Ben Weisburd
A5062252445- Genomics and Rare Diseases
- Genomic variations and chromosomal abnormalities
- RNA modifications and cancer
- Genomics and Phylogenetic Studies
- Genetic Associations and Epidemiology
- Neurogenetic and Muscular Disorders Research
- RNA and protein synthesis mechanisms
- Genetic Neurodegenerative Diseases
- RNA Research and Splicing
- Cancer Genomics and Diagnostics
- Muscle Physiology and Disorders
- Cutaneous Melanoma Detection and Management
- Genetics and Neurodevelopmental Disorders
- Melanoma and MAPK Pathways
- CRISPR and Genetic Engineering
- Glycogen Storage Diseases and Myoclonus
- Virus-based gene therapy research
- Amyotrophic Lateral Sclerosis Research
- Prenatal Screening and Diagnostics
- Parkinson's Disease Mechanisms and Treatments
- Genetic factors in colorectal cancer
- Cancer-related molecular mechanisms research
- Protein Degradation and Inhibitors
- Genomics and Chromatin Dynamics
- Inflammatory Bowel Disease
Broad Institute
2016-2025
Massachusetts General Hospital
2016-2024
University of Wisconsin–Madison
2024
Hanover College
2024
Boston Children's Hospital
2023-2024
Broad Center
2021-2024
Massachusetts Institute of Technology
2017-2024
Brigham and Women's Hospital
2023-2024
Harvard University
2020-2024
Harry Perkins Institute of Medical Research
2023
Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation DNA sequence changes. Here we describe aggregation analysis high-quality exome (protein-coding region) 60,706 individuals diverse ancestries generated as part Exome Aggregation Consortium (ExAC). This catalogue diversity contains an average one variant every eight bases exome, provides direct evidence presence widespread mutational recurrence. We have used this to calculate...
Abstract Genetic variants that inactivate protein-coding genes are a powerful source of information about the phenotypic consequences gene disruption: crucial for function an organism will be depleted such in natural populations, whereas non-essential tolerate their accumulation. However, predicted loss-of-function enriched annotation errors, and tend to found at extremely low frequencies, so analysis requires careful variant very large sample sizes 1 . Here we describe aggregation 125,748...
Summary Genetic variants that inactivate protein-coding genes are a powerful source of information about the phenotypic consequences gene disruption: critical for an organism’s function will be depleted such in natural populations, while non-essential tolerate their accumulation. However, predicted loss-of-function (pLoF) enriched annotation errors, and tend to found at extremely low frequencies, so analysis requires careful variant very large sample sizes 1 . Here, we describe aggregation...
Structural variants (SVs) rearrange large segments of DNA
Transcriptome sequencing improves the diagnostic rate for Mendelian disease in patients whom genetic analysis has not returned a diagnosis.
Worldwide, hundreds of thousands humans have had their genomes or exomes sequenced, and access to the resulting data sets can provide valuable information for variant interpretation understanding gene function. Here, we present a lightweight, flexible browser framework display large population datasets genetic variation. We demonstrate its use exome sequence from 60 706 individuals in Exome Aggregation Consortium (ExAC). The ExAC provides gene- transcript-centric displays variation, critical...
Dissecting HCMV Gene Expression Most of us are infected with human cytomegalovirus (HCMV), but severe disease is almost always limited to immunocompromised individuals or newborn infants. The virus has a relatively large (∼240 kb) DNA genome and shows complex pattern gene transcription, hinting at regulatory coding capacity. Stern-Ginossar et al. (p. 1088 ) mapped ribosome positions on transcripts during the course viral infection fibroblast cells. data suggest presence novel open reading...
Productive herpesvirus infection requires a profound, time-controlled remodeling of the viral transcriptome and proteome. To gain insights into genomic architecture gene expression control in Kaposi's sarcoma-associated (KSHV), we performed systematic genome-wide survey transcriptional translational activity throughout lytic cycle. Using mRNA-sequencing ribosome profiling, found that transcripts encoding genes are promptly bound by ribosomes upon reactivation, suggesting their regulation is...
Abstract The acceleration of DNA sequencing in samples from patients and population studies has resulted extensive catalogues human genetic variation, but the interpretation rare variants remains problematic. A notable example this challenge is existence disruptive dosage-sensitive disease genes, even apparently healthy individuals. Here, by manual curation putative loss-of-function (pLoF) haploinsufficient genes Genome Aggregation Database (gnomAD) 1 , we show that one explanation for...
Abstract Naturally occurring human genetic variants that are predicted to inactivate protein-coding genes provide an in vivo model of gene inactivation complements knockout studies cells and organisms. Here we report three key findings regarding the assessment candidate drug targets using loss-of-function variants. First, even essential genes, which not tolerated, can be highly successful as inhibitory drugs. Second, most sufficiently rare genotype-based ascertainment homozygous or compound...
Upstream open reading frames (uORFs) are tissue-specific cis-regulators of protein translation. Isolated reports have shown that variants create or disrupt uORFs can cause disease. Here, in a systematic genome-wide study using 15,708 whole genome sequences, we show new upstream start codons, and disrupting stop sites existing uORFs, under strong negative selection. This selection signal is significantly stronger for arising genes intolerant to loss-of-function variants. Furthermore, creating...
Exome and genome sequencing have become the tools of choice for rare disease diagnosis, leading to large amounts data available analyses. To identify causal variants in these datasets, powerful filtering decision support that can be efficiently used by clinicians researchers are required. address this need, we developed seqr - an open-source, web-based tool family-based monogenic analysis allows work collaboratively search annotate genomic callsets. date, is being several research pipelines...
Genetic variants that cause rare disorders may remain elusive even after expansive testing, such as exome sequencing. The diagnostic yield of genome sequencing, particularly a negative evaluation, remains poorly defined.
Summary Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation DNA sequence changes. Here we describe aggregation analysis high-quality exome (protein-coding region) 60,706 individuals diverse ethnicities generated as part Exome Aggregation Consortium (ExAC). The resulting catalogue diversity contains an average one variant every eight bases exome, provides direct evidence presence widespread mutational recurrence. We show that...
CDK9 is the kinase subunit of positive transcription elongation factor b (P-TEFb) that enables RNA polymerase (Pol) II's transition from promoter-proximal pausing to productive elongation. Although considerable interest exists in as a therapeutic target, little progress has been made due lack highly selective inhibitors. Here, we describe development i-CDK9 such an inhibitor potently suppresses phosphorylation substrates and causes genome-wide Pol II pausing. While most genes experience...
Multi-nucleotide variants (MNVs), defined as two or more nearby existing on the same haplotype in an individual, are a clinically and biologically important class of genetic variation. However, tools typically do not accurately classify MNVs, understanding their mutational origins remains limited. Here, we systematically survey MNVs 125,748 whole exomes 15,708 genomes from Genome Aggregation Database (gnomAD). We identify 1,792,248 across genome with constituent falling within 2 bp distance...
Abstract Human genetic variants predicted to cause loss-of-function of protein-coding genes (pLoF variants) provide natural in vivo models human gene inactivation and can be valuable indicators function the potential toxicity therapeutic inhibitors targeting these 1,2 . Gain-of-kinase-function LRRK2 are known significantly increase risk Parkinson’s disease 3,4 , suggesting that inhibition kinase activity is a promising strategy. While preclinical studies model organisms have raised some...
Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) is a progressive late-onset, neurological disease. Recently, pentanucleotide expansion in intron 2 of RFC1 was identified as the genetic cause CANVAS. We screened an Asian-Pacific cohort for CANVAS novel repeat motif, (ACAGG)exp, three affected individuals. This motif associated with additional clinical features including fasciculations elevated serum creatine kinase. These have not previously been described individuals...
Abstract Hundreds of thousands genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier develops disease (termed penetrance) is unknown for virtually all them. Additionally, clinical utility common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult individuals (38,618 multi-ancestral type 2 diabetes case-control study and 38,566 participants UK Biobank, whom genotype array data were also available), we...
Abstract Pregnancy loss and perinatal death are devastating events for families. We assessed ‘genomic autopsy’ as an adjunct to standard autopsy 200 families who had experienced fetal or newborn death, providing a definitive candidate genetic diagnosis in 105 Our cohort provides evidence of severe atypical utero presentations known disorders identifies novel phenotypes disease genes. Inheritance 42% diagnoses were either autosomal recessive (30.8%), X-linked (3.8%) dominant (excluding de...
Abstract Oculopharyngodistal myopathy (OPDM) is an inherited manifesting with ptosis, dysphagia and distal weakness. Pathologically it characterised by rimmed vacuoles intranuclear inclusions on muscle biopsy. In recent years CGG • CCG repeat expansion in four different genes were identified OPDM individuals Asian populations. None of these have been found affected non-Asian ancestry. this study we describe the identification expansions ABCD3 , ranging from 118 to 694 repeats, 35 across...
As part of a broader collaborative network exome sequencing studies, we developed jointly called data set 5,685 Ashkenazi Jewish exomes. We make publicly available resource site and allele frequencies, which should serve as reference for medical genetics in the Ashkenazim (hosted at https://ibd.broadinstitute.org, also gnomAD http://gnomad.broadinstitute.org). estimate that 34% protein-coding alleles present population frequencies greater than 0.2% are significantly more frequent (mean...