Genomics Insights Into High-Latitude Adaptation of Tibetan Macaques

Few nonhuman primates inhabit high-latitude regions that pose significant adaptive challenges. The Tibetan macaque (Macaca thibetana) represents a rare primate species entirely distributed north of the Tropic of Cancer. To investigate the genetic basis underlying its adaptation to high latitudes, we generated a refined Tibetan macaque reference genome (99.41% completeness). Genomic analyses identified a species-specific homozygous mutation (Pro71Thr) in the TBX6 gene, which potentially explains their characteristic shortened tail morphology. Functional validation using CRISPR-Cas9-edited mice demonstrated that this mutation reduces caudal vertebrae count, providing a mechanistic basis for the shortened tail. Quantitative CT revealed that Tibetan macaques accumulated approximately 9.3-fold more abdominal fat than rhesus macaques. Genomic analysis uncovered enhanced lipid metabolic capacity supported by multiple sources of evidence: (1) positive selection on genes associated with lipid storage (DGAT2, DYSF, CAV1), adipogenesis (PRKD1), and appetite regulation (LEPR); (2) a 390-bp deletion in CPE; (3) expansions of gene families on oxidative phosphorylation and gluconeogenesis/glycolysis. These genetic variations may account for the marked differences in adipose tissue gene expression between the two macaque species. The shortened tail and increased fat accumulation represent key adaptations for thermoregulation and energy conservation in high-latitude habitats. Notably, all Tibetan macaque populations experienced long-term selection pressures from cold at high latitudes, which have not only shaped distinctive adaptive traits, but may also render the species particularly vulnerable to contemporary climate warming, particularly for the eastern populations.