Eric Vallabh Minikel
A5033344556- Prion Diseases and Protein Misfolding
- Genomics and Rare Diseases
- Neurological diseases and metabolism
- Trace Elements in Health
- RNA regulation and disease
- Genetic Associations and Epidemiology
- RNA Research and Splicing
- Genomic variations and chromosomal abnormalities
- CRISPR and Genetic Engineering
- Folate and B Vitamins Research
- Genomics and Phylogenetic Studies
- RNA and protein synthesis mechanisms
- HIV Research and Treatment
- Bacteriophages and microbial interactions
- Health Systems, Economic Evaluations, Quality of Life
- Cardiomyopathy and Myosin Studies
- Inflammatory Bowel Disease
- Nutrition, Genetics, and Disease
- Genomics and Chromatin Dynamics
- Infectious Encephalopathies and Encephalitis
- Traffic and Road Safety
- Parkinson's Disease Mechanisms and Treatments
- Cancer Genomics and Diagnostics
- Computational Drug Discovery Methods
- Pharmacogenetics and Drug Metabolism
Broad Institute
2016-2025
Massachusetts General Hospital
2016-2025
Harvard University
2016-2025
Prion Alliance
2014-2025
Center for Pain and the Brain
2023
Sorbonne Université
2019-2020
Ikerbasque
2020
University of Zurich
2020
Massachusetts Institute of Technology
2011-2019
National Institute of Allergy and Infectious Diseases
2019
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
The accurate interpretation of variation in Mendelian disease genes has lagged behind data generation as sequencing become increasingly accessible. Ongoing large efforts present huge interpretive challenges, but they also provide an invaluable opportunity to characterize the spectrum and importance rare variation.We analyzed sequence from 7,855 clinical cardiomyopathy cases 60,706 Exome Aggregation Consortium (ExAC) reference samples obtain a better understanding genetic representative...
Large genomic reference data sets reveal a spectrum of pathogenicity in the prion protein gene and provide genetic validation for therapeutic strategy disease.
PurposeWhole-exome and whole-genome sequencing have transformed the discovery of genetic variants that cause human Mendelian disease, but discriminating pathogenic from benign remains a daunting challenge. Rarity is recognized as necessary, although not sufficient, criterion for pathogenicity, frequency cutoffs used in analysis are often arbitrary overly lenient. Recent very large reference datasets, such Exome Aggregation Consortium (ExAC), provide an unprecedented opportunity to obtain...
Expression, genetic variation, and tissues Human genomes show extensive variation across individuals, but we have only just started documenting the effects of this on regulation gene expression. Furthermore, a few been examined per variant. In order to examine how expression varies among within Genotype-Tissue Expression (GTEx) Consortium collected 1641 postmortem samples covering 54 body sites from 175 individuals. They identified quantitative traits that affect determined which these...
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...
Abstract The cost of drug discovery and development is driven primarily by failure 1 , with only about 10% clinical programmes eventually receiving approval 2–4 . We previously estimated that human genetic evidence doubles the success rate from to 5 In this study we leverage growth in over past decade better understand characteristics distinguish failure. estimate probability for mechanisms support 2.6 times greater than those without. This relative varies among therapy areas phases,...
Prion disease is caused by misfolding of the prion protein (PrP) into pathogenic self-propagating conformations, leading to rapid-onset dementia and death. However, elimination endogenous PrP halts progression. In this study, we describe Coupled Histone tail for Autoinhibition Release Methyltransferase (CHARM), a compact, enzyme-free epigenetic editor capable silencing transcription through programmable DNA methylation. Using histone H3 tail-Dnmt3l fusion, CHARM recruits activates...
Abstract Prion disease is a fatal neurodegenerative caused by the misfolding of prion protein (PrP) encoded PRNP gene. While there currently no cure for disease, depleting PrP in brain an established strategy to prevent or stall templated PrP. Here we developed vivo cytosine and adenine base strategies delivered adeno-associated viruses permanently modify locus achieve knockdown mouse brain. Systemic injection dual-adeno-associated virus PHP.eB encoding BE3.9max single guide RNA installing...
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...
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...
Prion disease is a fatal, incurable neurodegenerative of humans and other mammals caused by conversion cellular prion protein (PrPC) into self-propagating neurotoxic conformer (prions; PrPSc). Strong genetic proofs concept support lowering PrP expression as therapeutic strategy. Antisense oligonucleotides (ASOs) can provide practical route to 1 target mRNA in the brain, but their development for has been hindered 3 unresolved issues from prior work: uncertainty about mechanism action,...
Although its involvement in prion replication and neurotoxicity during transmissible spongiform encephalopathies is undisputed, the physiological role of cellular protein (PrPC) remains enigmatic. A plethora functions have been ascribed to PrPC based on phenotypes Prnp−/− mice. However, all currently available lines were generated embryonic stem cells from 129 strain laboratory mouse mostly crossed non-129 strains. Therefore, Prnp-linked loci polymorphic between backcrossing resulted...
Lowering of prion protein (PrP) expression in the brain is a genetically validated therapeutic hypothesis disease. We recently showed that antisense oligonucleotide (ASO)-mediated PrP suppression extends survival and delays disease onset intracerebrally prion-infected mice both prophylactic delayed dosing paradigms. Here, we examine efficacy this approach across diverse paradigms, varying dose regimen, strain, treatment timepoint, examining symptomatic, survival, biomarker readouts....
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...
To determine whether preventive trials in genetic prion disease could be designed to follow presymptomatic mutation carriers onset of disease.We assembled age at or death data from 1,094 individuals with high penetrance mutations the protein gene (PRNP) order generate survival and hazard curves test for modifiers onset. We used formulae simulations estimate statistical power clinical trials.Genetic varies over several decades most common neither sex, parent's onset, nor PRNP codon 129...
Antisense oligonucleotides (ASOs) designed to lower prion protein (PrP) expression in the brain through RNase H1-mediated degradation of PrP RNA are development as disease therapeutics. ASOs were previously reported sequence-independently interact with and inhibit accumulation cell culture, yet vivo studies using a new generation found that only PrP-lowering sequences effective at extending survival. Cerebrospinal fluid (CSF) has been proposed pharmacodynamic biomarker for trials such ASOs,...