Human Phenome Research Progress Report(2020)-复旦大学人类表型组研究院.pdf 
Human Phenome Research Progress Report(2020)-复旦大学人类表型组研究院.pdf
Human Phenome Research Progress Report 2020 Background introduction Definition of human phenome Genes and the environment interact to determine the traits of the human body, and these traits are known as the phenotype. The phenome was initially defined as the sum of all the traits of an organism. Following deepened research of the human phenotype, the phenome is now defined as the biological, physical and chemical characteristics – they include the morphological characteristics, functions, behaviors, and the rule of molecular composition - of an organism, from its embryonic development to birth, growth, aging, and death. Illustration 1-Concepts of phenotype and phenome Strategic new height in the post-genomics era Many experts have forecast that the human phenome will take over the human genome to become the next strategic height in the post-genomics era. The precise measurement of the human phenotype and comprehensive analysis of the human phenome will systematically deconstruct the strong relationship between phenotypes, construct a phenotype network, open up multi-dimensional and cross-scale correlations between the macro and micro phenotypes, and clarify the cross-scale correlation among phenotypes. These important clues to decode the life sciences shall serve to enhance precise health management. The multidimensional, cross-scale, high-precision and comprehensive measurement of the 1 Human Phenome Research Progress Report 2020 human body will draw a "navigation map" of life sciences in the era of big data, explore the universe of the human body, and safeguard human health. Accelerated deployment of human phenome research The United States, the United Kingdom and Germany have accelerated their scientific research support for human phenome research, with the number of related research projects constantly rising in recent years. The American Human Phenome Research Program kicked off such efforts at an earlier stage - in 2006, the MIND Institute at the University of California, Davis, launched the Autism Phenome Project 1. Since then, the National Cancer Institute (NCI) has established the Clinical Proteomic Tumor Analysis Consortium (CPTAC)2. The comprehensive protein-genomic analysis further explained the gene mutations that drive the disease phenotype and clarified the tumor pathophysiology to explore personalized and precise clinical treatments. In its 2015 fiscal year budget, the National Science Foundation (NSF) Directorate for Biological Sciences (BIO)3 identified the "prediction of individual traits (genome to phenome) based on DNA sequence" as one of the key projects to support. The National Heart, Lung, and Blood Institute (NHLBI) also launched the Trans-Omics (TOPMed) project4, which collects whole-genome sequencing and other omics data, and combines them with molecular, behavioral, imaging, environmental and clinical data to improve the prevention and treatment of heart, lung, blood diseases and sleeping disorders. Meanwhile, the US NIH launched the TGAC pilot project5, using project databases such as that of the ExAC to study the influence of genes and gene mutations on phenotypes. The NSF, in 1 Autism Phenome Project. Available from: https://health.ucdavis.edu/mindinstitute/research/autism-phenome-project/index.html. 2 National Cancer Institute’s Clinical Proteomic Tumor Analysis Consortium (CPTAC) Available from: https://proteomics.cancer.gov/programs/cptac. 3 2015 fiscal year budget Available from: https://www.nsf.gov/about/congress/reports/nsf13079. pdf 4 Trans-Omics for Precision Medicine Program. Available from: https://www.nhlbi.nih.gov/science/trans-omics-precision-medicine-topmed-program. 5 NIH pilot project will match researchers to genes, gene variants of interest.; Available from: https://www.nih.gov/news-events/news-releases/nih-pilot-project-will-match-researchers-genesgene-variants-interest 2 Human Phenome Research Progress Report 2020 partnership with the Simons Foundation6, also launched four new centers to bring mathematical perspectives to biological research in its search for the rules of life. The latest precision health research project7 established by the National Human Genome Research Center (NHGRI) under the NIH focuses on using "Reverse Phenotyping" to perform reverse engineering of genomic data. In this process, phenotypes are refined based on genetic marker data in order to analyze genetic big data. Reverse Phenotyping uses cutting-edge genomes and computing tools to develop and evaluate next-generation health care methods in order to make improvements to disease diagnosis, treatment and prevention. Autism Phenome Project (US) Clinical Proteomic Tumor Analysis Consortium established by NCI (US) Human Phenotype Ontology Project (Germany) The Project Baseline by Google (US) Human phoneme prioritized as an action plan under integration strategy, HDR (UK) Human phenome as a key developmental direction in MRC Delivery Plan 2019 (UK) National Phenomics Resource Project, HDR (UK) NAM Healthy Longevity Global Competition (US) Grant from National Science Foundation (NSF) Directorate for Biological Sciences in fiscal year 2015 NHLBI Trans-Omics (TOPMed) Program (US) NIH TGAC Project (US) NSF-Simons Research Centers for Mathematics of Complex Biological Systems(US) NHGRI Precision Health Research Program using Reverse Phenotyping (US) Illustration 2-Human phenome-related research projects in developed countries Phenotype-related health research projects have also been rolled out in recent years. For example, Google launched a large-scale health project in 2017 titled Project Baseline8. The project used a variety of new health tools to collect massive volumes of health data by continuously tracking volunteers’ conditions of gut microbiota, sleep, exercise, and mental state in multiple dimensions, so as to create a "standardized human health map" and offer clues 6 NSF-Simons centers to search for the Rules of Life. Available from: https://www.nsf.gov/news/news_summ.jsp?cntn_id=245523&org=NSF&from=news 7 NHGRI Precision Health Research Program Using Reverse Phenotyping to Better Understand Genomics. Available from: https://www.genomeweb.com/researchfunding/nhgri-precision-health-research-program-usingreverse-phenotyping-betterunderstand#.X5puLEfitPZ. 8 Project Baseline. Available from: https://www.projectbaseline.com/ 3 Human Phenome Research Progress Report 2020 for disease prediction. The National Academy of Medicine also launched the Healthy Longevity Global Competition9 in 2019 as part of its efforts to achieve breakthrough innovations that would extend human health and improve bodily functions of the elderly. Europe has also successively introduced scientific research projects related to the human phenotype. Charite-Universitatsmedizin in Berlin, Germany launched the Human Phenotype Ontology (HPO) project10 in 2008. The team used ontology engineering and computer science to structurally summarize the phenotypic information from medical literature, provide standard vocabulary for phenotypic abnormalities in human diseases, and establish tiers for phenotyperelated vocabulary. As the first country to build a human phenome research platform, the United Kingdom has also made human phenotype research a priority funding project. In April 2019, Health Data Research UK published an integration strategy and the 2019-2020 annual plan11, in which the human phenome was prioritized as an action plan, and commenced a national human phenome resource project12. The MRC 2019 annual plan13 also identified the human phenome plan as a key developmental direction. China has taken the lead in launching the human phenome plan and has systematically deployed its research. In 2015, the Ministry of Science and Technology conducted a fundamental research titled "Survey on Physical Conditions of Various Ethnic Groups in China Through the Lens of Phenotype", which laid out the foundation for collecting physical phenotypic characteristics of 56 ethnic groups. In May that same year, the CPC Shanghai Municipal 9 National Academy of Medicine Launches Global Competition Seeking Solutions for Improving Healthy Longevity. Available from: https://nam.edu/national-academy-of-medicine-launches-global-competition-seeking-solutionsfor-improving-healthy-longevity/ 10 Human Phenotype Ontology(HPO). Available from: www.humanphenotypeontology.org 11 HDR UK. Available from: https://www.hdruk.ac.uk/ 12 National Phenomics Resource Project. Available from: https://www.hdruk.ac.uk/projects/ national-phenomics-resource/ 13 MRC Delivery Plan 2019. Available from: https://www.ukri.org/files/about/dps/mrcdp-2019/. 4 Human Phenome Research Progress Report 2020 Committee and the Shanghai Municipal Government issued the "Opinions on Accelerating the Construction of a Science and Technology Innovation Center with Global Influence", which positioned "international human phenome" at the frontier of major science and technology breakthroughs. In April 2016, the State Council issued "The Plan of Shanghai to Systematically Promote the Pilot Program of Comprehensive Innovation and Reform and Accelerate the Building of a Globally Influential Center for Scientific and Technological Innovation", in which the International Human Phenome Project was listed under major science projects that required deployment. In the same month, the Shanghai Zhangjiang High-tech Park launched the Molecular Phenome International Joint Center project and became an important part of the Zhangjiang Comprehensive National Science Center. In June that same year, the Shanghai Science and Technology Commission launched a major project titled "Research on Cross-scale Associations of Human Phenotypes and Their Genetic Mechanisms", which focused on the gene-environmentphenotype interaction mechanism and systematically measured the phenotypic characteristics of the Chinese natural population, characterizing the phenotypic traits of the healthy and the sick population, clarifying the genetic mechanism of the cross-scale correlation of human phenotypes, and promoting humanity in an all-round manner. In August 2016, the "13th Five-Year" plan for scientific and technological innovation in Shanghai listed the "international human phenome" as a strategic direction in the promotion of major breakthroughs in indigenous innovation. The Ministry of Science and Technology conducted a fundamental research titled “Survey on Physical Conditions of Various Ethnic Groups in China Through the Lens of Phenotype”. The CPC Shanghai Municipal Committee and the Shanghai Municipal Government issued the “Opinions on Accelerating the Construction of a Science and Technology Innovation Center with Global Influence.” The State Council approved “The Plan of Shanghai to Systematically Promote the Pilot Program of Comprehensive Innovation and Reform and Accelerate the Building of a Globally Influential Center for Scientific and Technological Innovation.” Shanghai Zhangjiang High-tech Park launched the Molecular Phenome International Joint Center project. The Shanghai Science and Technology Commission launched a major project titled “Research on Cross-scale Associations of Human Phenotypes and Their Genetic Mechanisms.” The “13th Five-Year” plan for scientific and technological innovation in Shanghai listed the “international human phenome” as a strategic direction in the promotion of major breakthroughs in indigenous innovation. The “International Human Phenome Project (Phase I)” project (2017) was among the first batch of major municipal-level projects in Shanghai. Illustration 3-Deployment of human phenome research projects in China 5 Human Phenome Research Progress Report 2020 Part I Human Phenome Research at a breaking point Human Phenome research at a fast-development phase Human phenome research has entered a period of rapid development in the past ten years. The number of papers on human phenomics and the popularity of human phenomics research increased significantly in 2020. Take the reports submitted to the American Society of Human Genetics Annual Meeting as an example. There were only 15 reports with the themes of "phenome", "genomephenome", and "PheWAS" in 2017. In 2019, there were 59. The integration of multi-omics methods of phenomics and genomics to comprehensively analyze diseases and the development of personalized treatments are now trending topics. Phenome project a consensus among the academia In 2003, Nelson Freimer and Chiara Sabatti published an article in Nature Genetics, hence initiating the Human Phenome Project (HPP)14 to gather a more powerful, standardized and diverse human phenotype database and integrate a series of science disciplines. At the same time, the initiative will promote cooperation between public institutions such as the National Institutes of Health (NIH) and the Wellcome Trust of the United Kingdom (Wellcome Trust) and non-profit organizations, biopharmaceutical companies, and other industries. Since the human phenome project was put forward, its importance has gradually become recognized by the entire academic community. On the 125th anniversary of Science journal in 2005 15, the magazine published a list containing what it called the 125 most challenging scientific 14 15 Freimer, N. and C. Sabatti, The human phenome project. Nat Genet, 2003. 34(1): p. 15-21. Kennedy, D. and C. Norman, What don't we know? Science, 2005. 309(5731): p. 75. 7 Human Phenome Research Progress Report 2020 problems of the contemporary era. Topping the list were genetic and development-related questions such as "To What Extent Are Genetic Variation and Personal Health Linked?", "Why Do Humans Have So Few Genes?", and "What Genetic Changes Made Us Uniquely Human?". The bottleneck of these issues lies in the failure to interrelate genes, environmental factors and the phenotype. In 2010, the British New Scientist journal listed 50 ideas16 that could change the course of future science, among which the phenome was ranked 13th. The article argues that the phenome is one of the most important scientific research priorities at the current stage, and is poised to bring tremendous breakthroughs. In 2013, Nature 17 reviewed the necessity of omics, which was experiencing rapid development. Phenomes are perceived to be able to systematically sort out disease-related phenotypic information, which may hold the key to unlocking medical and health big data. In 2016, the NSF published an article18 in Science which laid out the blueprint for the development of NSF in the next few decades and proposed six research frontiers and three suggestions for reform. Among them, "understanding the rules of life (i.e. predicting phenotypes from genotypes)" was ranked 3rd. In 2018, in Nature journal’s Technology Outlook section, "linking genotype and phenotype" was listed as one of the technology fields that can change life science research. In 2019, Science journal published a special edition19 titled "Genotype to Phenotype", which analyzed and summarized the relationship between genotype and phenotype. In 2020, Nature Review Genetics magazine published a review article titled "The Future of Genetics and Genomics". Aravinda Chakravarti, a member of the National Academy of Sciences, the National Academy of Medicine, and the Indian National Science Academy, listed "decoding multifactorial phenotypes" as 16 Fifty ideas that will change science forever, in New Scientist. 2010: UK. p. 18. Baker, M., Big biology: The 'omes puzzle. Nature, 2013. 494(7438): p. 416-9. Available from: https://www.nature.com/articles/494416a 18 Mervis, J., SCIENCE POLICY. NSF director unveils big ideas. Science, 2016. 352(6287): p. 755-6. Powell, K., Technology to watch in 2018. Nature, 2018. 553(7689): p. 531-534. 19 McGuire, A.L., et al., The road ahead in genetics and genomics. Nat Rev Genet, 2020. 21(10): p. 581-596. 17 8 Human Phenome Research Progress Report 2020 one of the future research directions. :OSK :NK.[SGT6NKTUSK6XUPKIZLOXYZVXUVUYKJ 4K]9IOKTZOYZ ROYZKJVNKTUSKGYUTKUL OJKGYZNGZIU[RJINGTMK ZNKIU[XYKULYIOKTIKYG_OTMZNKVNKTUSKOYUTKULZNKSUYZ OSVUXZGTZXKYKGXINVXOUXOZOKYZUHXOTMZXKSKTJU[YHXKGQZNXU[MNY 4GZ[XK :NKL[Z[XKULVNKTUSK XKYKGXINOYVXUSOYOTM 9_YZKSGZOIGRR_YUXZOTMU[ZJOYKGYKXKRGZKJVNKTUZ_VKY NURJYZNKQK_ZU [TRUIQOTMSKJOIGRGTJNKGRZNHOMJGZG 49,: “;TJKXYZGTJOTMZNKX[RKYUL ROLK ：6XKJOIZOTMVNKTUZ_VK“ XGTQKJGSUTMZUVYO^XKYKGXIN LXUTZOKXY 9IOKTIK “-KTUZ_VKZU6NKTUZ_VK” /SVXU\OTM[TJKXYZGTJOTMULZNKIUSVRK^XKRGZOUTYNOVHKZ]KKTMKTUZ_VK GTJVNKTUZ_VK]ORRGJ\GTIKYIOKTZOLOIXKYKGXINJOGMTUYOYGTJZXKGZSKTZ 4GZ[XK8K\OK]Y-KTKZOIY ROYZKJ“JKIUJOTMS[RZOLGIZUXOGR VNKTUZ_VKYGYUTKULZNKL[Z[XKXKYKGXINJOXKIZOUTY Illustration 5: Some commentaries by the academic community In addition to the above academic reviews, various disciplines have also realized the importance of phenome research. In 2012, the American Society of Human Genetics (ASHG) annual meeting, which is the world’s largest human genetics conference, held the 2012 Forum of the Human Variome Project 20 themed "Getting Ready for the Human Phenome Project", which clarified the necessity and feasibility of establishing a human phenome project. Since then, the research based on phenomics, genome-phenome and Phenome-wide Association Studies (PheWAS) has increased yearly. In 2019, Nature21 published a brief historical review of human disease genetics, systematically reviewing the milestones in the development of human disease genetics, and pointed out the following: to fully realize the potential of genomics, continuous collaborative efforts in multiple aspects are required to create a more comprehensive genotypephenotype map so that a thorough understanding of the disease can be established to provide basis and targets for future clinical treatment. 20 Oetting, W.S., et al., Getting ready for the Human Phenome Project: the 2012 forum of the Human Variome Project. Hum Mutat, 2013. 34(4): p. 661-6. 21 Claussnitzer, M., et al., A brief history of human disease genetics. Nature, 2020. 577(7789): p. 179-189. BOX 1 9 Human Phenome Research Progress Report 2020 In 2020, the top cardiovascular journal Circulation published expert opinions22 suggesting that epidemiology can only moderately predict the risk of cardiovascular disease. However, the study of the phenome through imaging can systematically determine its risk, and phenotype measurement is more meaningful for cardiovascular disease risk prediction. At the end of 2020, the American Association for Dental Research adopted "Science for the Next Century: Deep Phenotyping" as the theme for its annual conference. In the lecture on deep phenotyping, dental experts introduced the progress and highlights of dental caries, periodontal disease, dental microbiome, and craniofacial anomalies. The content was published in the Journal of Dental Research23. Countries accelerating investment in human phenome research facilities In 1996, Europe initiated the construction of the Orpha knowledge base for rare diseases and related drugs and created standard terminologies for 1,000 to 2,000 rare disease phenotypes. Orpha.net24, which was launched in 2000, has become the preferred information provider and partner for patients, hospitals, major research institutions and pharmaceutical companies for its detailed and authoritative rare disease data. The United Kingdom had an early start in phenotype research. It had as early as 1999 proposed the building of the UK Biobank25, which was eventually launched in 2007. The biobank provides researchers with materials including human phenotype and is one of the largest health research projects in the UK. In 2012, the Medical Research Council (MRC), in cooperation with the National Institute for Health Research (NIHR), announced the establishment of the MRC-NIHR Phenome Centre26 (MRC-NIHR Phenome Centre) in the 22 Wierzbicki, A.S., Phenomics, Not Genomics, for Cardiovascular Risk Assessment. Circulation, 2020. 142(9): p. 821-823. 23 WRIGHT, J. T. & HERZBERG, M. C. 2021. Science for the Next Century: Deep Phenotyping. J Dent Res, 220345211001850. 24 orpha.net. Available from: https://www.orpha.net. 25 UK Biobank. Available from: https://www.ukbiobank.ac.uk/ 26 Payne, T., London 2012 anti-doping laboratory to be developed into the world's first Phenome Center. Bioanalysis, 2012. 4(16): p. 1975-1975. 10 Human Phenome Research Progress Report 2020 UK. This is the world's first phenome center. The center used the 2012 London Olympics drug metabolism testing laboratory facilities to create conducive conditions for researchers to explore disease characteristics and develop new drugs and treatment options. The National Phenotypic Screening Center27 (NPSC) for human, animal and plant phenotype screening provides biologists with an opportunity to verify phenotype analysis. In November 2012, the National Center for Biotechnology Information (NCBI) under the National Institutes of Health (NIH) in the United States announced the launch of a public free database called ClinVar28 that would 9IOKTZOLOILGIOROZOKY LUXN[SGTVNKTUSK support research on the relationship between human genotypes and medically XKYKGXIN important phenotypes. 英 国 4GZOUTGR6NKTUZ_VOI9IXKKTOTM )KTZKX469)2UTJUT ;1 )ROT