Isoform diversity

Scott Adamson

High throughput methods for identifying and validating variant effects on splicing regulation. Massively Parallel Reporter Assays (MPRAs).

Framework for high-throughput identification.

Aim 1. Hematological phenotype GWAS variants - coloc and ML predictions. Splicing relevant variants (sQTLs), SpliceAI high delta score, RNAprot high delta score.

Aim 2. Assay effects on splicing. CRISPR base editing, scRNA-seq library construction, hybrid capture of specific junctions and gRNAs, identification of splice-altering variants, validation of splice-altering variants on isoforms with ONT and mass spectrometry.

Prioritization of variants

sQTLs in 2953 clusters \(\rightarrow\) 7122 genomic loci for 15 phenotypes (UKBB and BCX) \(\rightarrow\) coloc with blood traits.

CRISPR base editing

44 tissue-cohort pairs. 10887 samples for sQTL analysis. 14 cohorts, ~29 tissues, 7 brain regions.