Methods for Identifying Allele-Specific Splicing Aberrations Associated With Human Hereditary Disease

Cygan, Kamil Jan

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Year:: 2018
Contributor:: Cygan, Kamil Jan (creator); Fairbrother, William (Advisor); Weinreich, Daniel (Reader); Neretti, Nicola (Reader); Helfand, Stephen (Reader); Sanford, Jeremy (Reader); Brown University. Division of Biology and Medicine (sponsor)
Genre:: theses
Subject:: Machine Learning; Population genetics; Computational biology; RNA splicing; Mutation (Biology); Variants; aberrations; Genetic disorders
Extent:: xxii, 154 p.
DOI: https://doi.org/10.26300/b2ww-3t36

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Abstract:: In eukaryotes, DNA is first transcribed into precursor-messenger RNA (pre-mRNA) which is then followed by extensive RNA processing events. One such event is RNA splicing, a process in which non-coding sequences (introns) are removed and the flanking protein-coding sequences (exons) are joined to generate mature RNA (mRNA) that can be translated into protein. It has been predicted that about one-third of human hereditary mutations affect RNA splicing. Most splicing mutations cause exon skipping, but may also lead to alternative splice site usage and intron retention. This thesis introduces a novel computational analysis for a massively parallel splicing reporter assay to detect human hereditary disease-associated allele-specific splicing events. Thousands of disease alleles and their wild-type counterparts were tested in high-throughput in vitro and in vivo assays for evidence of allelic imbalance and allele-specific aberrations in RNA splicing. Due to the plethora of information obtained from the study, we were able to observe that retinoblastomas are predominantly caused by defective splicing of the RB1 transcript. In a subsequent run of the assay, we investigated the splicing disruption potential of de novo variants in autism spectrum disorders. Using the results from the high-throughput experiments as a foundation for supervised statistical learning, we were able to extract relevant features that play significant roles in allele-specific splicing aberrations. We also generated multiple predictive tools for visualizing and identifying mutations that cause splicing defects, and measured the extent of aberrant splicing caused by these mutations.
Notes:: Thesis (Ph. D.)--Brown University, 2018

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Rights: In Copyright
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Cygan, Kamil Jan, "Methods for Identifying Allele-Specific Splicing Aberrations Associated With Human Hereditary Disease" (2018). Biology and Medicine Theses and Dissertations. Brown Digital Repository. Brown University Library. https://doi.org/10.26300/b2ww-3t36

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Biology and Medicine Theses and Dissertations

Theses and Dissertations for the Biology and Medicine department.
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