The landscape of allele-specific expression in human kidneys

Allele-specific expression (ASE), the preferential expression of one gene copy, is a key mechanism of genomic regulation. However, its role in human kidney disease remains poorly understood. In this study, we generated a high-quality, genome-wide ASE map using paired whole-genome sequencing and RNA sequencing from microdissected glomerular and tubulointerstitial compartments of patients with proteinuric kidney disease. We showed that the majority of common ASE events were deterministic and sequence-mediated. We also found that diseased kidneys exhibited significantly more ASE in glomeruli (GLOM) than tubulointerstitium (TUBE) compared to controls. Unexpectedly, higher ASE in GLOM than TUBE was significantly associated with improved kidney disease outcomes in the disease cohort. Differential gene expression analysis suggested that this was the result of an active, protective transcriptional response, including ribosome and adenosine 5'-triphosphate synthesis up-regulation, rather than pathogenic dysregulation. Our work reveals glomerular ASE as a marker of adaptive transcriptional activity in proteinuric kidney disease.