor (LF), is believed to be responsible for causing death in systemic anthrax infections. EF and LF can be transported by PA into the cytosol of many cell types. In mouse macrophages, LF can cause rapid necrosis that may be related to the pathology of systemic infections. Inbred mouse strains display variable sensitivity to LeTx-induced macrophage necrosis. This trait difference has been mapped to a locus on chromosome 11 named Ltxs1 (refs. 7,8). Here we show that an extremely polymorphic gene in this locus, Nalp1b, is the primary mediator of mouse macrophage susceptibility to LeTx. We also show that LeTx-induced macrophage death requires caspase-1, which is activated in susceptible, but not resistant, macrophages after intoxication, suggesting that Nalp1b directly or indirectly activates caspase-1 in response to LeTx.     

Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes

The Wellcome Trust Case Control Consortium (WTCCC) primary genome-wide association (GWA) scan on seven diseases, including the multifactorial autoimmune disease type 1 diabetes (T1D), shows associations at P < 5 x 10(-7) between T1D and six chromosome regions: 12q24, 12q13, 16p13, 18p11, 12p13 and 4q27. Here, we attempted to validate these and six other top findings in 4,000 individuals with T1D, 5,000 controls and 2,997 family trios independent of the WTCCC study. We confirmed unequivocally the associations of 12q24, 12q13, 16p13 and 18p11 (P(follow-up) 相似文献   

Recommendations of the 2006 Human Variome Project meeting

Lists of variations in genomic DNA and their effects have been kept for some time and have been used in diagnostics and research. Although these lists have been carefully gathered and curated, there has been little standardization and coordination, complicating their use. Given the myriad possible variations in the estimated 24,000 genes in the human genome, it would be useful to have standard criteria for databases of variation. Incomplete collection and ascertainment of variants demonstrates a need for a universally accessible system. These and other problems led to the World Heath Organization-cosponsored meeting on June 20-23, 2006 in Melbourne, Australia, which launched the Human Variome Project. This meeting addressed all areas of human genetics relevant to collection of information on variation and its effects. Members of each of eight sessions (the clinic and phenotype, the diagnostic laboratory, the research laboratory, curation and collection, informatics, relevance to the emerging world, integration and federation and funding and sustainability) developed a number of recommendations that were then organized into a total of 96 recommendations to act as a foundation for future work worldwide. Here we summarize the background of the project, the meeting and its recommendations.     

How to halve ploidy: lessons from budding yeast meiosis

Maintenance of ploidy in sexually reproducing organisms requires a specialized form of cell division called meiosis that generates genetically diverse haploid gametes from diploid germ cells. Meiotic cells halve their ploidy by undergoing two rounds of nuclear division (meiosis I and II) after a single round of DNA replication. Research in Saccharomyces cerevisiae (budding yeast) has shown that four major deviations from the mitotic cell cycle during meiosis are essential for halving ploidy. The deviations are (1) formation of a link between homologous chromosomes by crossover, (2) monopolar attachment of sister kinetochores during meiosis I, (3) protection of centromeric cohesion during meiosis I, and (4) suppression of DNA replication following exit from meiosis I. In this review we present the current understanding of the above four processes in budding yeast and examine the possible conservation of molecular mechanisms from yeast to humans.     

Mitochondrial DNA replication and disease: insights from DNA polymerase γ mutations

DNA polymerase γ (pol γ), encoded by POLG, is responsible for replicating human mitochondrial DNA. About 150 mutations in the human POLG have been identified in patients with mitochondrial diseases such as Alpers syndrome, progressive external ophthalmoplegia, and ataxia-neuropathy syndromes. Because many of the mutations are described in single citations with no genotypic family history, it is important to ascertain which mutations cause or contribute to mitochondrial disease. The vast majority of data about POLG mutations has been generated from biochemical characterizations of recombinant pol γ. However, recently, the study of mitochondrial dysfunction in Saccharomyces cerevisiae and mouse models provides important in vivo evidence for the role of POLG mutations in disease. Also, the published 3D-structure of the human pol γ assists in explaining some of the biochemical and genetic properties of the mutants. This review summarizes the current evidence that identifies and explains disease-causing POLG mutations.