Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder, and its incidence is rising rapidly with population aging. Pathologically, AD is characterized by the accumulation of amyloid-β (Aβ) plaques and hyperphosphorylated Tau neurofibrillary tangles. Human genomic studies have identified numerous risk alleles, with the APOE4 variant representing the strongest and most common genetic risk factor, present in approximately 75% of AD patients. However, APOE4 is neither necessary nor sufficient to cause disease, suggesting that additional genetic and environmental factors contribute to AD pathogenesis. Emerging evidence highlights a central role for oxidized lipid metabolism in AD. Disruption of lipid metabolism leads to lipid accumulation, reactive oxygen species (ROS) toxicity, and neurodegeneration, suggesting that oxidative stress may be a critical factor in enhancing AD susceptibility. To systematically investigate APOE function in vivo, we tested humanized Drosophila expressing the human APOE3, or APOE4 variants in place of the Drosophila ortholog Glial Lazarillo (GLaz). The lifespan of APOE3 and APOE4 flies do not differ under standard housing conditions, but the lifespan of APOE4 flies is significantly reduced when exposed to the ROS-promoting drug rotenone, supporting a multi-hit model of disease pathogenesis. APOE4 flies exposed to rotenone exhibit several AD-associated phenotypes, including age-related memory loss and chemosensory deficits, supporting the use of this model to investigate AD pathogenesis. Furthermore, progressive AD-associated phenotypes are also observed in APOE4 flies maintained on an obesogenic diet, suggesting that enhanced disease susceptibility is not specific to rotenone-induced stress but reflects a broader vulnerability to metabolic challenges. Together, these findings establish a scalable model to dissect APOE-dependent mechanisms and identify therapeutic targets in AD.
S. Biglari, Eshani Yeragi, David Bamisaye et al.· bioRxiv· 0 citations
Similar traits repeatedly evolve across independent populations in response to similar environmental conditions. For many repeatedly evolved traits, it is unknown if populations evolve similar traits through the same or different genetic mechanisms. To address this question, we leveraged the Mexican tetra fish, Astyanax mexicanus, which has repeatedly evolved many traits including reduced sleep duration, eye degeneration, and metabolic shifts to accommodate limited nutrient availability. We defined whether shared or independent genetic architecture governs the repeated evolution of sleep loss, increased food consumption, early onset adipose deposition, and eye loss in different evolutionary origins of the cavefish phenotype by using Quantitative Trait Locus (QTL) mapping across three cave x surface F2 mapping populations. We found that, among the traits evaluated, eye loss exhibits the most genetic repeatability, with ∼43% of QTL shared across lineages. Sleep loss and metabolic traits (i.e., feeding, adiposity) were genetically less repeatable, with only ∼25-33% of QTL shared across lineages. Next, we explored whether QTL for metabolism, eye loss, and sleep traits in cavefish co-localize in the cavefish genome and are inherited together to facilitate potential cavefish adaptation. Although these traits have repeatedly co-evolved in cave populations, we did not find evidence for extensive genetic linkage among them. Overall, we found that genetic repeatability is a common feature in the repeated evolution of cave traits, the extent of genetic repeatability varies across cave traits, and there is little evidence for widespread colocalization of sleep, eye loss, and metabolic traits within the genome.
Emilie Richards, Rachel L. Moran, Jonathan Wiese et al.· Genetics· 0 citations
The results reveal that recurrent deletion events have repeatedly contributed to the evolution of cave-adapted phenotypes and highlight deletions as underexplored contributors of adaptive evolution in a system characterized by trait loss.
Emma Y. Roback, Maggs X, Edward S. Ricemeyer et al.· bioRxiv· 1 citation
Zebrafish is established as an efficient vertebrate platform for functional interrogation of GWAS candidates and an evolutionarily conserved cerebellar role for MEIS1 in sleep maintenance is supported, indicating conserved regulatory architecture spanning the human insomnia-associated locus.
A. Zimmerman, Erika Almeraya Del Valle, M. Pahl et al.· Genome Research· 0 citations
Structural variants (SVs) are increasingly recognized as key contributors to adaptive evolution, yet they remain underexplored compared with single-nucleotide variation. To understand how large-scale genomic changes shape repeated evolution, we leveraged multiple levels of sequence data across the powerful evolutionary model system of the Mexican tetra fish (Astyanax mexicanus). We constructed one of the first pangenome graphs from a naturally evolving vertebrate, enabling comprehensive discovery of SVs among 120 fish from 11 populations. We discover substantial amounts of structural variation and explore the roles of genomic biases and selection in shaping the distribution of these variants. More than 2400 high-confidence cave-specific deletions are enriched in biological pathways involved in vision, metabolism, and behavior and cluster nonrandomly in quantitative trait loci linked to cavefish traits. Additionally, 67 genes harbor unique deletions between independent cavefish lineages. These reused genes show evidence of population-specific selection (99% contain selective sweeps compared with 8%-15% in genes lacking SVs), indicating that deletions likely rose in frequency through repeated positive selection rather than drift. Together, these results reveal that recurrent deletion events have repeatedly contributed to the evolution of cave-adapted phenotypes and highlight deletions as underexplored contributors of adaptive evolution in extreme environments.
Emma Y. Roback, Maggs X, Edward S. Ricemeyer et al.· Genome Research· 0 citations
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