PQG Seminar Series

The goal of the PQG Seminar Series is to encourage the exchanging of ideas and promote interaction, collaboration, and research in quantitative genomics.  It seeks to further the development and application of quantitative methods, especially for high dimensional data, as well as focus on the training of quantitative genomic scientists.

2021/2022 Seminar Organizers: Sasha Gusev and Hailiang Huang

Please direct any logistical questions to Amanda King

Upcoming Seminar


PQG seminar meetings for the semester will be held by Zoom.  The link to each meeting will be posted along with the talk information.

Tuesday, September 21, 2021
1:00-2:00 PM
Join Zoom meeting:
https://harvard.zoom.us/meeting/register/tJMtcOqopjMvH9XGONRZ7ZeZDr7pUkw8t1Sl

Kyle Gaulton

Assistant Professor
Department of Pediatrics, UC San Diego

Interpreting complex disease genetics using single cell epigenomics

Genetic risk variants for complex disease are primarily non-coding, and single cell epigenomics provides new opportunities to dissect the cell type-specific cis regulatory function of risk variant activity.  In our recent work we have combined genetic association mapping and single cell epigenomics to annotate mechanisms of complex disease risk, several of which are described below. First, we performed single nuclear ATAC-seq (snATAC-seq) in 15.3k cells from primary pancreatic islets, which revealed 228,873 cell type candidate cis-regulatory elements (cCREs) in endocrine and other cell types. Within endocrine cell types we further identified epigenomic heterogeneity representing hormone producing and signaling responsive cell states and defined state-specific cis-regulatory programs within endocrine cell types. Genetic variants associated with type 2 diabetes (T2D) were enriched in both beta cell states whereas fasting glucose-associated variants were enriched only in beta cells from the hormone producing state.  We annotated risk variants at 380 known T2D signals in cell type cCREs and that were predicted to alter cCRE activity using machine learning and linked to target genes with single cell co-accessibility.  At the KCNQ1 locus, causal T2D risk variant rs231361 was predicted to affect a beta cell state-specific cCRE co-accessible with the INS promoter over 500kb distal, which we validated using genome editing in stem cell-derived beta cells. Second, we performed a genetic association study of type 1 diabetes (T1D) in 520,580 samples and fine-mapping of 136 known and novel T1D signals, which we combined with cell type-specific cis-regulatory programs defined using snATAC-seq in 131,554 cells from pancreas and peripheral blood.  T1D risk variants were enriched in cCREs active in T cells and beta cells as well as other cell types not previously implicated in T1D risk such as acinar and ductal cells of the exocrine pancreas. T1D variants at multiple loci mapped in exocrine-specific cCREs that were linked to genes with exocrine-specific expression. For example, at the CFTR locus T1D risk variant rs7795896 mapped in a ductal cCRE which regulated CFTR expression in ductal cells.  Third, we performed snATAC-seq in 66,843 nuclei from 10 peripheral blood mononuclear cell (PBMC) samples, and mapped chromatin quantitative trait loci (caQTLs) for immune cell types and sub-types. In total we identified 6,248 immune cell type caQTLs, including caQTLs with cell type-specific effects as well as with opposed effects on different cell types which are masked from bulk assays. We fine-mapped loci for 16 complex immune traits and diseases and identified immune cell type caQTLs at 517 candidate causal variants, many of which had cell type-specific effects. For example, at the BACH2 locus associated with T1D and other diseases, fine-mapped variant rs72928038 was a caQTL in naïve CD4+ T cells. In total, combining genetics and single cell epigenomics identifies cell types, cell states, genes and variants involved in complex disease risk.

2020-2021 Dates


September 21, 2021 - Kyle Gaulton, UC San Diego

Kyle Gaulton

Assistant Professor, Department of Pediatrics
UC San Diego

Interpreting complex disease genetics using single cell epigenomics

Genetic risk variants for complex disease are primarily non-coding, and single cell epigenomics provides new opportunities to dissect the cell type-specific cis regulatory function of risk variant activity.  In our recent work we have combined genetic association mapping and single cell epigenomics to annotate mechanisms of complex disease risk, several of which are described below. First, we performed single nuclear ATAC-seq (snATAC-seq) in 15.3k cells from primary pancreatic islets, which revealed 228,873 cell type candidate cis-regulatory elements (cCREs) in endocrine and other cell types. Within endocrine cell types we further identified epigenomic heterogeneity representing hormone producing and signaling responsive cell states and defined state-specific cis-regulatory programs within endocrine cell types. Genetic variants associated with type 2 diabetes (T2D) were enriched in both beta cell states whereas fasting glucose-associated variants were enriched only in beta cells from the hormone producing state.  We annotated risk variants at 380 known T2D signals in cell type cCREs and that were predicted to alter cCRE activity using machine learning and linked to target genes with single cell co-accessibility.  At the KCNQ1 locus, causal T2D risk variant rs231361 was predicted to affect a beta cell state-specific cCRE co-accessible with the INS promoter over 500kb distal, which we validated using genome editing in stem cell-derived beta cells. Second, we performed a genetic association study of type 1 diabetes (T1D) in 520,580 samples and fine-mapping of 136 known and novel T1D signals, which we combined with cell type-specific cis-regulatory programs defined using snATAC-seq in 131,554 cells from pancreas and peripheral blood.  T1D risk variants were enriched in cCREs active in T cells and beta cells as well as other cell types not previously implicated in T1D risk such as acinar and ductal cells of the exocrine pancreas. T1D variants at multiple loci mapped in exocrine-specific cCREs that were linked to genes with exocrine-specific expression. For example, at the CFTR locus T1D risk variant rs7795896 mapped in a ductal cCRE which regulated CFTR expression in ductal cells.  Third, we performed snATAC-seq in 66,843 nuclei from 10 peripheral blood mononuclear cell (PBMC) samples, and mapped chromatin quantitative trait loci (caQTLs) for immune cell types and sub-types. In total we identified 6,248 immune cell type caQTLs, including caQTLs with cell type-specific effects as well as with opposed effects on different cell types which are masked from bulk assays. We fine-mapped loci for 16 complex immune traits and diseases and identified immune cell type caQTLs at 517 candidate causal variants, many of which had cell type-specific effects. For example, at the BACH2 locus associated with T1D and other diseases, fine-mapped variant rs72928038 was a caQTL in naïve CD4+ T cells. In total, combining genetics and single cell epigenomics identifies cell types, cell states, genes and variants involved in complex disease risk.

October 5, 2021 - TBD

 

November 16, 2021 - Oliver Stegle, EMBL Heidelberg

Oliver Stegle

Professor of Computational Genomics and Systems Genetics
EMBL Heidelberg

December 7, 2021 - Olivier Delaneau, University of Lausanne

Olivier Delaneau

Professor, Systems and Population Genetics Group, Department of Computational Biology
University of Lausanne

February 8, 2022 - Melissa Gymrek, UC San Diego

Melissa Gymrek

Assistant Professor, Medicine
UC San Diego

March 1, 2022 - Priya Moorjani, UC Berkeley

Priya Moorjani

Assistant Professor, Dept. of Molecular and Cell Biology
UC Berkeley

April 12, 2022 - Alex Marson, UCSF

Alex Marson

Associate Professor, Director of the Gladstone-UCSF Institute of Genomic Immunology
UCSF

May 3, 2022 - Haky Im, University of Chicago

Assistant Professor of Medicine and Human Genetics
University of Chicago


Seminar Archive