An Atlas of the Human uORFome and its Regulation across Tissues
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Upstream open reading frames (uORFs) are in frame start and stop codons starting in the 5’ leader of mRNAs. They have been found to regulate gene expression, primarily through translational inhibition by hindering ribosomes from reaching the protein coding ORF. Initial estimates concluded that almost half of the genes in the human genome contain uORFs, and studies have shown that uORF mediated mis-regulation can lead to health issues and disease. While some efforts have been made towards annotating uORFs, a comprehensive annotation of uORFs across the transcriptome and its regulation across tissues is lacking. This thesis presents methods for large scale detection of uORFs based on experimental and sequence-based data, and presents an atlas of the human uORFs and their use and regulation across more than 1000 samples in 122 tissues. uORFs need to be translated to act as regulators and from an initial population of 2.2 million candidates, my method identifies 21,766 uORFs as actively translated. Collectively, they show a strong bias towards a ATG/CTG start codon and disfavour codons known to disfavour translation, indicating that my method produces predictions of high accuracy.
PublisherThe University of Bergen
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