Comparison of degu (Octodon degus), Naked Mole Rat, Mouse and Human genomes identified common hallmarks of aging and Alzheimer's Disease

Abstract Background To provide new insight into the mechanisms of Alzheimer’s disease (AD) pathogenesis and aid the discovery of new therapies in humans it is important to expand and complement research using mouse models by developing, characterizing, and validating suitable new or unconventional mammalian, non‐murine models of AD. Our goal was to create genome assemblies at the chromosome level associated with AD‐like pathogenesis using two long‐lived animal models. The degu (Octodon degus) which naturally exhibits AD neuropathology and the naked mole rat (H. glaber) best known for its resistance to cancer and aging. To understand evolutionary paths to longevity and associated diseases like AD we characterized their genome features and identified common substitutions in long‐lived rodents that support enhanced tolerance to DNA damage. Method Synteny maps among M. musculus, H. glaber, H. sapiens and O. degus were created using SyMAP 5.0.6. To evaluate disease‐related mutations in humans a pairwise comparison of protein sequences was performed using the HGMD. Result We identified several synteny blocks that were part of the putative rodent ancestor genome. 78% genome was covered in H. glaber and 75% coverage in O. degus. In addition, 58 of the 426 synteny blocks were longer than 10 Mbp in M. musculus and 62 in O. degus. The identification of substitutions in orthologs at disease‐causing sites revealed that DNA damage and repair genes are under selection in long‐lived species. Our comparative genomic analyses identified that the top disease categories enriched in degu and naked mole rat were associated with lipid metabolism, DNA repair, stress and IGF‐1. Conclusion Our comparative genome analysis revealed changes in genes and pathways associated with adaptations to acquired longevity. Substitutions at AD causing sites may contribute to long‐term survival pathways affected by natural selection in long‐lived models. When compared to short‐lived mouse models, pathways associated with lipid metabolism, oxidative stress and DNA repair were identified. This data is particularly valuable for providing a within family (Rodentia) comparison for mouse AD model genomics to develop a comprehensive analysis to determine conserved genetic alterations between the unconventional animal models and to bridge our existing databases of mouse models and humans.