An international team of scientists jointly led by Professor Ye Kai from the School of Electronics and Information Engineering of XJTU and Professor Ian Graham from the University of York in UK, in partnership with researcher Ning Zemin from the Wellcome Trust Sanger Institute, have published the DNA sequence assembly of the opium poppy genome, and uncovered the key evolutionary steps in the productionof the pharmaceutical compounds noscapine, codeine and morphine.This breakthrough, published in the latest issue of Science, revealed the origins of the pathway leading to the production of the cough suppressant noscapineas well as the painkiller drugs codeine and morphine.

The opium poppy has been both a friend and foe of humanity throughout the history. Morphinan-based painkillers are among the most effective and cheapesttreatment for the relief of severe pain and palliative care. Opium poppy also produces cough suppressant and anti-cancer noscapine. However, due to the addictive properties of morphinans, careful medical prescription is essentialfor avoiding drugmisuse. Currently,a huge discrepancy around the world in the dose of morphine equivalent available to alleviate serious health-related suffering has existed, with the USA and Canada having over 3000% of the estimated need, 870% in Western Europe, 16% in China, 8% in Russia, 4% for India and 0.2% for Nigeria. The lack of access to pain relief or palliative care,especially among the poor people in low to middleincome countries,has recently been recognized as a global health and equity imperative. The genomedecodingof this important medicinal plant lays a foundation for exploiting its pharmaceutical potential through plant breeding and synthetic biology.

Professor Ye Kai and his colleagues produced a high quality assembly of the 2.7 GigaBase opium poppy genome sequence distributed across 11 chromosomes. Plants often have a remarkable capacity to duplicate their genomes.When ithappens,the duplicated genes are free in evolving forother things, allowing plants to develop a new machinery to make anamazingly diverse array of chemical compounds that are used to defend against the attacksfrom harmful microbes and herbivores,and to attract beneficial species,such as bees,to assist in pollination.Genome co-linearity analysis shows that opium poppy experienced a whole genome duplication (WGD) at around 7.8 million years ago, and additional ancient duplication events at least 110 million years ago.

Opium poppy genome features and evolutionary history

The genome assembly allowed the identification of a large cluster of 15 genes encoding enzymes involved in two distinct biosynthetic pathways for the production of both noscapine and the compounds leading to codeine and morphine.The genome assembly also allowed the identification of the ancestral genes comingtogether to produce the STORRgene fusion, whichis responsible for the first major step on the pathway to morphine and codeine. This fusion event happened before therelatively recent completion of genome duplication event in the opium poppy genome in 7.8 million years ago,but that is still long before the Homo sapien ancestors firstlyemerged on our planet about 200,000 years ago.

Compounds like noscapine, codeine and morphine are chemically complex, with theirchemical synthesis difficult and the price much more expensive than plant-based production. Synthetic biology-based approaches are now being developed,whereby genes from plantsare engineered into microbial systems,such as yeast, for enabling production in industrial fermenters. However, opium poppy remains the cheapest and the sole commercial source of these pharmaceutical compounds by some distance. The publication of the genome sequence will provide afoundation for further improvement of this medicinal plantin pharmaceutical industry throughmolecular breeding approaches.

XJTU Professor Ye Kai, the co-corresponding author of this paper, said, “Highly repetitive plant genome and the intermingled evolutionary events in the past 100 million years complicate our analysis. We utilized complementary cutting-edge genome sequencing technologies with sophisticated mathematic models and analysis methods in the investigation of the evolutionary history of opium poppy genome. It is intriguing that two biosynthetic pathwayscame from the same genomic region due to a series of duplication, shuffling and fusing structural events, enabling the concerted production of novel metabolic compounds.”

Professor Ian Graham,another co-corresponding author of this paperfrom the Centre for Novel Agricultural Products, Department of Biology,the University of York, said,“Biochemists have been curious for decades about how plants have evolved to become one of the richest sources of chemical diversity on the earth. Using high quality genome assembly, our study has deciphered how this has happened in opium poppy. At the same time,this research will provide afoundation for the development of molecular plant breeding tools whichcan be used to ensure that there is a reliable and cheap supply of the most effective painkillers available for pain relief and palliative care for societies in not just developed but also developing world countries”.