The annotation of <i>GBA1</i> has been concealed by its protein-coding pseudogene <i>GBAP1</i>

Abstract

Mutations in <i>GBA1</i> cause Gaucher disease and are the most important genetic risk factor for Parkinson's disease. However, analysis of transcription at this locus is complicated by its highly homologous pseudogene, <i>GBAP1</i>. We show that >50% of short RNA-sequencing reads mapping to <i>GBA1</i> also map to <i>GBAP1</i>. Thus, we used long-read RNA sequencing in the human brain, which allowed us to accurately quantify expression from both <i>GBA1</i> and <i>GBAP1</i>. We discovered significant differences in expression compared to short-read data and identify currently unannotated transcripts of both <i>GBA1</i> and <i>GBAP1</i>. These included protein-coding transcripts from both genes that were translated in human brain, but without the known lysosomal function-yet accounting for almost a third of transcription. Analyzing brain-specific cell types using long-read and single-nucleus RNA sequencing revealed region-specific variations in transcript expression. Overall, these findings suggest nonlysosomal roles for <i>GBA1</i> and <i>GBAP1</i> with implications for our understanding of the role of <i>GBA1</i> in health and disease.