Discovery of a polymorphic gene fusion via bottom-up chimeric RNA prediction.

Gene fusions and their chimeric products are commonly linked with cancer. However, recent studies have found chimeric transcripts in non-cancer tissues and cell lines. Large-scale efforts to annotate structural variations have identified 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, including notable cases such as SUZ12P1-CRLF3, TFG-ADGRG7 and TRPM4-PPFIA3, which possess distinct patterns across different ancestry groups. We provide direct evidence for an additional 29 polymorphic chimeric RNAs with associated structural variants, revealing 13 novel rare structural variants. Additionally, we utilize the All of Us dataset and a large cohort of clinical samples to characterize the association of the SUZ12P1-CRLF3-causing variant with patient phenotypes. Our study showcases SUZ12P1-CRLF3 as a representative example, illustrating the identification of elusive structural variants by focusing on those producing population-specific fusion transcripts.

Discovery of A Polymorphic Gene Fusion via Bottom-Up Chimeric RNA Prediction.

Gene fusions and their chimeric products are typically considered hallmarks of cancer. However, recent studies have found chimeric transcripts in non-cancer tissues and cell lines. In addition, efforts to annotate structural variation at large scale have found examples of gene fusions with potential to produce chimeric transcripts in normal tissues. In this report, we provide a means for targeting population-specific chimeric RNAs to enrich for those generated by gene fusion events. We identify 57 such chimeric RNAs from the GTEx cohort, including SUZ12P1-CRLF3 and TFG-ADGRG7 , whose distribution we assessed across the populations of the 1000 Genomes Project. We reveal that SUZ12P1-CRLF3 results from a common complex structural variant in populations with African heritage, and identify its likely mechanism for formation. Additionally, we utilize a large cohort of clinical samples to characterize the SUZ12P1-CRLF3 chimeric RNA, and find an association between the variant and indications of Neurofibramatosis Type I. We present this gene fusion as a case study for identifying hard-to-find and potentially functional structural variants by selecting for those which produce population-specific fusion transcripts. KEY POINTS: - Discovery of 57 polymorphic chimeric RNAs- Characterization of SUZ12P1-CRLF3 polymorphic chimeric RNA and corresponding rearrangement- Novel bottom-up approach to identify structural variants which produce transcribed gene fusions.