Discovery of a Polymorphic Gene Fusion via Bottom-Up Chimeric RNA Prediction: Case Study

Gene fusions and their associated chimeric RNAs have historically been recognized for their roles in cancer. However, recent research has increasingly detected chimeric transcripts in normal tissues and noncancerous cell lines. Extensive efforts have begun to annotate genomic structural variation, revealing gene fusions capable of generating chimeric transcripts even in normal tissues. In this study, we present a bottom-up approach targeting population-specific chimeric RNAs, identifying 58 such instances in the GTEx cohort. Among these, notable examples include SUZ12P1-CRLF3, TFG-ADGRG7, and TRPM4-PPFIA3, each associated with ancestry. We present direct genomic evidence for 29 polymorphic chimeric RNAs associated with structural variants, including 13 previously unreported rare variants. Additionally, utilizing data from the All of Us research program alongside a substantial clinical cohort, we characterized the clinical relevance of the SUZ12P1-CRLF3-associated variant. Collectively, our findings highlight the effectiveness of leveraging population-specific chimeric transcripts, exemplified by SUZ12P1-CRLF3, as a method for uncovering otherwise elusive transcribed genomic structural variants.