Genome-wide Association Study of Splicing in Humans

Balakrishnan, Aiswarya (2023) Genome-wide Association Study of Splicing in Humans. Masters thesis, Indian Institute of Science Education, and Research Kolkata.

Text (MS dissertatioon of Aiswarya Balakrishnan (18MS155)) Thesis_18MS155.pdf - Submitted Version Restricted to Repository staff only Download (2MB)

Abstract

The genomic DNA is transcribed into mRNA (messenger RNA), which is then translated into protein. After transcription, RNA undergoes a series of processing steps. RNA splicing is one of them in which some sections of the pre-mRNA (introns) are removed with the joining of the adjacent region (exons). The same RNA transcript can be differentially spliced into alternative isoforms with potentially different functions. About 95% of multi-exon genes in humans undergo alternative splicing. Which features govern splice-site choice? At present, we know that consensus splice sites (GU/AG) 5’ and 3’ splice sites, a polypyrimidine tract, and a branch point are required for a splicing reaction. Nevertheless, when multiple splice sites are present, how exactly splicing decisions are made is largely unknown. In addition, genetic variation can modulate splice-site choice, although the specific link between genetic variation and splicing decision is still very difficult to infer. This project uses a unique approach to understand the genomic determinants of splicing that govern the splice site choice in humans. The in-house tool named SpliSER (Splice-site strength/usage Estimate from RNA-Seq), has been used for the empirical quantification of the usage of individual splice-sites from GTEx[3] RNA-seq data. This quantification can then be used as a phenotype to carry out SpliSER-GWAS to map genetic variation associated with differences in splicesite usage. This thesis presents GWAS results for heart atrial tissue pointing out the variants that are associated with variation in splicing. There were 80% of cis association and the rest were trans. This shows that most of the splice sites and associated SNPs are co-localized in the genome. Out of the splicing associated SNPs picked up by SpliSER-GWAS, there were 6% overlaps with disease/trait-associated SNPs already cataloged in Phenoscanner. This Genome-wide comparison of splicing patterns associated with genotypic variation in humans can help us unravel the general principles and mechanisms associated with splicing.

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