Hypothesis\n\nIn reef-building corals, the dosage and inactivation state of the X chromosome directly modulate the expression of X-linked immune and oxidative‑stress genes that govern symbiont retention under thermal stress. Balanced X‑chromosome inactivation (XCI) yields a cellular mosaic that buffers deleterious alleles and enhances resilience, whereas skewed XCI compromises this buffering and increases bleaching susceptibility.\n\n### Mechanistic Insight\n\nThe X chromosome harbors a disproportionate number of genes involved in phagocytosis, pattern‑recognition receptors, and antioxidant enzymes (e.g., superoxide dismutase, catalase) that are critical for recognizing and regulating the intracellular Symbiodiniaceae. In female (XX) coral larvae, random XCI creates a mosaic of colonies where each cell expresses either the maternal or paternal X allele. This mosaicism ensures that, if one allele carries a loss‑of‑function variant, neighboring cells expressing the healthy allele can compensate via paracrine signaling, maintaining overall immune vigilance. With age or chronic stress, escape from X‑inactivation can up‑regulate a subset of these genes, boosting transcriptional output—an effect documented in mammalian hippocampus [[https://www.science.org/doi/10.1126/sciadv.ads8169]]. Conversely, skewed XCI, which increases with age and correlates with cardiovascular disease and cancer in mammals [[https://elifesciences.org/articles/78263]], reduces the frequency of compensatory cells, lowering the threshold for symbiont loss.\n\n### Testable Predictions\n\n1. Balanced XCI predicts higher symbiont density – XX larvae with a 50:50 maternal:paternal XCI ratio will retain significantly more Symbiodiniaceae cells after a 32 °C heat shock than larvae exhibiting >70 % skew toward one parental X.\n2. Artificial induction of Xist RNA to enforce monoallelic expression will phenocopy XY males – CRISPR‑dCas9‑XIST targeting to delete one active X in XX larvae will reduce survival and increase reactive oxygen species (ROS) levels under stress.\n3. Pharmacological alleviation of oxidative stress rescues the skewed‑XCI phenotype – Treatment with a superoxide dismutase mimetic will restore symbiont density in skewed‑XCI larvae to levels comparable with balanced controls.\n\n### Experimental Design (Falsifiable)\n\n- Generate isogenic lines of Acropora millepora larvae via controlled crosses to obtain known maternal and paternal X haplotypes distinguished by synonymous SNPs.\n- Allele‑specific RNA‑seq at 0 h, 6 h, and 24 h post‑heat shock to quantify XCI escape and allele‑specific expression of candidate X‑linked immune genes (e.g., Toll‑like receptor, NADPH oxidase).\n- Use fluorescence‑in‑situ hybridization (FISH) for X‑chromosome tracks to assess XCI skewness at the single‑cell level.\n- Measure symbiont density (chlorophyll a fluorescence), ROS (DCFDA assay), and larval survival over 72 h.\n- Apply the three manipulations above (natural skewness, Xist‑mediated monoallelic expression, antioxidant treatment) in a factorial layout.\n\nIf balanced XCI does not confer higher symbiont retention or survival, or if enforcing monoallelic expression fails to reduce resilience, the hypothesis is falsified. Conversely, confirmation would support the idea that the X chromosome functions as a longevity‑associated regulator of stress resilience even in non‑vertebrate, symbiotic marine organisms.