Characterizing gene regulation in developing systems using single cell expression data
Developmental Neurobiology
Cell Biology
Final Report Abstract
Cell-to-cell heterogeneity provides valuable information for studying and understanding developmental processes as well as identifying rare subpopulations of cells. Recently developed single-cell RNA-sequencing (scRNA-seq) technologies enable an unbiased and comprehensive insight into cellular heterogeneity even for cell populations that otherwise seem homogeneous. However, the intrinsic properties of scRNA-seq data, such as low molecule read counts, zero inflation, overdispersion, are fundamentally different from bulk data and require the development of appropriate statistical models. As part of this project, I explored sensible mathematical models to describe the technical variation observed in scRNA-seq data. Of the models tested, the most promising was a negative binomial regression model with a regularized (i.e constrained) variance parameter. This model passes cleaner data into the downstream analysis, allowing for the discovery of subtle biological differences. In an application of the newly developed methods, I and other members of the Satija and Fishell labs detailed for the first time how interneurons emerge and diversify in the brain. We traced the lineage of interneurons from their earliest precursor states to their mature forms in mice, and identified key genetic programs that determine the fate of developing interneurons, as well as when these programs are switched on or off. The findings serve as a guide for efforts to shed light on interneuron function and may help inform new treatment strategies for disorders involving their dysfunction. The study has been published in the journal Nature and was covered by several online media outlets.
Publications
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Developmental diversification of cortical inhibitory interneurons. Nature 555, 457 (2018)
Mayer, Christian; Hafemeister, Christoph; Bandler, Rachel C.; Machold, Robert; Batista Brito, Renata; Jaglin, Xavier; Allaway, Kathryn; Butler, Andrew; Fishell, Gord & Satija, Rahul
