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Kartha, Vinay

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Kartha

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Kartha, Vinay

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20192

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Author's Publications: search.filters.isAuthorOfPublication.0bcee112-dcc3-4361-9b08-a2773354efaf

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    Interrogation of human hematopoiesis at single-cell and single-variant resolution
    (Springer Science and Business Media LLC, 2019-03-11) Ulirsch, Jacob; Lareau, Caleb A.; Bao, Erik L.; Ludwig, Leif S.; Guo, Michael H.; Benner, Christian; Satpathy, Ansuman T.; Kartha, Vinay; Salem, Rany M.; Hirschhorn, Joel; Finucane, Hilary; Aryee, Martin; Buenrostro, Jason; Sankaran, Vijay
    Widespread linkage disequilibrium and incomplete annotation of cell-to-cell state variation represent substantial challenges to elucidating mechanisms of trait-associated genetic variation. Here, we perform genetic fine-mapping for blood cell traits in the UK Biobank to identify putative causal variants. These variants are enriched in genes encoding for proteins in trait-relevant biological pathways and in accessible chromatin of hematopoietic progenitors. For regulatory variants, we explore patterns of developmental enhancer activity, predict molecular mechanisms, and identify likely target genes. In several instances, we localize multiple independent variants to the same regulatory element or gene. We further observe that variants with pleiotropic effects preferentially act in common progenitor populations to direct the production of distinct lineages. Finally, we leverage fine-mapped variants in conjunction with continuous epigenomic annotations to identify trait-cell type enrichments within closely related populations and in single cells. Our study provides a comprehensive framework for single-variant and single-cell analyses of genetic associations.
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    Droplet-Based Combinatorial Indexing for Massive-Scale Single-Cell Chromatin Accessibility
    (Springer Science and Business Media LLC, 2019-06-24) Lareau, Caleb A.; Duarte, Fabiana; Chew, Jennifer G.; Kartha, Vinay; Burkett, Zach D.; Kohlway, Andrew S.; Pokholok, Dmitry; Aryee, Martin; Steemers, Frank J.; Lebofsky, Ronald; Buenrostro, Jason
    Recent technical advancements have facilitated the mapping of epigenomes at single-cell resolution; however, the throughput and quality of these methods have limited their widespread adoption. Here we describe a high-quality (105 nuclear fragments per cell) droplet-microfluidics-based method for single-cell profiling of chromatin accessibility. We use this approach, named ‘droplet single-cell assay for transposase-accessible chromatin using sequencing’ (dscATAC-seq), to assay 46,653 cells for the unbiased discovery of cell types and regulatory elements in adult mouse brain. We further increase the throughput of this platform by combining it with combinatorial indexing (dsciATAC-seq), enabling single-cell studies at a massive scale. We demonstrate the utility of this approach by measuring chromatin accessibility across 136,463 resting and stimulated human bone marrow-derived cells to reveal changes in the cis- and trans-regulatory landscape across cell types and under stimulatory conditions at single-cell resolution. Altogether, we describe a total of 510,123 single-cell profiles, demonstrating the scalability and flexibility of this droplet-based platform.