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

Abstract

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 genome for domestic Bactrian camel and integrate comparative genomics analyses to uncover genomic adaptation in arid-desert ungulates. We find elevated molecular evolution rates with intensified positive selection among desert-adapted lineages. Convergent positively selected genes are mainly involved in energy metabolism, and ion transport and homeostasis. In addition, we identify further evidence reveals numerous parallel amino acid substitution genes associated with lipid/sterol metabolism, particularly cholesterol biosynthesis. Cross-species metabolomics reveal 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 emerge as a key candidate. Functional validation reveals that the INSIG1 mutation enhances lipid synthesis in energy-rich hepatocytes and promotes lipolysis during fasting in genome-edited male mice. Altogether, these findings highlight lipid/sterol plasticity as a cornerstone of desert adaptation, providing insights into breeding drought-resistant livestock and advancing therapeutic strategies for human metabolic disorders.