UBA1-CDK16: A female-specific chimeric RNA emerging through evolution and involved in immune regulation

Chimeric RNAs resulting from intergenic splicing represent a distinct mechanism for transcriptome expansion. To explore the role of this previously unidentified layer of the transcriptome in sex-specific immunity, we analyzed RNA sequencing data from 425 blood samples and identified a female-specific chimeric RNA, UBA1-CDK16, which was further validated in more than 1200 blood samples. This chimeric RNA forms via cis-splicing between two adjacent X-linked parental genes, UBA1 and CDK16, despite both being expressed in both sexes. We demonstrated that a female-specific chromatin loop at the UBA1-CDK16 junction sites facilitates the intergenic splicing. Evolutionary analysis revealed that UBA1-CDK16 became female specific in humans through at least two independent paths. Functional studies suggested that UBA1-CDK16 is enriched in the myeloid lineage and may regulate myeloid cell development. Notably, its abnormal expression in female patients with COVID-19 correlates with altered neutrophil counts, highlighting its potential role in the disease progression.