Broad Institute

About: Broad Institute is a nonprofit organization based out in Cambridge, Massachusetts, United States. It is known for research contribution in the topics: Population & Genome-wide association study. The organization has 6584 authors who have published 11618 publications receiving 1522743 citations. The organization is also known as: Eli and Edythe L. Broad Institute of MIT and Harvard.

Assemblathon 1: A competitive assessment of de novo short read assembly methods

Abstract: Low-cost short read sequencing technology has revolutionized genomics, though it is only just becoming practical for the high-quality de novo assembly of a novel large genome We describe the Assemblathon 1 competition, which aimed to comprehensively assess the state of the art in de novo assembly methods when applied to current sequencing technologies In a collaborative effort, teams were asked to assemble a simulated Illumina HiSeq data set of an unknown, simulated diploid genome A total of 41 assemblies from 17 different groups were received Novel haplotype aware assessments of coverage, contiguity, structure, base calling, and copy number were made We establish that within this benchmark: (1) It is possible to assemble the genome to a high level of coverage and accuracy, and that (2) large differences exist between the assemblies, suggesting room for further improvements in current methods The simulated benchmark, including the correct answer, the assemblies, and the code that was used to evaluate the assemblies is now public and freely available from http://wwwassemblathonorg/

Metabolic determinants of cancer cell sensitivity to glucose limitation and biguanides

Abstract: New apparatus is used to maintain proliferating cancer cells in low-glucose conditions, demonstrating that mitochondrial oxidative phosphorylation (OXPHOS) is essential for optimal proliferation in these conditions; the most sensitive cell lines are defective in OXPHOS upregulation and may therefore be sensitive to current antidiabetic drugs that inhibit OXPHOS. Using a new continuous-flow culture apparatus called Nutrostat, designed to ensure constant and controlled extracellular nutrient levels, David Sabatini and colleagues screened cancer cell lines for genes important when cells experience low glucose levels. They found that the ability of cells to increase mitochondrial oxidative phosphorylation under conditions of low glucose was crucial. Cancer cells unable to do so due to impaired glucose utilization or mitochondrial DNA mutations were particularly sensitive to a class of compounds, biguanides, which are in use to treat diabetes. These findings may lead to new therapeutic applications of these drugs to treat tumours displaying such defects. As the concentrations of highly consumed nutrients, particularly glucose, are generally lower in tumours than in normal tissues1,2, cancer cells must adapt their metabolism to the tumour microenvironment. A better understanding of these adaptations might reveal cancer cell liabilities that can be exploited for therapeutic benefit. Here we developed a continuous-flow culture apparatus (Nutrostat) for maintaining proliferating cells in low-nutrient media for long periods of time, and used it to undertake competitive proliferation assays on a pooled collection of barcoded cancer cell lines cultured in low-glucose conditions. Sensitivity to low glucose varies amongst cell lines, and an RNA interference (RNAi) screen pinpointed mitochondrial oxidative phosphorylation (OXPHOS) as the major pathway required for optimal proliferation in low glucose. We found that cell lines most sensitive to low glucose are defective in the OXPHOS upregulation that is normally caused by glucose limitation as a result of either mitochondrial DNA (mtDNA) mutations in complex I genes or impaired glucose utilization. These defects predict sensitivity to biguanides, antidiabetic drugs that inhibit OXPHOS3,4, when cancer cells are grown in low glucose or as tumour xenografts. Notably, the biguanide sensitivity of cancer cells with mtDNA mutations was reversed by ectopic expression of yeast NDI1, a ubiquinone oxidoreductase that allows bypass of complex I function5. Thus, we conclude that mtDNA mutations and impaired glucose utilization are potential biomarkers for identifying tumours with increased sensitivity to OXPHOS inhibitors.

Practical aspects of imputation-driven meta-analysis of genome-wide association studies

Abstract: Motivated by the overwhelming success of genome-wide association studies, droves of researchers are working vigorously to exchange and to combine genetic data to expediently discover genetic risk factors for common human traits. The primary tools that fuel these new efforts are imputation, allowing researchers who have collected data on a diversity of genotype platforms to share data in a uniformly exchangeable format, and meta-analysis for pooling statistical support for a genotype-phenotype association. As many groups are forming collaborations to engage in these efforts, this review collects a series of guidelines, practical detail and learned experiences from a variety of individuals who have contributed to the subject.