Comprehensive Measurement of Inter‐Individual Variation in DNA Repair Capacity in Healthy Individuals

Rare genetic DNA repair deficiency syndromes can cause immunodeficiency, neurological disorders, and cancer. In the general population, inter-individual variation in DNA repair capacity (DRC) influences susceptibility to cancer and age-related diseases. Genome-wide association studies and functional analyses indicate that defects in multiple DNA repair pathways jointly increase disease risk, but previous technologies do not permit comprehensive population-level analysis. Fluorescence multiplex host cell reactivation (FM-HCR) assays now allow direct quantification of DRC across six major DNA repair pathways. DRC is assessed in phytohemagglutinin-stimulated primary lymphocytes from 56 healthy individuals, with reproducibility validated in 10 individuals across up to five independent blood draws. Generalized analytical pipelines are developed to systematically correct batch effects and experimental confounders. Significant inter-individual variation is observed across 10 reporter assays measuring distinct repair processes, with weak correlations between pathways suggesting independent disease susceptibility contribution. A complementary pipeline analyzing comet repair kinetics allows integration with previously reported comet data from the same individuals. This study underscores the sensitivity of FM-HCR assays in detecting subtle biological differences and establishes standardized methodologies for population research. The findings and open-source tools advance precision health by enabling comprehensive exploration of genetic and environmental determinants of DRC, supporting targeted interventions to maintain genomic integrity.