A5090448681- Genomics and Chromatin Dynamics
- Protein Degradation and Inhibitors
- Genomics and Phylogenetic Studies
- interferon and immune responses
- ATP Synthase and ATPases Research
- CRISPR and Genetic Engineering
- Epigenetics and DNA Methylation
- RNA and protein synthesis mechanisms
- Chromosomal and Genetic Variations
- Single-cell and spatial transcriptomics
- RNA modifications and cancer
- Genetic Mapping and Diversity in Plants and Animals
- Genetic Associations and Epidemiology
- RNA Research and Splicing
- Neuroblastoma Research and Treatments
- Cancer therapeutics and mechanisms
- Computational Drug Discovery Methods
- Ubiquitin and proteasome pathways
- Immune Cell Function and Interaction
- Adipose Tissue and Metabolism
- Bioinformatics and Genomic Networks
- Genetic Syndromes and Imprinting
- Receptor Mechanisms and Signaling
- Cancer, Hypoxia, and Metabolism
- Genetic diversity and population structure
Salk Institute for Biological Studies
2016-2025
University of California, San Diego
2021-2023
Stanford University
2013-2015
University of Chicago
2011-2014
Dana-Farber Cancer Institute
2014
Howard Hughes Medical Institute
2012-2013
University of Washington
2009-2010
European Bioinformatics Institute
2004
Wellcome Trust
2004
Noncoding genetic variation is a major driver of phenotypic diversity, but functional interpretation challenging. To better understand common associated with brain diseases, we defined noncoding regulatory regions for cell types the human brain. Whereas psychiatric disorders were primarily variants in transcriptional enhancers and promoters neurons, sporadic Alzheimer's disease (AD) largely confined to microglia enhancers. Interactome maps connecting disease-risk cell-type-specific revealed...
Selection acting on genomic functional elements can be detected by its indirect effects population diversity at linked neutral sites. To illuminate the selective forces that shaped hominid evolution, we analyzed distributions of human polymorphisms and sequence differences among five primate species relative to locations conserved features. Neutral in ancestral populations is substantially reduced near such features, resulting a surprisingly large genome average reduction due selection...
DNA Differences The extent to which genetic variation affects an individual's phenotype has been difficult predict because the majority of lies outside coding regions genes. Now, three studies examine chromatin individuals with diverse ancestry and (see Perspective by Furey Sethupathy ). Kasowski et al. (p. 750 , published online 17 October) examined how differences in states their correlation histone modifications, as well more general binding factors. Kilpinen 744 document is linked...
Nucleosomes are important for gene regulation because their arrangement on the genome can control which proteins bind to DNA. Currently, few human nucleosomes thought be consistently positioned across cells; however, this has been difficult assess due limited resolution of existing data. We performed paired-end sequencing micrococcal nuclease-digested chromatin (MNase–seq) from seven lymphoblastoid cell lines and mapped over 3.6 billion MNase–seq fragments create highest-resolution map...
DNA methylation is an important epigenetic regulator of gene expression. Recent studies have revealed widespread associations between genetic variation and levels. However, the mechanistic links remain unclear. To begin addressing this gap, we collected data at ∼300,000 loci in lymphoblastoid cell lines (LCLs) from 64 HapMap Yoruba individuals, genome-wide bisulfite sequence ten these individuals. We identified (at FDR 10%) 13,915 cis QTLs (meQTLs)—i.e., CpG sites which changes are...
Natural selection at one site shapes patterns of genetic variation linked sites. Quantifying the effects 'linked selection' on levels diversity is key to making reliable inference about demography, building a null model in scans for targets adaptation, and learning dynamics natural selection. Here, we introduce first method that jointly infers parameters distinct modes selection, notably background selective sweeps, from genome-wide data, functional annotations maps. The central idea...
Comparison of protein-coding DNA sequences from diverse primates can provide insight into these species' evolutionary history and uncover the molecular basis for their phenotypic differences. Currently, number available primate reference genomes limits genome-wide comparisons. Here we use targeted capture methods designed human to sequence regions, or exomes, four non-human species (three Old World monkeys one New monkey). Despite average divergence up 4% probes, are able ∼96% coding...
Abstract The amygdala processes positive and negative valence contributes to addiction, but the cell-type-specific gene regulatory programs involved are unknown. We generated an atlas of single-nucleus expression chromatin accessibility in outbred rats with high low cocaine addiction-like behaviors following prolonged abstinence. Differentially expressed genes between groups were enriched for energy metabolism across cell types. Rats addiction index (AI) showed increased relapse-like...
A scarcity of functionally validated enhancers in the human genome presents a significant hurdle to understanding how these cis-regulatory elements contribute diseases. We carry out highly multiplexed CRISPR-based perturbation and sequencing identify required for cell proliferation fitness 10 cancer lines. Our results suggest that enhancers, unlike their target genes, display high cell-type specificity chromatin features. They typically adopt modular structure, comprised activating enriched...
Chromatin architectural proteins interact with nucleosomes to modulate chromatin accessibility and higher-order structure. While these are almost certainly important for gene regulation they have been studied far less than the core histone proteins. Here we describe genomic distributions functional roles of two proteins: H1 high mobility group protein HMGD1 in Drosophila S2 cells. Using ChIP-seq, biochemical specific approaches, find that binds highly accessible regulatory active promoters....
Most GWAS loci are presumed to affect gene regulation, however, only ∼43% colocalize with expression quantitative trait (eQTLs). To address this colocalization gap, we identify eQTLs, chromatin accessibility QTLs (caQTLs), and histone acetylation (haQTLs) using molecular samples from three early developmental (EDev) tissues. Through colocalization, annotate 586 for 17 traits by QTL complexity, phenotype, temporal specificity. We show that highly enriched complex modules multiple elements...
Abstract Deep learning sequence models trained on personalized genomics can improve variant effect prediction, however, applications of these are limited by computational requirements for storing and reading large datasets. We address this with GenVarLoader, which stores genomic data in new memory-mapped formats optimal locality to achieve ∼1,000x faster throughput ∼2,000x better compression compared existing alternatives.
A longstanding barrier in genome engineering with CRISPR-Cas9 has been the inability to measure Cas9 edit outcomes and their functional effects at single-cell resolution. Here we present Superb-seq , a new technology that leverages T7 situ transcription RNA sequencing jointly on- off-target edits on gene expression. We performed 10,000 K562 cells, targeting four chromatin remodeler genes seven guide RNAs. identified 11,891 events 6,230 edited cells all on-target sites an additional 36 sites....
Transcribed regions in the human genome differ from adjacent intergenic transposable element density, crossover rates, and asymmetric substitution sequence composition patterns. We tested whether these differences reflect selection or are instead a byproduct of germline transcription, using publicly available gene expression data variety somatic tissues. Crossover rate shows strong negative correlation with meiotic tissues, suggesting that is inhibited by transcription. Strand-biased (G+T...
GATA3 is essential for T cell differentiation and surrounded by genome-wide association study (GWAS) hits immune traits. Interpretation of these GWAS challenging because gene expression quantitative trait locus (eQTL) studies lack power to detect variants with small effects on in specific types the genome region containing contains dozens potential regulatory sequences. To map sequences GATA3, we performed a high-throughput tiling deletion screen 2 Mb Jurkat cells. This revealed 23 candidate...
Abstract While many genetic variants have been associated with risk for human diseases, how these affect gene expression in various cell types remains largely unknown. To address this gap, the DICE (database of immune expression, quantitative trait loci (eQTLs), and epigenomics) project was established. Considering all conditions studied, we identified cis-eQTLs a total 12,254 unique genes, which represent 61% protein-coding genes expressed types. Strikingly, large fraction (41%) showed...
Summary A single gene may have multiple enhancers, but how they work in concert to regulate transcription is poorly understood. To analyze enhancer interactions throughout the genome, we developed a generalized linear modeling framework, GLiMMIRS, for interrogating effects from single-cell CRISPR experiments. We applied GLiMMIRS published dataset and tested between 46,166 pairs corresponding genes, including 264 ’high-confidence’ pairs. found that combine multiplicatively with limited...
Abstract Allele-specific sequencing reads provide a powerful signal for identifying molecular quantitative trait loci (QTLs), however they are challenging to analyze and prone technical artefacts. Here we describe WASP, suite of tools unbiased allele-specific read mapping discovery QTLs. Using simulated reads, RNA-seq ChIP-seq demonstrate that our approach has low error rate is far more than existing QTL approaches.
Abstract Genetic variants and de novo mutations in regulatory regions of the genome are typically discovered by whole-genome sequencing (WGS), however WGS is expensive most reads come from non-regulatory regions. The Assay for Transposase-Accessible Chromatin (ATAC-seq) generates sequences could potentially be used as a low-cost ‘capture’ method variant discovery, but its use this purpose has not been systematically evaluated. Here we apply seven callers to bulk single-cell ATAC-seq data...