Evolutionary hotspots of structural variation drive inter-individual differences in the expression of fusion transcripts in the human brain

Alternative splicing is a well-known contributor to transcriptomic diversity between individuals. Less explored are inter-gene splicing events, which generate fusion transcripts—RNA molecules combining exons from two or more distinct genes. In cancer, fusion transcripts frequently result from somatic structural rearrangements, yet it remains unclear to what extent germline structural variants in non-cancer tissues contribute to fusion transcript formation and inter-individual variability. We conducted a genome-wide fusion transcript analysis in post-mortem human brain tissues from 312 individuals, identifying 1458 distinct fusion transcripts in temporal cortex and cerebellum. We showed that many fusion transcripts have protein coding potential, further supported by ribosome profiling data. Fusion transcripts that were present in only part of the human population were predominantly located within segmental duplication (SD) ‘hotspots,’ highly copy number-variable genomic regions that are frequently linked to neurodevelopmental and neurodegenerative disorders. None of these variable fusion transcripts were present in chimpanzees or rhesus macaques, suggesting they are human-specific. Our study reveals that inter-individual variation in fusion transcript expression is a largely underappreciated source of genetic and transcriptomic diversity. Variable fusion transcripts originating from disease-associated SD hotspots in our genome may have yet unexplored functional consequences for physiological and pathophysiological processes in each individual.