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RNA processing mechanisms, such as alternative splicing and RNA editing, have been recognized as critical means to expand the transcriptome. Chimeric RNAs formed by intergenic splicing provide another potential layer of RNA diversification. By analyzing a large set of RNA-Seq data and validating results in over 1,200 blood samples, we identified UBA1-CDK16 , a female-specific chimeric transcript. Intriguingly, both parental genes, are expressed in males and females. Mechanistically, UBA1-CDK16 is produced by cis-splicing between the two adjacent X-linked genes, originating from the inactive X chromosome. A female-specific chromatin loop, formed between the junction sites, facilitates the alternative splicing of its readthrough precursor. This unique chimeric transcript exhibits evolutionary conservation, evolving to be female-specific from non-human primates to humans. Furthermore, our investigation reveals that UBA1-CDK16 is enriched in the myeloid lineage and plays a regulatory role in myeloid differentiation. Notably, female COVID-19 patients who tested negative for this chimeric transcript displayed higher counts of neutrophils, highlighting its potential role in disease pathogenesis. These findings support the notion that chimeric RNAs represent a new repertoire of transcripts that can be regulated independently from the parental genes, and a new class of RNA variance with potential implications in sexual dimorphism and immune responses.

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.