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

## TL;DR

This study identifies genetic adaptations in desert ungulates, particularly in lipid/sterol metabolism, that help them survive extreme environments.

## Contribution

The study reveals parallel amino acid substitutions in INSIG1, a gene involved in cholesterol biosynthesis, as a novel driver of metabolic flexibility in desert ungulates.

## Key findings

- Camel and antelope desert ungulates show convergent positive selection in genes related to energy metabolism and ion transport.
- INSIG1 mutations enhance lipid synthesis in energy-rich conditions and promote lipolysis during fasting in mice.
- Lower steroid-lipid levels in fasting camels suggest metabolic trade-offs for desert survival.

## 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.

A chromosome-level Bactrian camel genome and multi-omics comparisons reveal adaptive evolution and convergent selection in desert ungulates, highlighting lipid/sterol metabolism—especially INSIG1—as a key driver of metabolic flexibility for desert survival.