INSIG1 parallel substitution drives lipid/sterol metabolic plasticity mediating desert adaptation in ungulates

Desert ungulates, such as Camelus bactrianus and Hippotraginae antelopes, exhibit extraordinary adaptation to extreme environment. Deciphering these genetic adaptations is critical for understanding evolutionary resilience under climate change. Here, we generate a chromosome-level domestic Bactrian camel genome and integrate comparative genomics analyses to uncover genomic adaptation in arid-desert ungulates. We found elevated molecular evolution rates with intensified positive selection among desert-adapted lineages. Convergent positive selection genes mainly involved in energy metabolism, and ion transport and homeostasis. Further evidence reveal numerous parallel amino acid substitution genes are involved in lipid/sterol metabolism, particularly cholesterol biosynthesis. Cross-species metabolomics further revealed lower steroid-lipid levels in fasting camel serum, suggesting that genetic adaptation promotes metabolic trade-offs for desert survival. INSIG1 involved in cholesterol biosynthesis process emerged as a key candidate. Functional validation revealed that the INSIG1 (H150R) mutation enhances lipid synthesis in energy-rich hepatocytes and promotes lipolysis during fasting in genome-edited INSIG1H150R/H150R mice. These findings highlight lipid/sterol plasticity as a cornerstone of desert adaptation, offering insights for breeding drought-resistant livestock and advancing therapeutic strategies for human metabolic disorders.