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Interestingly, many of the discovered interactions are associated with reduced disease risk while a substantially smaller number are associated with increased disease risk. We applied this approach to a Parkinson's disease (PD) GWAS study and found 50 statistically significant (FDR ?0.25) pathway level interactions, suggesting large genetic interaction structures indeed exist and can be discovered by leveraging structural properties with prior information on pathways. We developed a method that explicitly searches for such large structures, guided by established sets of genes belonging to characterized pathways. The key motivation, derived from the extensive analysis of genetic interaction networks in yeast, is that genetic interactions tend to occur between functionally compensatory modules rather than between isolated pairs of genes.
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We proposed a novel computational approach for discovering disease-specific, pathway-pathway genetic interactions from GWAS data. However, existing methods for identifying genetic interactions, which mainly focus on testing individual locus pairs, lack statistical power. Genetic interactions (epistasis) are important factors in complex diseases that may contribute to unexplained heritability in genome-wide association studies (GWAS). In contrast, we found little correlation between the likelihood of degradation by NMD and 3' UTR length in any of the three species. We found that the 50nt rule is a strong predictor of NMD degradation in human, and has an effect in zebrafish and in fly. We found that thousands of genes produce alternative isoforms degraded by NMD in the three species. To survey the targets of NMD genome-wide in human, zebrafish, and fly, we performed RNA-Seq analysis on cells where NMD has been inhibited via knockdown of UPF1, a critical NMD protein. There is also evidence that a longer 3’ UTR triggers NMD in plants, flies, and mammals. There is evidence that this rule holds in Arabidopsis but not in other eukaryotes such as Drosophila.
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The canonical model of defining a PTC in mammals is the 50nt rule: a termination codon more than 50 nucleotides upstream of an exon-exon junction is premature and triggers degradation. NMD coupled with alternative splicing is a mechanism of post-transcriptional gene regulation. Nonsense-mediated mRNA decay (NMD) is an RNA surveillance system that degrades isoforms containing a premature termination codon (PTC).