Author(s) :

Karen Song.

Volume/Issue :

Abstract :

Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder characterized by motor neuron degeneration and progressive paralysis. Familial ALS, which accounts for 5–10% of cases, remains largely uncharacterized, shown by the large variability in disease progression among patients. Emerging evidence suggests that the disruption of DNA damage response (DDR) pathways may contribute to genome instability, a feature implicated in neurodegeneration. In this study, the model organism Caenorhabditis elegans is used to investigate how natural variation in DNA damage checkpoint genes: mrt-2, hus-1, hpr-17, and atm-1, all of which interact with or participate in the 9-1- 1 DNA damage response pathway, predicts vulnerability to oxidative stress. RNA-seq expression data from 208 genetically diverse C. elegans strains were normalized for sequencing depth (counts per million) after filtering out low-count transcripts. Three of the four genes showed significant differences in gene expression between the strains, with hpr-17 displaying the highest heritability. Cis-expression quantitative trait locus (cis-eQTL) mapping was used to analyze hard-filtered variant information from Caenorhabditis elegans Natural Diversity Resource (CaeNDR), revealing no strong local signal after kinship correction, suggesting trans-regulation, rare-variant effects, or epigenetics as influences of expression differences. To evaluate whether checkpoint gene expression predicts oxidative stress vulnerability, paraquat sensitivity data were obtained from the CaeNDR Public Phenotype Database and analyzed. The lower body length after paraquat exposure indicates greater sensitivity. Predictive models, including Ridge regression and XGBoost, were then applied to test whether checkpoint gene expression predicts sensitivity. Results suggest that variation in checkpoint expression does not predict oxidative stress sensitivity; however, an exploratory genetic scan identified a locus near hpr-17 that was associated with paraquat response, survived kinship correction, and was independently replicated using a larger imputed variant set, warranting further research to understand its direct effect on neuron health.