Allele-specific alternative splicing in diploid human genomes. N. Raghupathy, K. Choi, S. C. Munger, G. A. Churchill The Jackson Laboratory, Bar Harbor, ME.

   Current practices for RNA-seq analysis employ three separate pipelines to quantify gene expression abundance, allele-specific expression (ASE), and alternative splicing. Gene-level abundance is estimated from alignment of all reads genome-wide, whereas ASE is assessed by analyzing only reads that overlap known SNP locations and alternative splicing is estimated by analyzing reads overlapping annotated splice junctions. We have developed computational tools, Seqnature and EMASE, to build individualized diploid genomes from phased genetic variations, align RNA-seq reads to individualized diploid transcriptomes, and estimate transcript abundance. The EM algorithm implemented in EMASE simultaneously estimates expression at the level of the allele, isoform and gene. Here we extend EMASE to include a splice-aware feature that enables the simultaneous estimation of allele-specific alternative splicing in addition to allele-specific and total gene abundances. The EM algorithm probabilistically allocates both allele and gene multi-mapping reads to estimate effective read counts at exons and splice-junctions. These read counts can be used to derive allele, isoform, and gene expression estimates. We demonstrate the utility of the approach using simulated and real human RNA-seq data from the 1000 Genomes Project Yoruban population as well as single cell RNA-seq data.

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