A5033605698- Genetic Associations and Epidemiology
- Neuroinflammation and Neurodegeneration Mechanisms
- Single-cell and spatial transcriptomics
- Genomic variations and chromosomal abnormalities
- Bipolar Disorder and Treatment
- Immune Cell Function and Interaction
- Cell Image Analysis Techniques
- T-cell and B-cell Immunology
- Genomics and Rare Diseases
- Complement system in diseases
- Tumors and Oncological Cases
- Innovative Microfluidic and Catalytic Techniques Innovation
- Ubiquitin and proteasome pathways
- Digital Imaging in Medicine
- Mitochondrial Function and Pathology
- Systemic Lupus Erythematosus Research
- Endoplasmic Reticulum Stress and Disease
- Receptor Mechanisms and Signaling
- Vascular Malformations and Hemangiomas
- Surgical Sutures and Adhesives
- Organ and Tissue Transplantation Research
- Cancer Genomics and Diagnostics
- Genetic Neurodegenerative Diseases
- Biosensors and Analytical Detection
- CRISPR and Genetic Engineering
Harvard University
2015-2025
Broad Institute
2014-2025
Brigham and Women's Hospital
2023-2024
Massachusetts Institute of Technology
2023
Boston VA Research Institute
2022
Howard Hughes Medical Institute
2015
Boston Children's Hospital
2015
Stanley Foundation
2015
Stanley Center for Psychiatric Research
2015
Cells use ubiquitin to mark proteins for proteasomal degradation. Although the proteasome also eliminates that are not ubiquitinated, how this occurs mechanistically is unclear. Here, we found midnolin promoted destruction of many nuclear proteins, including transcription factors encoded by immediate-early genes. Diverse stimuli induced midnolin, and its overexpression was sufficient cause degradation targets a mechanism did require ubiquitination. Instead, associated with via an α helix,...
Abstract Human brains vary across people and over time; such variation is not yet understood in cellular terms. Here we describe a relationship between people’s cortical neurons astrocytes. We used single-nucleus RNA sequencing to analyse the prefrontal cortex of 191 human donors aged 22–97 years, including healthy individuals with schizophrenia. Latent-factor analysis these data revealed that, whose more strongly expressed genes encoding synaptic components, astrocytes distinct functions...
Abstract Huntington Disease (HD) is a fatal genetic disease in which most striatal projection neurons (SPNs) degenerate. The central biological question about HD pathogenesis has been how the disease-causing DNA repeat expansion (CAG n ) huntingtin ( HTT gene leads to neurodegeneration after decades of apparent latency. Inherited alleles with longer CAG hasten onset; length this also changes over time, generating somatic mosaicism, and genes that regulate DNA-repeat stability can influence...
A somatic mutation in GNAQ (c.548G>A; p.R183Q), encoding Gαq, has been found syndromic and sporadic capillary malformation tissue. However, the specific cell type containing is unknown. The purpose of this study was to determine which cells malformations have mutation.Human tissue obtained from 13 patients during a clinically indicated procedure. Droplet digital polymerase chain reaction, capable detecting mutant allelic frequencies as low 0.1 percent, used quantify abundance Six specimens...
Abstract Copy number variants (CNVs) are among the largest genetic variants, yet CNVs have not been effectively ascertained in most association studies. Here we protein-altering from UK Biobank whole-exome sequencing data ( n = 468,570) using haplotype-informed methods capable of detecting subexonic and variation within segmental duplications. Incorporating into analyses rare predicted to cause gene loss function (LOF) identified 100 associations LOF with 41 quantitative traits. A...
Determining the chromosomal phase of pairs sequence variants – arrangement specific alleles as haplotypes is a routine challenge in molecular genetics. Here we describe Drop-Phase, method for quickly ascertaining DNA (separated by 1-200 kb) without cloning or manual single-molecule dilution. In each Drop-Phase reaction, genomic segments are isolated tens thousands nanoliter-sized droplets together with allele-specific fluorescence probes, single reaction well. Physically linked partition...
Summary The midnolin-proteasome pathway degrades many nuclear proteins without ubiquitination, but how it operates mechanistically remains unclear. Here, we present structures of the complex, revealing established proteasomal components are repurposed to enable a unique form proteolysis. While subunit PSMD2/Rpn1 binds ubiquitinated or ubiquitin-like proteins, discover that also interacts with midnolin localization sequence, elucidating midnolin’s activity is confined nucleus. Likewise,...
Abstract Bipolar disorder (BD) is a heritable mental illness with complex etiology. We performed genome-wide association study (GWAS) of 41,917 BD cases and 371,549 controls European ancestry, which identified 64 associated genomic loci. risk alleles were enriched in genes synaptic signaling pathways brain-expressed genes, particularly those high specificity expression neurons the prefrontal cortex hippocampus. Significant signal enrichment was found encoding targets antipsychotics, calcium...
Abstract Retrotransposons comprise about 45% of the human genome 1 , but their contributions to trait variation and evolution are only beginning be explored 2,3 . Here, we find that a sequence SVA retrotransposon insertions in an early intron ASIP (agouti signaling protein) gene has probably shaped pigmentation several times. In UK Biobank ( n = 169,641), recent 3.3-kb insertion polymorphism associated strongly with lighter skin (0.22 [0.21–0.23] s.d.; P 2.8 × 10 −351 ) increased cancer risk...
It is largely unknown which human genetic variants shape a person's oral microbiome and potentially promote its dysbiosis. We characterized the microbiomes of 12,519 people by analyzing whole-genome sequencing reads from previously sequenced saliva-derived DNA. Human variation at 11 loci (10 novel) associated with differences in composition. Nearly all these associations implicated candidate genes readily interpretable functions, several related to carbohydrate availability. The strongest...
Genome-wide association studies (GWAS) have identified thousands of disease-associated loci, yet their interpretation remains limited by the heterogeneity underlying biological processes. We propose Joint Pleiotropic and Epigenomic Partitioning (J-PEP), a clustering framework that integrates pleiotropic SNP effects on auxiliary traits tissue-specific epigenomic data to partition loci into biologically distinct clusters. To benchmark J-PEP against existing methods, we introduce...
The mammalian brain is composed of diverse, specialized cell populations, few which we fully understand. To more systematically ascertain and learn from cellular specializations in the brain, used Drop-seq to perform single-cell RNA sequencing 690,000 cells sampled nine regions adult mouse brain: frontal posterior cortex (156,000 99,000 cells, respectively), hippocampus (113,000), thalamus (89,000), cerebellum (26,000), all basal ganglia – striatum (77,000), globus pallidus externus/nucleus...