Integrated detection and population-genetic analysis of SNPs and copy number variation

Dissecting the genetic basis of disease risk requires measuring all forms of genetic variation, including SNPs and copy number variants (CNVs), and is enabled by accurate maps of their locations, frequencies and population-genetic properties. We designed a hybrid genotyping array (Affymetrix SNP 6.0) to simultaneously measure 906,600 SNPs and copy number at 1.8 million genomic locations. By characterizing 270 HapMap samples, we developed a map of human CNV (at 2-kb breakpoint resolution) informed by integer genotypes for 1,320 copy number polymorphisms (CNPs) that segregate at an allele frequency >1%. More than 80% of the sequence in previously reported CNV regions fell outside our estimated CNV boundaries, indicating that large (>100 kb) CNVs affect much less of the genome than initially reported. Approximately 80% of observed copy number differences between pairs of individuals were due to common CNPs with an allele frequency >5%, and more than 99% derived from inheritance rather than new mutation. Most common, diallelic CNPs were in strong linkage disequilibrium with SNPs, and most low-frequency CNVs segregated on specific SNP haplotypes.     

Clustering and clique partitioning: Simulated annealing and tabu search approaches

We study the application of simulated annealing and tabu search to the solution of the clique partitioning problem. We illustrate the effecveness of these techniques by computational results associated not only with randomly generated problems, but also with real-life problems arising from applications concerning the optimal aggregation of binary relations into an equivalence relation. The need for these approaches is emphasized by the example of a special class of instances of the clique partitioning problem for which the most commonly used heuristics perform arbitrarily badly, while tabu search systematically obtains the optimal solution.

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Résumé Nous étudions dans cet article l'application du recuit simulé et de la méthode de recherche tabou dans la résolution du problème de partitionnement de graphes en cliques. Nous illustrons l'efficacité de ces techniques par des résultats numériques associés soit à des problèmes génerés au hasard, soit à des problèmes réels concernant l'agrégation de relations binaires dans une relation d'équivalence. L'intérêt de ces approches est mis en évidence à travers une classe de problèmes pour lesquels les heuristiques les plus connues ont une performance arbitrairement mauvaise, tandis que la méthode de recherche tabou obtient systématiquement des solutions optimales.

     

Mapping determinants of human gene expression by regional and genome-wide association

To study the genetic basis of natural variation in gene expression, we previously carried out genome-wide linkage analysis and mapped the determinants of approximately 1,000 expression phenotypes. In the present study, we carried out association analysis with dense sets of single-nucleotide polymorphism (SNP) markers from the International HapMap Project. For 374 phenotypes, the association study was performed with markers only from regions with strong linkage evidence; these regions all mapped close to the expressed gene. For a subset of 27 phenotypes, analysis of genome-wide association was performed with >770,000 markers. The association analysis with markers under the linkage peaks confirmed the linkage results and narrowed the candidate regulatory regions for many phenotypes with strong linkage evidence. The genome-wide association analysis yielded highly significant results that point to the same locations as the genome scans for about 50% of the phenotypes. For one candidate determinant, we carried out functional analyses and confirmed the variation in cis-acting regulatory activity. Our findings suggest that association studies with dense SNP maps will identify susceptibility loci or other determinants for some complex traits or diseases.     

A RING-type ubiquitin ligase family member required to repress follicular helper T cells and autoimmunity

Despite the sequencing of the human and mouse genomes, few genetic mechanisms for protecting against autoimmune disease are currently known. Here we systematically screen the mouse genome for autoimmune regulators to isolate a mouse strain, sanroque, with severe autoimmune disease resulting from a single recessive defect in a previously unknown mechanism for repressing antibody responses to self. The sanroque mutation acts within mature T cells to cause formation of excessive numbers of follicular helper T cells and germinal centres. The mutation disrupts a repressor of ICOS, an essential co-stimulatory receptor for follicular T cells, and results in excessive production of the cytokine interleukin-21. sanroque mice fail to repress diabetes-causing T cells, and develop high titres of autoantibodies and a pattern of pathology consistent with lupus. The causative mutation is in a gene of previously unknown function, roquin (Rc3h1), which encodes a highly conserved member of the RING-type ubiquitin ligase protein family. The Roquin protein is distinguished by the presence of a CCCH zinc-finger found in RNA-binding proteins, and localization to cytosolic RNA granules implicated in regulating messenger RNA translation and stability.     

Signaling pathways between the plasma membrane and endoplasmic reticulum calcium stores

This review discusses multiple ways in which the endoplasmic reticulum participates in and is influenced by signal transduction pathways. The endoplasmic reticulum provides a Ca2+ store that can be mobilized either by calcium-induced calcium release or by the diffusible messenger inositol 1,4,5-trisphosphate. Depletion of endoplasmic reticulum Ca2+ stores provides a signal that activates surface membrane Ca2+ channels, a process known as capacitative calcium entry. Depletion of endoplasmic reticulum stores can also signal long-term cellular responses such as gene expression and programmed cell death or apoptosis. In addition to serving as a source of cellular signals, the endoplasmic reticulum is also functionally and structurally modified by the Ca2+ and protein kinase C pathways. Elevated cytoplasmic Ca2+ causes a rearrangement and fragmentation of endoplasmic reticulum membranes. Protein kinase C activation reduces the storage capacity of the endoplasmic reticulum Ca2+ pool. In some cell types, protein kinase C inhibits capacitative calcium entry. Protein kinase C activation also protects the endoplasmic reticulum from the structural effects of high cytoplasmic Ca2+. The emerging view is one of a complex network of pathways through which the endoplasmic reticulum and the Ca2+ and protein kinase C signaling pathways interact at various levels regulating cellular structure and function.     

The relationship between the orientation of the early chick embryo and the shape of the egg shell

Résumé La forme de la coquille de l'uf, chez la poule, a une influence réelle sur l'orientation de l'embryon. Si la coquille est très allongée, le plan de symétrie de l'embryon est perpendiculaire à l'axe long de la coquille et l'orientation de l'embryon conforme à la règle devon Baer. Au contraire, si la coquille est arrondie, l'orientation de l'embryon est quelconque et, souvent, non conforme à la règle devon Baer.     

The role of interactional expertise in interpreting: the case of technology transfer in the steel industry

I analyse the case of three Japanese-Portuguese interpreters who have given support to technology transfer from a steel company in Japan to one in Brazil for more than thirty years. Their job requires them to be ‘interactional experts’ in steel-making. The Japanese–Portuguese interpreters are immersed in more than the language of steel-making as their job involves a great deal of ‘physical contiguity’ with steel-making practice. Physical contiguity undoubtedly makes the acquisition of interactional expertise easier. This draws attention to the lack of empirical work on the exact way that the physical and the linguistic interact in the acquisition of interactional expertise, or any other kind of expertise.