Adaptive variation in butyrylcholinesterase-influenced lipid metabolism during horse domestication

Lipid metabolism influences horse athletic performance, yet its genetic basis remains unclear. Here, we investigate the genetic basis of lipid metabolic traits by quantifying key metabolic parameters and sequencing the genomes of 298 horses. We identify a missense mutation (ECA19:9,198,989, G>C) in the BCHE gene that is strongly associated with lipid metabolism, especially butyrylcholinesterase (BChE) activity. The "C" allele is associated with increased BChE activity and reduced intracellular triglyceride levels, hepatic adiposity, and overall fat mass, highlighting a central role for BCHE in lipid hydrolysis and fat storage in horses. This variant evolved neutrally across most of the horse domestication history outside Asia, but underwent strong positive selection in Asia until the 13th century CE. This spatiotemporal divergence suggests that Asian and non-Asian horses experienced distinct selective pressures on lipid metabolism, possibly reflecting differences in management practices, environmental conditions, or energetic demands before the rise of the Great Mongolian Empire.