Thread by @thatdnaguy

#ASHG20 XX
Deciphering the function of single-nucleotide variants in the RNA.
Xinshu Xiao.

#ASHG20 XX How do you go from genotype to phenotypes with so much genetic data? Long way to go to tackle this challenge. Many different players from genotypes - phenotypes. Complex, interacting pathways lead to final phenotype.

#ASHG20 XX Many steps exist between RNA expression to degradation. Alternative polyadenylation. Alternative isoforms. RNA editing. From same DNA sequence diverse spectrum of RNA molecules can be produced.

#ASHG20 XX One of these steps is pre-mRNA splicing. Controlled by cis-acting motifs and trans-acting proteins. Complex network to control splicing decisions. Many RNA-binding proteins recognize specific RNA motifs. Means motif disruption can change binding kinetics.

#ASHG20 XX How do you identify these variants? One approach is to look for proteins that exhibit allele-specific binding to a particular target.

#ASHG20 XX transcriptome-wide discovery of ribosomal binding proteins (RBP) using eCLIP-seq.

#ASHG20 XX Use new method, BEAPR, to identify allele-specific binding from eCLIP data.
bit.ly/389maL9

#ASHG20 XX What is the functional consequence of allele-specific binding? Allele-specific splicing can be detected from RNA-Seq data.

#ASHG20 XX Allele-specific alternative splicing they are also calling genetically modulated alternative splicing (GMAS) events. Looked for these patterns in GTEx. Predict causal SNPs from GMAS events.

#ASHG20 XX How do GMAS patterns vary across tissues and individuals? Roughly equivalent variability between individuals as between tissues. [ Interesting! ]

#ASHG20 XX Low variance genes are often related to essential cellular function. Lots of variability in immune-system and immune-response genes.

#ASHG20 XX Concordance analysis. Looks to be able to model with Gaussian distributions. Help identify which SNP is functionally driving effect. Identified >1k putatively causative SNPs. Show positional bias around splice sites.

#ASHG20 XX 72% of GMAS SNPs are in LD with GWAS SNPs. Individual GWAS traits, see biggest relative enrichment with immune function and particular neurological disease categories.

#ASHG20 XX What tissues are enriched with each phenotype? GMAS enriched in brain-related tissues for bipolar trait GWAS hits.