Domesticated cannabinoid synthases amid a wild mosaic cannabis pangenome

Ryan C. Lynch (), Lillian K. Padgitt-Cobb (), Andrea R. Garfinkel, Brian J. Knaus, Nolan T. Hartwick, Nicholas Allsing, Anthony Aylward, Philip C. Bentz, Sarah B. Carey, Allen Mamerto, Justine K. Kitony, Kelly Colt, Emily R. Murray, Tiffany Duong, Heidi I. Chen, Aaron Trippe, Alex Harkess, Seth Crawford, Kelly Vining and Todd P. Michael ()
Additional contact information
Ryan C. Lynch: The Salk Institute for Biological Studies
Lillian K. Padgitt-Cobb: The Salk Institute for Biological Studies
Andrea R. Garfinkel: Oregon CBD
Brian J. Knaus: Oregon State University
Nolan T. Hartwick: The Salk Institute for Biological Studies
Nicholas Allsing: The Salk Institute for Biological Studies
Anthony Aylward: The Salk Institute for Biological Studies
Philip C. Bentz: HudsonAlpha Institute for Biotechnology
Sarah B. Carey: HudsonAlpha Institute for Biotechnology
Allen Mamerto: The Salk Institute for Biological Studies
Justine K. Kitony: The Salk Institute for Biological Studies
Kelly Colt: The Salk Institute for Biological Studies
Emily R. Murray: The Salk Institute for Biological Studies
Tiffany Duong: The Salk Institute for Biological Studies
Heidi I. Chen: The Salk Institute for Biological Studies
Aaron Trippe: Oregon CBD
Alex Harkess: HudsonAlpha Institute for Biotechnology
Seth Crawford: Oregon CBD
Kelly Vining: Oregon State University
Todd P. Michael: The Salk Institute for Biological Studies

Nature, 2025, vol. 643, issue 8073, 1001-1010

Abstract: Abstract Cannabis sativa is a globally important seed oil, fibre and drug-producing plant species. However, a century of prohibition has severely restricted development of breeding and germplasm resources, leaving potential hemp-based nutritional and fibre applications unrealized. Here we present a cannabis pangenome, constructed with 181 new and 12 previously released genomes from a total of 144 biological samples including both male (XY) and female (XX) plants. We identified widespread regions of the cannabis pangenome that are surprisingly diverse for a single species, with high levels of genetic and structural variation, and propose a novel population structure and hybridization history. Across the ancient heteromorphic X and Y sex chromosomes, we observed a variable boundary at the sex-determining and pseudoautosomal regions as well as genes that exhibit male-biased expression, including genes encoding several key flowering regulators. Conversely, the cannabinoid synthase genes, which are responsible for producing cannabidiol acid and delta-9-tetrahydrocannabinolic acid, contained very low levels of diversity, despite being embedded within a variable region with multiple pseudogenized paralogues, structural variation and distinct transposable element arrangements. Additionally, we identified variants of acyl-lipid thioesterase genes that were associated with fatty acid chain length variation and the production of the rare cannabinoids, tetrahydrocannabivarin and cannabidivarin. We conclude that the C. sativa gene pool remains only partially characterized, the existence of wild relatives in Asia is likely and its potential as a crop species remains largely unrealized.

Date: 2025
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DOI: 10.1038/s41586-025-09065-0

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