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Single cell transcriptomic technologies which capture high dimensional measurements of gene expression in individual cells have been exponentially scaling in the number of cells that can be sequenced and analyzed simultaneously. Capturing a snapshot of the landscape for possible gene expression measurements from a collection of cells enables researchers to observe the space of molecular variation inherent to specific biological systems, termed atlasing. A challenge to building deeply characterized atlases of complex biological systems such as the human brain is in the identification and correction of confounding factors which do not relate to the underlying biology but instead arise from technical confounders. In this dissertation I present deep learning models applied to single cell genomics which remove unwanted technical variation and contamination as well as perform novel analysis not previously possible using standard methods. The construction of single cell genomics atlases leverages recent advances in single cell RNA sequencing technologies such as 10X and SmartSeq which can capture thousands of cells in single experiment. When the sequencing of individual cells is performed on different technologies this introduces unwanted technical variation (bias) specific to the technology and confounds attempts to merge scRNA-seq experiments into more complete atlases. To address this challenge, we developed scAlign to remove the effects of unwanted technical variation on gene expression specifically, scRNA-seq alignment based on advances in computer vision. scAlign, an unsupervised deep learning method, performs data alignment that can incorporate partial, overlapping or a complete set of cell labels, and estimate per-cell differences in gene expression across datasets or conditions to characterize specific expression changes due to conditions such as age or disease. With the recent surge of atlases efforts across complex tissues, conditions, and species another challenge is how to integrate the deep characterizations of cell state with lower resolution assays of single cell or bulk genomics. Specifically, spatial and multi-omics assays do not collect RNA from a single cell but instead from a spot containing multiple cells or in the later contamination from the unintended collection of additional cells. We developed scProjection to join deeply sequenced atlases with lower resolution genomic assays to address the unwanted heterogeneity in mixed samples and project such samples in a way that recovers the underlying single-cell measurements. scProjection is demonstrated to accurately estimate the abundance of cell types that compose a mixed RNA sample while simultaneously identifying the gene expression measurements consistent for each cell type in the sample to identify cell type specific changes due spatial location of cells or disease state.

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