Inbreeding depression is classically attributed to homozygosity of deleterious recessive alleles. However, environmental factors significantly modulate its severity. This hypothesis proposes that cellular receptors (e.g., glucocorticoid, nutrient-sensing, stress-response receptors) serve as key modulators of gene expression via epigenetic mechanisms. In variable or challenging environments (diverse diet, physical activity, temperature fluctuations), receptors maintain sensitivity, facilitating adaptive epigenetic responses (e.g., DNA methylation adjustments) that suppress or mitigate genetic defects. In contrast, static or sedentary lifestyles (predictable diet, low physical activity, minimal environmental challenges) induce receptor downregulation and desensitization through negative feedback loops and homeostatic dysregulation, impairing signal transduction and epigenetic repair pathways. This leads to increased manifestation of genetic defects, even in low-inbreeding or outbred populations. Supporting evidence from existing literature includes: ACE2 receptor variants explaining COVID-19 severity variations despite high genomic similarity. TRPM8/TRPV1 receptor activity differences in temperature tolerance. Captive animal studies showing glucocorticoid receptor desensitization and transgenerational amplification of inbreeding effects under static conditions (e.g., Malo et al., 2024). Sedentary behavior altering DNA methylation in immune and metabolic genes (Plaza-Florido et al., 2022; Światowy et al., 2021). Historical cases (Habsburg dynasty) and cultural practices (sibling marriage taboos) consistent with environment-dependent effects. The framework bridges epigenetics and receptor signaling, predicting that lifestyle interventions promoting variability could reverse desensitization. Testable predictions include receptor assays and epigenetic profiling in static vs. variable breeding models. Keywords: Receptor desensitization, epigenetic inheritance, inbreeding depression, sedentary lifestyle, glucocorticoid signaling, environmental modulation, evolutionary biology.
SK Chandra (Tue,) studied this question.