RNA-seq-based allele-specific expression reveals candidate expressed-variant differences in DMDmdx rat muscle

Abstract Duchenne muscular dystrophy (DMD) is a severe X-linked disorder characterized by progressive muscle degeneration due to dystrophin deficiency. While the primary variant in the DMD gene is well-characterized, disease severity often varies, suggesting the involvement of additional genetic modifiers. In this study, we performed high-resolution allele-specific expression (ASE) and single-nucleotide polymorphism (SNP) analyses using RNA-Seq in DMD mdx and wild-type (WT) Sprague-Dawley rats derived from the same breeding lineage. Despite this shared lineage, we detected a higher number of significant RNA-seq-supported ASE-associated SNPs in DMD mdx rats (3,440) compared to WT controls (1,883). However, these findings should be interpreted as candidate allelic imbalances requiring orthogonal validation. Functional annotation and in silico protein stability analyses predicted that several missense variants, including variants in Myh2 , Myh3 , Ttn , Obscn , and Aldoa , may affect protein function or stability. Functional enrichment analyses identified pathways related to muscle contraction, cytoskeletal organization, and immune responses. Together, these findings indicate differences in the RNA-seq-supported ASE profiles of DMD mdx and WT muscle and provide candidate loci for independent validation and further investigation of potential disease-modifying mechanisms in DMD.