Whole genome sequencing identifies genetic variants associated with senescence-accelerated phenotype of OXYS rats

Age is the primary risk factor for age-related diseases, the early onset of which manifests as premature aging, whereas delayed development forms the basis for healthy aging and longevity. Adverse genetic variants contribute to premature aging and its diverse manifestations, including increased multimorbidity. Identifying the genetic underpinnings of premature aging and developing preventive approaches are essential to extending the human healthspan, which requires fundamental research using animal models. In this study, we performed whole-genome sequencing (coverage depth >25×) of OXYS rats – a unique model of premature aging characterized by the early onset of geriatric disorders, including cataracts, AMD-like retinopathy, Alzheimer’s disease-like pathology, osteoporosis, sarcopenia, and hypertrophic cardiomyopathy – using the parental Wistar/Icgn rat strain as a control. The screening for singlenucleotide variants (SNVs), short insertions/deletions (indels), and copy number variations (CNVs) and comparative genomic analysis revealed genetic variants unique to OXYS rats that are absent in other rat strains. Specifically, we identified a large deletion in the Fat1 enhancer, deletions in the promoter regions of Abcf1 and Gsta6, and missense variants in Cic, Akap6, Nqo2, Cerkl, Bfsp1, and Cmya5 that lead to amino acid substitutions in highly conserved protein regions. Bioinformatic analysis suggested that these variants may contribute to the key features of premature aging in OXYS rats. Notably, deletions in the Fat1 enhancer and Gsta6 promoter, alongside missense substitutions in Cic, Akap6, and Nqo2, may drive early neurodegeneration and cognitive deficits by disrupting neurogenesis, reducing neuronal survival, and impairing antioxidant defense. The deletion in the Abcf1 promoter and the missense variants in Cerkl may induce retinopathy features by disrupting retinal homeostasis and weakening the protection of photoreceptors and retinal pigment epithelium (RPE) cells against oxidative stress and apoptosis. Furthermore, the missense substitution in Bfsp1 likely contributes to early cataract development by reducing the stability of lens intermediate filaments. Finally, missense variants in Cmya5 and Akap6 may promote sarcopenia and cardiomyopathy via the destabilization of myofibrils in skeletal muscles and cardiomyocytes (Cmya5) and through impaired skeletal muscle regeneration and structural disorganization of cardiomyocytes (Akap6).

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