Yoon, J. G. | bioRxiv Science

bioRxiv2025

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-seq from microdissected glomerular (GLOM) and tubulointerstitial (TUBE) 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 GLOM than 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 this was the result of an active, protective transcriptional response, including ribosome and ATP synthesis upregulation, rather than pathogenic dysregulation. Our work reveals glomerular ASE as a marker of adaptive transcriptional activity in proteinuric kidney disease.

genomics↗

bioRxiv2025

A predictive framework for stop-loss variants with C-terminal extensions

Stop codons dictate translation termination, and variants occurring at these sites can result in stop-loss variants, leading to C-terminal extensions with potentially significant functional consequences. Despite their clinical relevance, existing prediction tools--primarily developed for missense variants--lack sufficient accuracy for assessing stop-loss variants, mainly due to their insufficiency in accounting for the sequence features of the extended peptide. To address this gap, we developed TAILVAR (Terminal codon Analysis and Improved prediction of Lengthened VARiants), a machine-learning classifier that integrates multi-omics features spanning transcript- and protein-level properties, along with variant effect annotations. Our analyses showed that transcripts lacking downstream stop codons in the 3 untranslated region exhibit lower evolutionary constraints. Additionally, we observed that deleterious variants exhibit greater C-terminal hydrophobicity, which is associated with reduced protein stability and increased degradation, as well as a higher aggregation propensity. TAILVAR outperformed existing benchmarks, demonstrating the highest correlation with functional experiments and establishing thresholds to classify variants as benign or pathogenic. This work offers a systematic framework for interpreting stop-loss variants, providing precise predictions of elongated protein effects that may aid genetic diagnosis and facilitate the discovery of novel disease-associated genes. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=72 SRC="FIGDIR/small/673407v1_ufig1.gif" ALT="Figure 1"> View larger version (15K): org.highwire.dtl.DTLVardef@1d53baaorg.highwire.dtl.DTLVardef@403289org.highwire.dtl.DTLVardef@b5c8b4org.highwire.dtl.DTLVardef@8bd61a_HPS_FORMAT_FIGEXP M_FIG C_FIG

genetics↗