Manolis Kellis
@manoliskellis1·24.9K subscribers·255 videos
Single-cell dissection of human disease circuitry - Manolis Kellis at MGH DS Genetics Grand Rounds
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April 16, 2020
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1:03:04Now PlayingFrom Genomics to Therapeutics: single-cell dissection and manipulation of disease circuitry
Speaker: Manolis Kellis
Hosts: Brian Skotko and David Sweetster
Venue: MGH Genetics Grand Rounds
Date: April 16, 2020
Outline:
1. Reference epigenomes to predict disease-relevant tissues
- Epigenomic maps of non-coding elements across many cell types
- Immune causal basis of Alzheimer’s Disease: microglia vs. neurons
2. Combine genetic + epigenetic + expression variation in disease
- Mediation analysis: GWAS, mQTLs, MWAS, iMWAS. Imputation-based MWAS
- Causal genes, tissues, and directionality in known loci. Predict new loci
3. Single-cell dissection of epigenomic + transcriptional variation
- snRNA-seq in post-mortem brain: brain cell types, AD-specific global changes
- Stronger efct in women, scATAC, mosaicism. Scale: N=1123, regions, Sz/BD/ALS/FTD/HD
4. Cell-type-specific genetic effects: Integrate sc +bulk +GWAS +QTLS
- Deconvolution: 3000+ bulk with 48 sc. Cell fraction changes with AD / aging
- Genetics: Cell-fraction QTLs. Cell-type-specific eQTL effects for AD GWAS loci
5. Multi-phenotype integration: medical records imputation + expr
- AD sub-phenotypes: distinct epigenomic & functional enrichment signatures
- Medical records: EHR completion + imputation. Integration with expr in PTSD
6. Multi-tissue convergence/biomarkers in obesity/cancer/AD/aging
- Longitudinal multi-tissue multi-omics: metabolism, cancer/imm., convergence
- Blood monitoring: cfDNA, exosomes, immune epigenome, aging rate vs. APOE
7. High-throughput dissection of gene-regulatory circuitry in disease
- Modular/program. iPSC CRISPR Cas9/dCas9: gene/enhancer/SNP modulation
- Massively parallel assays: 384-plex KO/KD assays; HiDRA; brain in vivo MPRAs
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