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Ripe millet. Photo courtesy of the millet variety exhibition base in Lvdian, Yichuan, Henan

What was the staple food eaten by the ancestors of Mentougou in Beijing more than 10 thousand years ago? What did Qinghai people use to make noodles more than 4000 years ago? 6,000 years ago, the population of the Central Plains increased greatly for the first time because of what crops?

Archaeology has proved that the answer is millet, which is commonly known as millet.

Recently, Nature-Genetics published online the first high-quality pan-genome map of millet completed by Diao Xianmin, a researcher at the Institute of Crop Science of Chinese Academy of Agricultural Sciences. This study not only proved that China is the only origin of millet from the genome level, but also created a precise and efficient breeding method of millet genome, which laid a theoretical foundation and provided a technical path for cultivating breakthrough varieties.

Li Jiayang, a researcher at the Institute of Genetics and Developmental Biology of Chinese Academy of Sciences and an academician of China Academy of Sciences, pointed out that this is the first high-quality map pan-genome in the field of coarse cereals, which is of special importance for future breeding applications. This achievement is not only another milestone in millet research, but also the best interpretation of "small crops, great achievements" and will bring important impetus to other crop research.

Identity change of millet

Millet belongs to the genus Setaria in Gramineae, which is the oldest domesticated crop in the world and the main crop formed in Asian/Chinese farming civilization.

The earliest millet found in archaeology appeared in the site of Donghulin in Mentougou District, Beijing, 11,500 years ago. There is no millet in Europe earlier than 3500 years ago.

Diao Xianmin, the correspondent of the paper, told China Science Journal that millet had long occupied the position of staple food in farming culture before the arrival of agricultural production system with high input (water conservancy, fertilizer and pesticide).

From Xia and Shang Dynasties to Wei, Jin, Southern and Northern Dynasties, millet has always occupied a primary position in grain. Especially in the Wei, Jin, Southern and Northern Dynasties, millet in the south developed unprecedentedly and reached the peak of historical prosperity. During the Sui and Tang Dynasties, millet entered the first recession, and the status of rice and wheat rose, replacing the traditional status of millet, forming a pattern of southern rice and northern wheat, but millet was still the core crop at that time.

Since modern times, with the breakthrough of green revolution of wheat, rice and other crops, the advantage of millet as a staple food has been gradually weakened. "In fact, it is only nearly 40 years since millet changed from a big crop to a small crop." Diao Xianmin said that Heilongjiang was the largest millet planting province in China in the early days of the founding of New China. In 1978, the millet planting area in Heilongjiang Province reached 20 million mu, but now the total millet planting area in China is only 20 million mu.

However, millet, the kernel of millet, has high nutritional value, which makes it a popular miscellaneous grain.

In recent years, with the increasingly obvious problems of climate change, agricultural sustainability and food security, scientists have placed new hopes on millet with the characteristics of drought tolerance, barren tolerance, strong environmental adaptability, easy transformation and easy laboratory operation.

Diao Xianmin has been engaged in millet research since 1987, and has collected more than 1,500 materials of Setaria from more than 20 species. "China’s millet farm varieties and bred varieties are the most abundant in the world. There are about 27,000 farm varieties, and the breeding level is the most advanced in the world. "

Diao Xianmin said that in order to make better use of these materials, it is necessary to accurately identify the genotype and phenotype of millet. "Now, compared with other big crops, the yield level of millet is still very low. The yield per mu of millet is generally 250 kg ~300 kg without watering and fertilization; Typical high-yield fields have water and fertilizer, with a maximum yield of 700 kg. This is mainly because we have no clear understanding of the population structure, evolutionary relationship and history of wild species, farm species and bred species of millet. "

These problems include that the level of genomic variation of millet is not very clear, especially there is no information on structural variation; The information of resource phenotype identification record is incomplete; It is not clear which genes, segments and loci have been selected during the domestication and breeding of millet. "This requires us to study more deeply."

Draw the first miscellaneous grains "heavenly book"

"The research published now is actually a part of the above-mentioned big project and a by-product. It is not decided to do it in a short time, but with the deepening of research and technological progress, it has been integrated with breeding and production needs and accumulated for a long time. Research results." As the chief scientist of the national millet sorghum industrial technology system, Diao Xianmin hopes to thoroughly understand the millet crop, and cultivate better varieties on this basis, so that millet can play its due role in the grain system.

Because of this, millet has become the first crop with map-pan genome in miscellaneous grains.

The so-called pan-genome refers to all the genetic information of a species, while the graph genome contains all the structural variations in the genome of a species. In other words, the map-pan-genome is the clearest, most detailed and comprehensive genome information of a species that can be drawn by using the current science and technology, which is equivalent to the "heavenly book" of the species genome.

Diao Xianmin’s team analyzed 1,844 core germplasm resources such as wild millet, farmed millet and modern bred millet, assembled 110 high-quality genomes of millet and Setaria from scratch, drew the first genome variation map of Setaria, recognized the basic situation of millet resource variation, and systematically analyzed the genome variation during the domestication and improvement of millet.

He Qiang, the co-first author of the paper and a postdoctoral fellow at the Institute of Crop Science, Chinese Academy of Agricultural Sciences, introduced that the species of Setaria could be clearly clustered by using high-magnification sequencing of 1844 core germplasm-foxtail millet and Setaria viridis. Among them, Setaria viridis is divided into 4 subgroups. Before Setaria viridis was domesticated into millet, there was an older subgroup C3, which was more geographically distributed and had stronger environmental suitability, which was of great significance for improving the environmental suitability of millet in the future.

Liu Xu, a researcher at the Institute of Crop Science of the Chinese Academy of Agricultural Sciences and an academician of the China Academy of Engineering, said that this confirmed the theory of the single origin center of millet, namely the origin center of China, and was a typical representative of resource research using new technologies.

Not only that, they also studied how millet was domesticated and improved. He Qiang introduced that they identified a total of 4582 structural variations related to millet domestication, 152 structural variations related to millet breeding improvement, and identified 680 structural variation-related genes that were continuously selected in domestication improvement, which were mainly enriched in metabolic pathways such as reproduction, photoperiod, pigment and nitrogen utilization.

2023 is the International Year of Millet. The Food and Agriculture Organization of the United Nations believes that millet deserves attention and has a place in people’s dietary structure, because millet can grow in harsh climatic conditions, which can help solve the problem of food shortage. Contribute to a healthy diet; Climate resilience; There is much to be done in improving the livelihood of small farmers; Xiaomi trade can enhance the diversity of the global food system; There are many innovative uses in the fields of treatment and pharmacy.

Diao Xianmin believes that publishing the map of millet pan-genome is the best support of China scientists for the International Year of Millet.

Establish a breeding database

It is already a huge task just to map the pan-genome. However, the team of Diao Xianmin did not stop there.

"What is different from other work is that we have done a lot of phenotypic identification." Diao Xianmin said that they relied on 17 units to investigate the basic agronomic traits of 680 materials and 22 environments in 13 places across the country for 10 years, which is the real multi-year and multi-point experimental data.

"We not only investigated the common traits such as plant height, panicle length, tiller number and grain weight per panicle, but also studied the drought resistance, grain dropping, beige color and grain quality traits in germination stage, seedling stage and whole life cycle, and formed 68 traits and 226 groups of phenotypic data, which is actually a phenotypic group." Diao Xianmin said that they focused on more practical character identification related to breeding. For example, they made a three-year drought-resistance survey in Xinjiang, a three-year drought-resistance survey in Shanxi, and a drought-resistance survey in Hengshui, Hebei.

More importantly, they also docked the two big data, the map pan-genome and the phenotype group, and discovered a total of 1084 phenotypic-related loci, of which structural variation accounted for 5.8%.

Tang Sha, the co-first author of the paper and an associate researcher at the Institute of Crop Science, Chinese Academy of Agricultural Sciences, told reporters that structural variation in the genome could not be seen before the genome was mapped. However, some important agronomic characters of millet, such as starch, flowering period and ear weight, are determined by structural variation genes.

"With these genes and their information, we can build a molecular breeding module. This information provides a method for genotype and phenotype mutual estimation and phenotype estimation by genotype, which is genome-wide selection breeding. " Diao Xianmin said that this is a database from which you can know what is the optimal gene for a certain trait. With this family background, good genes can be gathered together in breeding in the future, providing molecular and phenotypic basis for future breeding.

"This makes us more clearly see the importance of genome structural variation in discovering gene functions." Qian Qian, a researcher at the Institute of Crop Science of the Chinese Academy of Agricultural Sciences and an academician of the China Academy of Sciences, said.

Han Bin, director of the Center for Excellence and Innovation in Molecular Plant Science of China Academy of Sciences and academician of China Academy of Sciences, said: "The phenotypic prediction accuracy of whole genome selection in this study is over 90%, which shows us the application potential of whole genome selection in millet breeding. I think this research is not only a classic work of’ pan-genome-quantitative inheritance-breeding’ in millet but also in crop field, which has important guiding significance for future crop genetic improvement. "

Related paper information:https://doi.org/10.1038/s41588-023-01423-w

　　"Crayfish is really a bug shrimp", "Seedless grapes are covered with birth control pills" and "Eating large-scale chicken can infect bird flu" … … The rapid development of the Internet, while bringing convenience to people, is also easy to make rumors spread like wildfire. Statistics show that "rumors on the tip of the tongue" account for 45% of online rumors, and the food safety field has become the hardest hit by online rumors.

　　On April 17th, the State Food and Drug Administration held a briefing, inviting the heads of relevant departments, experts and scholars, and employees of Internet platforms such as Tencent and Sina, from the Ministry of Agriculture, the State Health Planning Commission, the General Administration of Quality Supervision, Inspection and Quarantine, the National Network Information Office, Tsinghua University and China Academy of Social Sciences, to have a discussion on how to effectively control food rumors through multi-party linkage. Yan Jiangying, spokesperson of the Food and Drug Administration, said that it is necessary to increase the punishment and accountability of food safety rumor makers, improve public scientific literacy, and make rumors nowhere to hide.

　　Rumors are refurbished and confuse the audience.

　　According to Yan Jiangying’s analysis, food safety rumors have four characteristics:

　　Deliberately fabricated, with ulterior motives. The rumormongers disregard the facts, fabricate the so-called truth out of thin air, and even direct and perform themselves, and concoct "evidence" such as pictures and videos to seek illegitimate interests. For example, in February this year, several videos showing "plastic laver" were widely spread on the Internet. In the video, some people said that laver produced by several enterprises in Jinjiang, Fujian Province was "made of plastic" and said that laver was chewy, urging netizens to "stop eating", which triggered a round of "plastic laver" storm.

　　Steal the concept and confuse the audience. Rumor makers use exaggerated and distorted processing methods to blur the truth and the whole picture, and frequently use irritating language such as "toxic", "carcinogenic" and "lethal" to fool the public’s cognition. Because such rumors are "mixed with the truth", it is difficult to identify and obtain evidence, and it is difficult to refute rumors.

　　Old news is stirred up and deliberately discredited. With the food and drug safety incident as the background, the rumormonger has completely changed what happened in the past; Change the date of new bottles of old wine; The date is blurred or deleted in disguise, so as to achieve the purpose of forwarding each other and misleading people’s consumption.

　　Joke and ridicule, negative communication. The rumor mongers dub the film and television clips, make jokes and ridicule pictures and videos, and use the characteristics of the Internet that young people are the main group and young audiences are curious, forming a fission spread, and the follow-up effect will be difficult to eliminate for a long time.

　　Disturb consumption judgment and damage the development of the industry

　　"Today, with the high popularity of the Internet, online food safety rumors disturb social trust, weaken the credibility of the government, affect public confidence in food safety, and pose a threat to social harmony and stability." Yan Jiangying said that in recent years, people have been extremely vigilant about the "lessons from the past" of problem foods, and they have tightened their nerves at the slightest sign of trouble. Once food-related rumors appear on the Internet, people’s anxiety and sensitive nerves are immediately touched, and rumors will quickly ferment, which will further disrupt people’s consumption judgments and damage the development of the industry. For example, a rumor of "plastic laver" may cause a loss of nearly 100 million yuan to the laver industry in Jinjiang, Fujian and other places.

　　"From the perspective of communicators, some rumor communicators have obvious interests, and there are many motives such as economic extortion, public opinion and business wars, and eye games." Su Jing, deputy director of Tsinghua University Institute of Health Communication, said that the circle of friends on WeChat has become the main position of rumor spreading, and WeChat mini-videos, articles from the media in WeChat official account and WeChat short messages are the main forms of rumor spreading. Some food safety rumors are often spread by means of video, lacking basic elements such as time, place and people. Some food safety rumors use people’s fear appeals and moral kidnapping to emphasize the serious consequences, and use inflammatory words, such as "emergency" and "shock", which have strong impact.

　　Governance should make heavy punches and increase illegal costs.

　　Yan Jiangying said that to control food safety rumors, it is necessary to make a heavy blow, and all sectors of society need to participate together to establish a long-term mechanism for multi-social subjects to jointly control rumors, so that government departments, professionals, related enterprises, news media and the public can form a joint force.

　　In recent years, the Food and Drug Administration has upgraded and revised its website, adding a column of "popular science knowledge" and a "rumor platform", which has become an important platform for all sectors to obtain food and drug safety supervision information. The column of "Verification" of People’s Daily has also published investigation reports for many times, and scientifically verified the food safety rumors such as "plastic laver", "seedless grape smearing contraceptives", "eating strawberries causes cancer" and "crayfish is a bug shrimp" for the first time, and quickly dispelled the rumors, eliminating public misunderstanding and panic.

　　"There are many online food rumors and spread quickly. One of the important reasons is that the illegal cost is low." Jong Li, a researcher at the Institute of Law of the Chinese Academy of Social Sciences, said that China’s food safety law clearly stipulates that no unit or individual may fabricate or disseminate false food safety information, and set corresponding penalties for offenders. "In the future, it is necessary to further increase the punishment for illegal acts, especially for hell to pay, a bad act of spreading food safety rumors through the Internet to disrupt market order and profit from it, and improve the law enforcement shock."

　　Zhao Huajun, Emergency Department of Agricultural Products Quality and Safety Supervision Bureau of the Ministry of Agriculture, believes that it is very important to improve the public’s scientific literacy of food safety, which is essential to prevent rumors from "goodwill".

　　Yan Jiangying said that in the next step, the State Food and Drug Administration plans to establish a "green channel for food and drug safety rumors" in cooperation with the Central Network Information Office, and control the key nodes of rumor dissemination at the first time, and at the same time unite major news units, new media and well-known popular science organizations to establish a "food and drug safety popular science communication alliance" to promptly rumor and release authoritative information in a timely manner.

　　Since the State Food and Drug Administration started the self-inspection and verification of drug clinical trial data for one year, it has been found that over 80% of the clinical data of new drugs are involved in fraud, and the regulatory links behind them have fallen behind, and the violations of relevant subjects such as pharmaceutical companies, intermediaries and doctors are prominent.

　　Some people in the medical field believe that with the advance of the verification storm, negative arguments such as "too advanced" and "one size fits all" have risen. The state should adhere to zero tolerance for clinical fraud and reverse the medical ecology of bad money expelling good money with stricter supervision.

　　The enterprise intentionally concealed and omitted the records of adverse reactions.

　　The results of the verification of the authenticity and standardization of the data of 1622 drug clinical trial projects to be produced by the Food and Drug Administration caused a shock in the whole industry. Some people in the medical field revealed that with the deepening of self-examination and verification, more problems of untrue and irregular clinical trial data of drugs have been exposed. At present, over 80% of new drug applications have been withdrawn by pharmaceutical companies or rejected by the State Food and Drug Administration.

　　A staff member of the food and drug department said that during the verification, it was found that the clinical trial data of many drugs were incomplete, the analysis data had no differential trajectory, and some data could not be traced back. Other companies deliberately concealed or omitted the adverse reaction records, and revised the test data that failed to meet expectations.

　　"Before this round of self-examination and verification storm, clinical data fraud was an open secret in the industry." The dean of a top-three hospital in the west said that pharmaceutical companies randomly combined old drugs and found several hospitals to do clinical experiments. Of course, they all reported according to the expected results. Finally, the State Food and Drug Administration approved the new drugs. "How can this stew-style drug research and development model ensure the quality and safety of drugs?"

　　"The direct consequence of clinical data fraud is poor efficacy." A person in charge of research and development of a pharmaceutical company in Nanjing said that in a clinical trial, the company replaced the domestic anti-diabetic drug metformin taken by the subjects with the original drug Gehuazhi. Unexpectedly, after taking it for four weeks, the blood sugar of the subjects actually dropped to the level that they could not be enrolled in the group. Previously, the subjects had been taking domestic metformin, but their blood sugar could not be lowered.

　　According to insiders, most domestic generic drugs can’t meet the original research standards. In order to pass the evaluation, it is very common to conceal the discarded data and selectively use the data in clinical experiments. In this regard, the state launched the consistency evaluation of generic drugs’ quality and efficacy this year, requiring all generic drugs approved for marketing before October 1, 2007 to complete the consistency evaluation before the end of 2018, among which clinical effectiveness tests and varieties with special circumstances need to be carried out, and consistency evaluation should be completed before the end of 2021; If it is not completed within the time limit, it will not be registered again.

　　Yu Dechao, Chairman of Cinda Bio-Pharmaceutical, predicted that with the consistent evaluation of generic drugs’ quality and efficacy, more than 50% of the existing generic drugs will be eliminated, and the phenomenon of "bad money driving out good money" in the pharmaceutical field is expected to be initially reversed.

　　Absence of intermediary supervision encourages clinical fraud

　　In 1998, the relevant departments of the state promulgated the "Management Standard for Drug Clinical Trials (Trial)" (GCP for short), which was revised and implemented in 2003. The reporter’s investigation found that the binding force in the implementation of GCP is not strong, and the violations of relevant subjects such as pharmaceutical companies, intermediaries and doctors are prominent.

　　Driven by interests, some pharmaceutical companies have launched generic drugs, and the important and necessary link of clinical trials has been "ignored". The person in charge of a large pharmaceutical company in Jiangsu said that he had participated in the research and development of new drugs in a pharmaceutical company, in fact, he copied the newly developed innovative pharmaceutical materials from abroad. This pharmaceutical company spent a week preparing materials, and did not conduct clinical trials for six months at all. It even got the approval of "exclusive innovative drugs" very quickly. As a result, the effect of five domestic generic drugs is not obvious, but one foreign original drug is effective but can’t get in, which is a typical phenomenon of "bad money driving out good money".

　　The absence of supervision by CRO encourages the falsification of clinical data. A person in charge of a CRO revealed that CRO should be a third-party inspection agency, which plays a role in quality control of drug research and development, clinical application and approval. However, due to the lack of transfer threshold of domestic CROs and vicious competition of a large number of unscrupulous enterprises, many CROs have become accomplices in data fraud driven by interests. "Some pharmaceutical companies know that CRO is fraudulent, but considering that CRO shares the illegal costs and risks, they often turn a blind eye. What’s more, some pharmaceutical companies made it clear that if the test fails to pass the acceptance, it will not pay, forcing CRO to make fraud. "

　　A law enforcement officer of the food and drug supervision department said that during the inspection, it was found that the main body of clinical trials should be doctors, but some CROs hired a large number of assistant researchers instead of doctors to do clinical observation, data statistics and quality verification, which was an important reason for the irregular and untrue data.

　　Clinicians’ professional ethics is out of order, which opens the door for data fraud. The chief physician of a third-class hospital in Guangdong said that he had participated in the third-phase clinical trial of an obstetric drug under the leadership of another hospital. "The actual operation is not strict." Many records that are beneficial to the marketing of this drug have been saved, and adverse clinical cases or experimental data have been erased. Especially compared with similar drugs, the fraud situation is more prominent. "Doctors are very busy, clinical trials will not be done seriously, and there is no time to make such rigorous records. Many of them are done by CRO, and the authenticity is naturally greatly reduced."

　　Clinical supervision has become a weak link in the drug supervision system. Some people in the industry believe that drug regulatory authorities at all levels are generally short of regulatory talents and technical teams with clinical background, and long-term emphasis on system certification and neglect of clinical project process supervision, especially the safety and effectiveness evaluation of post-marketing drug clinical trials, and supervision is almost blank. A staff member of Jiangsu drug supervision system said that compared with GMP inspection team, there is a big gap in the ability of local clinical verification GCP team, and the personnel and technology can not keep up with the current requirements.

　　Beware of negative arguments weakening supervision.

　　The reporter’s investigation found that over the past year, the self-inspection and verification of drug clinical trial data has achieved remarkable results, initially curbing the situation of large-scale data fraud, and some pharmaceutical companies feel unprecedented pressure.

　　"In the past, there was almost no clinical supervision. Now we suddenly asked for self-examination and verification, which caught us off guard." A person in charge of a pharmaceutical company in Inner Mongolia complained that the storm of verification of clinical trial data was "a matter of punishing the Qing Dynasty with the laws of the Republic of China". The state’s policies can’t be changed constantly, and we can’t take the "opinions" and "regulations" issued today to consider what we did before.

　　The person in charge questioned why so many CRO companies were approved. Why did the test data provided by CRO company pass the review before? Why are clinical trial institutions approved by administrative departments not conducting regular trials? Why should the applicant bear most of the responsibility for a series of mistakes made by the regulatory authorities? "These problems need to be paid attention to by relevant management departments and explained reasonably."

　　Some people in the industry believe that there are two negative arguments to be vigilant against this unprecedented storm of clinical supervision. First, the introduction of policies should conform to China’s national conditions, and the requirements for innovation at this stage should not be too advanced; Second, the policy cannot be uniform, and some clinical data are just not standardized, not fraudulent, and should be allowed to exist.

　　Yu Dechao said that at present, it is a critical period to control "bad money drives out good money" in the field of drugs, and real innovation must be encouraged with the strictest system. Once the clinical fraud is spared, the result must be "a small gap becomes a big hole." "If a pharmaceutical company is allowed to falsify, then other pharmaceutical companies will follow suit. Therefore, we must adhere to zero tolerance and not relax about clinical fraud. "

　　In fact, compared with the United States, China’s drug supervision still needs to be strengthened. The State Food and Drug Administration has made it clear that if the clinical research data are fraudulent, the applicant’s new application for drug registration will not be accepted within three years, and the clinical trial data of the person directly responsible for participating in the research or organizing the research will not be accepted within ten years.

　　Dr Liao Guojuan, CEO of Suzhou Jinweizhi Biotechnology Co., Ltd. said that in the United States, once data fraud occurs, pharmaceutical companies and R&D personnel will be blacklisted and will not be allowed to enter related fields for life.

　　Insiders suggest that the country should actively integrate domestic pharmaceutical companies with the international market, establish an internal supervision system for pharmaceutical companies, and truly form core competitiveness through innovation in order to occupy a place in international competition.

What I brought today is a very distinctive model in the joint venture car. Next, let’s see if its highlights can attract you with Xiaobian.

Let’s look at the appearance of Willanda first. The front face of Willanda looks clean, and the air intake grille adopts a multi-frame shape, which looks very sporty. The headlights are very comfortable and the design takes the sports route. The car is equipped with LED daytime running lights, front fog lights, automatic opening and closing, adaptive far and near light and so on. Coming to the side of the car body, the size of the car body is 4665MM*1855MM*1680MM, and the car adopts lovely lines, which gives people a very delicate feeling. With large-sized thick-walled tires, the shape is quite atmospheric. In the rear design, the overall shape of the rear of Willanda echoes the front of the car, and the taillights look very cold and elegant.

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