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Institution

Broad Institute

NonprofitCambridge, Massachusetts, United States
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.


Papers
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Journal ArticleDOI
24 Apr 2008-Nature
TL;DR: Tribolium castaneum is a member of the most species-rich eukaryotic order, a powerful model organism for the study of generalized insect development, and an important pest of stored agricultural products.
Abstract: Tribolium castaneum is a member of the most species-rich eukaryotic order, a powerful model organism for the study of generalized insect development, and an important pest of stored agricultural products. We describe its genome sequence here. This omnivorous beetle has evolved the ability to interact with a diverse chemical environment, as shown by large expansions in odorant and gustatory receptors, as well as P450 and other detoxification enzymes. Development in Tribolium is more representative of other insects than is Drosophila, a fact reflected in gene content and function. For example, Tribolium has retained more ancestral genes involved in cell-cell communication than Drosophila, some being expressed in the growth zone crucial for axial elongation in short-germ development. Systemic RNA interference in T. castaneum functions differently from that in Caenorhabditis elegans, but nevertheless offers similar power for the elucidation of gene function and identification of targets for selective insect control.

1,248 citations

Journal ArticleDOI
TL;DR: A new phasing algorithm, Eagle2, is introduced that attains high accuracy across a broad range of cohort sizes by efficiently leveraging information from large external reference panels (such as the Haplotype Reference Consortium; HRC) using a new data structure based on the positional Burrows-Wheeler transform.
Abstract: Po-Ru Loh, Alkes Price and colleagues present Eagle2, a reference-based phasing algorithm that allows for highly accurate and efficient phasing of genotypes across a broad range of cohort sizes. They demonstrate an approximately 10% improvement in accuracy and 20% improvement in speed compared to a competing method, SHAPEIT2.

1,246 citations

Posted ContentDOI
03 Oct 2019-bioRxiv
TL;DR: Analysis of the v8 data provides insights into the tissue-specificity of genetic effects, and shows that cell type composition is a key factor in understanding gene regulatory mechanisms in human tissues.
Abstract: The Genotype-Tissue Expression (GTEx) project was established to characterize genetic effects on the transcriptome across human tissues, and to link these regulatory mechanisms to trait and disease associations. Here, we present analyses of the v8 data, based on 17,382 RNA-sequencing samples from 54 tissues of 948 post-mortem donors. We comprehensively characterize genetic associations for gene expression and splicing in cis and trans, showing that regulatory associations are found for almost all genes, and describe the underlying molecular mechanisms and their contribution to allelic heterogeneity and pleiotropy of complex traits. Leveraging the large diversity of tissues, we provide insights into the tissue-specificity of genetic effects, and show that cell type composition is a key factor in understanding gene regulatory mechanisms in human tissues.

1,243 citations

Journal ArticleDOI
TL;DR: CERES, a computational method to estimate gene-dependency levels from CRISPR–Cas9 essentiality screens while accounting for the copy number–specific effect, is developed and found that CERES decreased false-positive results and estimated sgRNA activity for both this data set and previously published screens performed with different sg RNA libraries.
Abstract: The CRISPR-Cas9 system has revolutionized gene editing both at single genes and in multiplexed loss-of-function screens, thus enabling precise genome-scale identification of genes essential for proliferation and survival of cancer cells. However, previous studies have reported that a gene-independent antiproliferative effect of Cas9-mediated DNA cleavage confounds such measurement of genetic dependency, thereby leading to false-positive results in copy number-amplified regions. We developed CERES, a computational method to estimate gene-dependency levels from CRISPR-Cas9 essentiality screens while accounting for the copy number-specific effect. In our efforts to define a cancer dependency map, we performed genome-scale CRISPR-Cas9 essentiality screens across 342 cancer cell lines and applied CERES to this data set. We found that CERES decreased false-positive results and estimated sgRNA activity for both this data set and previously published screens performed with different sgRNA libraries. We further demonstrate the utility of this collection of screens, after CERES correction, for identifying cancer-type-specific vulnerabilities.

1,239 citations

Journal ArticleDOI
28 Apr 2011-Nature
TL;DR: In this paper, Shank3 gene deletions were found to lead to repetitive grooming and impaired social interaction in mice with autism spectrum disorders (ASDs) and other non-syndromic ASDs.
Abstract: Autism spectrum disorders (ASDs) comprise a range of disorders that share a core of neurobehavioural deficits characterized by widespread abnormalities in social interactions, deficits in communication as well as restricted interests and repetitive behaviours. The neurological basis and circuitry mechanisms underlying these abnormal behaviours are poorly understood. SHANK3 is a postsynaptic protein, whose disruption at the genetic level is thought to be responsible for the development of 22q13 deletion syndrome (Phelan–McDermid syndrome) and other non-syndromic ASDs. Here we show that mice with Shank3 gene deletions exhibit self-injurious repetitive grooming and deficits in social interaction. Cellular, electrophysiological and biochemical analyses uncovered defects at striatal synapses and cortico-striatal circuits in Shank3 mutant mice. Our findings demonstrate a critical role for SHANK3 in the normal development of neuronal connectivity and establish causality between a disruption in the Shank3 gene and the genesis of autistic-like behaviours in mice. Autism and autism spectrum disorders (ASDs) are neurodevelopmental disorders diagnosed based on a triad of criteria: deficits in communication, impaired social interaction, and repetitive or restricted interests and behaviours 1 . ASDs are highly heritable disorders with concordance rates as high as 90% for monozygotic twins 2 . Recent genetic and genomic studies have identified a large number of candidate genes for ASDs 3 , many of which encode synaptic proteins 4–6 , indicating synaptic dysfunction may have a critical role in ASDs 7,8 . One of the most promising ASD candidate genes is Shank3, which codes for a key postsynaptic density (PSD) protein at glutamatergic synapses. Disruption of Shank3 is thought to be the cause of core neurodevelopmental and neurobehavioural deficits in the 22q13 deletion syndrome (Phelan–McDermid syndrome), an autism spectrum disorder 9–11 . Furthermore, recent genetic screens have identified several mutations/rare variants of the Shank3 gene in ASD patients outside of diagnosed 22q13 deletion syndrome 12,13 . The Shank family of proteins (SHANK1–3) directly bind SAPAP (also known as DLGAP) to form the PSD-95–SAPAP–SHANK complex 14,15 (PSD-95 is also known as DLG4). This core of proteins is thought to function as a scaffold, orchestrating the assembly of the macromolecular postsynaptic signalling complex at glutamatergic synapses. Currently, however, little is known about the in vivo function of SHANK3 at the synapse and how a disruption of Shank3 may contribute to ASDs. Here we demonstrate that genetic disruption of Shank3 in mice leads to compulsive/repetitive behaviour and impaired social interaction, resembling two of the cardinal features of ASDs. Biochemical, morphological and electrophysiological studies revealed synaptic dysfunction at corticostriatal synapses, part of the neural circuits strongly implicated as dysfunctional in ASDs. Our studies provide a synaptic and circuitry mechanism underlying Shank3 disruption and ASD-like behaviours. Shank3B 2/2 mice display repetitive grooming

1,234 citations


Authors

Showing all 7146 results

NameH-indexPapersCitations
Eric S. Lander301826525976
Albert Hofman2672530321405
Frank B. Hu2501675253464
David J. Hunter2131836207050
Kari Stefansson206794174819
Mark J. Daly204763304452
Lewis C. Cantley196748169037
Matthew Meyerson194553243726
Gad Getz189520247560
Stacey Gabriel187383294284
Stuart H. Orkin186715112182
Ralph Weissleder1841160142508
Chris Sander178713233287
Michael I. Jordan1761016216204
Richard A. Young173520126642
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Performance
Metrics
No. of papers from the Institution in previous years
YearPapers
202337
2022627
20211,727
20201,534
20191,364
20181,107