World’s First Cannabis Chromosome Map Reveals the Plant’s Evolutionary History
The herb’s past points to its future as a potential medicine
Tetrahydrocannabinol (THC) and cannabidiol (CBD), bioactive substances produced by cannabis and sought by medical patients and recreational users, were created thanks to ancient colonization of the plant’s genome by viruses, which researchers at the Icahn School of Medicine at Mount Sinai and the University of Toronto report that they have identified for the first time.
The finding is only one of many insights revealed by the long-awaited cannabis genome map detailing gene arrangement on the chromosomes, published November 8, 2018, in the journal Genome Research. Among other revelations are discovery of a gene responsible for the production of cannabichromene (CBC), a lesser-known cannabinoid, and new insights into how the potency of a particular strain is determined.
“The chromosome map is an important foundational resource for further research which, despite cannabis’ widespread use, has lagged behind other crops due to restrictive legislation,” says Tim Hughes, PhD, a professor in the Donnelly Centre for Cellular and Biomolecular Research and co-leader of the study. Dr. Hughes is also a professor in the Department of Molecular Genetics and Senior Fellow at the Canadian Institute for Advancement of Research.
The researchers expect the map will speed up breeding efforts to create new strains with desired medical properties as well as varieties that can be grown more sustainably, or with increased resistance to diseases and pests.
The study was a three-part collaboration between Dr. Hughes’ team and those of Jonathan Page, PhD, of Aurora Cannabis and the University of British Columbia, and Harm van Bakel, PhD, of the Icahn School of Medicine at Mount Sinai in New York.
Drs. Hughes, Page, and van Bakel first got together in 2011 when they released the first draft of the cannabis genome, which was too fragmented to reveal gene position on chromosomes at the time.
The new map reveals how hemp and marijuana, which belong to the same species Cannabis sativa, evolved as separate strains with distinct chemical properties. Cannabis plants grown for drug use (“marijuana”) are abundant in psychoactive tetrahydrocannabinol, or THC, whereas hemp produces cannabidiol, or CBD, popular of late for its medicinal potential. Some people use CBD to relieve pain and it is also being tested as a treatment for epilepsy, schizophrenia, and Alzheimer’s disease.
The enzymes making THC and CBD are encoded by THCA and CBDA synthase genes, respectively. Both are found on chromosome 6 of the 10 chromosomes the cannabis genome is packaged into. There, the enzyme genes are surrounded by vast swathes of garbled DNA which came from virus-like elements that colonized the genome millions of years ago. These retroelements, made copies of itself that spread across the genome by jumping into other sites in the host cell’s DNA.
“Plant genomes can contain millions of retroelement copies,” says Dr. van Bakel, Assistant Professor of Genetics and Genomic Sciences and faculty member of the Icahn Institute for Data Science and Genomic Technology at the Icahn School of Medicine at Mount Sinai. “This means that linking genes on chromosomes is analogous to assembling a huge puzzle where three-quarters of the pieces are nearly the same color. The combination of a genetic map and PacBio sequencing technology allowed us to increase the size of the puzzle pieces and find enough distinguishing features to facilitate the assembly process and pinpoint the synthase genes.”
The researchers believe that gene duplication of the ancestral synthase gene and expanding retroelements drove ancient cannabis to split into chemically distinct types. Humans subsequently selected for plants containing desirable chemistry such as high THC.
The gene sequences for the THCA and CBDA synthases are nearly identical, supporting the idea that they come from the same gene which was duplicated millions of years ago. Over time, each gene copy evolved separately, and eventually came to encode the two different enzymes that produce the distinct cannabinoids.
Because the genes encoding enzymes are so similar at the DNA level, prior to this study it was not clear whether they were encoded by separate genes or by two versions of the same gene. Adding to the confusion was the fact that most strains produce both CBD and THC despite breeders’ efforts to grow hemp varieties free from the mind-altering THC for users looking to avoid it.
The chromosome map now clearly shows that two distinct genes are at play, which should make it possible to separate them during breeding to grow plants without THC.
Some psychoactive effects in medical strains could be coming from CBC, a lesser-known cannabinoid that has unusual pharmacology including anti-inflammatory properties. The discovery of the gene responsible for CBC synthesis will make it possible for breeders to tailor its content in future varieties.
“Mainstream science has still not done enough because of research restrictions,” says Dr. Page, of UBC and Chief Scientific Officer at Aurora, one of Canada’s largest producers of medical cannabis. “Legalization and looming ease of research regulation really provide for opportunities for more research to be done. And Canada is leading the way.”
The study was funded by research grants from the Canadian Institutes of Health and Research.
About the Mount Sinai Health System
The Mount Sinai Health System is New York City's largest integrated delivery system encompassing (with the addition of South Nassau Communities Hospital) eight hospital campuses, a leading medical school, and a vast network of ambulatory practices throughout the greater New York region. Mount Sinai's vision is to produce the safest care, the highest quality, the highest satisfaction, the best access and the best value of any health system in the nation. The Health System includes approximately 7,480 primary and specialty care physicians; 11 joint-venture ambulatory surgery centers; more than 410 ambulatory practices throughout the five boroughs of New York City, Westchester, Long Island, and Florida; and 31 affiliated community health centers. The Icahn School of Medicine is one of three medical schools that have earned distinction by multiple indicators: ranked in the top 20 by U.S. News & World Report's "Best Medical Schools", aligned with a U.S. News & World Report's "Honor Roll" Hospital, No. 12 in the nation for National Institutes of Health funding, and among the top 10 most innovative research institutions as ranked by the journal Nature in its Nature Innovation Index. This reflects a special level of excellence in education, clinical practice, and research. The Mount Sinai Hospital is ranked No. 18 on U.S. News & World Report's "Honor Roll" of top U.S. hospitals; it is one of the nation's top 20 hospitals in Cardiology/Heart Surgery, Gastroenterology/GI Surgery, Geriatrics, Nephrology, and Neurology/Neurosurgery, and in the top 50 in six other specialties in the 2018-2019 "Best Hospitals" issue. Mount Sinai's Kravis Children's Hospital also is ranked nationally in five out of ten pediatric specialties by U.S. News & World Report. The New York Eye and Ear Infirmary of Mount Sinai is ranked 11th nationally for Ophthalmology and 44th for Ear, Nose, and Throat. Mount Sinai Beth Israel, Mount Sinai St. Luke's, Mount Sinai West, and South Nassau Communities Hospital are ranked regionally.