Description: To gain insight into the genomic basis of diffuse large B-cell lymphoma (DLBCL), we performed massively parallel whole-exome sequencing of 55 primary tumor samples from patients with DLBCL and matched normal tissue. We identified recurrent mutations in genes that are well known to be functionally relevant in DLBCL, including MYD88, CARD11, EZH2, and CREBBP. We also identified somatic mutations in genes for which a functional role in DLBCL has not been previously suspected. These genes include MEF2B, MLL2, BTG1, GNA13, ACTB, P2RY8, PCLO, and TNFRSF14. Further, we show that BCL2 mutations commonly occur in patients with BCL2/IgH rearrangements as a result of somatic hypermutation normally occurring at the IgH locus. The BCL2 point mutations are primarily synonymous, and likely caused by activation-induced cytidine deaminase–mediated somatic hypermutation, as shown by comprehensive analysis of enrichment of mutations in WRCY target motifs. Those nonsynonymous mutations that are observed tend to be found outside of the functionally important BH domains of the protein, suggesting that strong negative selection against BCL2 loss-of-function mutations is at play. Last, by using an algorithm designed to identify likely functionally relevant but infrequent mutations, we identify KRAS, BRAF, and NOTCH1 as likely drivers of DLBCL pathogenesis in some patients. Our data provide an unbiased view of the landscape of mutations in DLBCL, and this in turn may point toward new therapeutic strategies for the disease.

Description: Canada is a largely forested country, and the economic, environmental, and social effects of the country's wildland fire management are of great importance from an industry and public policy perspective. Investment in research can improve the efficiency of wildland fire management and has an important role in the decision-making process. There is a long history of research investment in Canada related to wildland fire management, including the development of the Canadian Forest Fire Danger Rating System (CFFDRS). To demonstrate the range of net benefits of the CFFDRS to Canadian society, a cost-benefit study was conducted on research related to enhancing the current system. The benefits of research were measured as the difference in economic returns with additional investment in research, primarily achieved through reduction in damages to timber resources and savings in suppression expenditure (the "with-research scenario") and those that would have resulted with no changes to the current CFFDRS (the "without-research scenario"). A triangular probability distribution was used to address uncertainty and the results indicated high levels of net economic benefit if the CFFDRS were to be enhanced by additional research investment, with "most likely" estimates of net present value ranging from $30 million to $1.5 billion ($Cdn).

Description: There is a general assumption that intraspecific populations originating from relatively arid climates will be better adapted to cope with the expected increase in drought from climate change. For ecologically and economically important species, more comprehensive, genecological studies that utilize large distributions of populations and direct measures of traits associated with drought-resistance are needed to empirically support this assumption because of the implications for the natural or assisted regeneration of species. We conducted a space-for-time substitution, common garden experiment with 35 populations of coastal Douglas-fir ( Pseudotsuga menziesii var. menziesii ) growing at three test sites with distinct summer temperature and precipitation (referred to as ‘cool/moist’, ‘moderate’ or ‘warm/dry’) to test the hypotheses that 1) there is large genetic variation among populations and regions in traits associated with drought-resistance, 2) the patterns of genetic variation are related to the native source-climate of each population, in particular with summer temperature and precipitation, 3) the differences among populations and relationships with climate are stronger at the warm/dry test site owing to greater expression of drought-resistance traits (i.e. a genotype × environment interaction). During mid-summer 2012, we measured the rate of water loss after stomatal closure (transpiration min ), water deficit (% below turgid saturation), and specific leaf area (SLA, cm 2 g −1 ) on new growth of sapling branches. There was significant genetic variation in all plant traits, with populations originating from warmer and drier climates having greater drought-resistance (i.e., lower transpiration min , water deficit and SLA), but these trends were most clearly expressed only at the warm/dry test site. Contrary to expectations, populations from cooler climates also had greater drought-resistance across all test sites. Multiple regression analysis indicated that Douglas-fir populations from regions with relatively cool winters and arid summers may be most adapted to cope with drought conditions that are expected in the future. This article is protected by copyright. All rights reserved.

Description: A comprehensive understanding of the molecular vulnerabilities of every type of cancer will provide a powerful roadmap to guide therapeutic approaches. Efforts such as The Cancer Genome Atlas Project will identify genes with aberrant copy number, sequence, or expression in various cancer types, providing a survey of the genes that may have a causal role in cancer. A complementary approach is to perform systematic loss-of-function studies to identify essential genes in particular cancer cell types. We have begun a systematic effort, termed Project Achilles, aimed at identifying genetic vulnerabilities across large numbers of cancer cell lines. Here, we report the assessment of the essentiality of 11,194 genes in 102 human cancer cell lines. We show that the integration of these functional data with information derived from surveying cancer genomes pinpoints known and previously undescribed lineage-specific dependencies across a wide spectrum of cancers. In particular, we found 54 genes that are specifically essential for the proliferation and viability of ovarian cancer cells and also amplified in primary tumors or differentially overexpressed in ovarian cancer cell lines. One such gene, PAX8, is focally amplified in 16% of high-grade serous ovarian cancers and expressed at higher levels in ovarian tumors. Suppression of PAX8 selectively induces apoptotic cell death of ovarian cancer cells. These results identify PAX8 as an ovarian lineage-specific dependency. More generally, these observations demonstrate that the integration of genome-scale functional and structural studies provides an efficient path to identify dependencies of specific cancer types on particular genes and pathways.

Description: : Next-generation sequencing is rapidly becoming the approach of choice for transcriptional analysis experiments. Substantial advances have been achieved in computational approaches to support these technologies. These approaches typically rely on existing transcript annotations, introducing a bias towards known genes, require specific experimental design and computational resources, or focus only on identification of splice variants (ignoring other biologically relevant transcribed features contained within the data that may be important for downstream analysis). Biologically relevant transcribed features also include large and small non-coding RNA, new transcription start sites, alternative promoters, RNA editing and processing of coding transcripts. Also, many existing solutions lack accessible interfaces required for wide scale adoption. We present a user-friendly, rapid and computation-efficient feature annotation framework (RNA-eXpress) that enables identification of transcripts and other genomic and transcriptional features independently of current annotations. RNA-eXpress accepts mapped reads in the standard binary alignment (BAM) format and produces a study-specific feature annotation in GTF format, comparison statistics, sequence extraction and feature counts. The framework is designed to be easily accessible while allowing advanced users to integrate new feature-identification algorithms through simple class extension, thus facilitating expansion to novel feature types or identification of study-specific feature types. Availability and implementation: RNA-eXpress software, source code, user manuals, supporting tutorials, developer guides and example data are available at http://www.rnaexpress.org . Contact: paul.hertzog@monash.edu Supplementary information: Supplementary data are available at Bioinformatics online.