Research
CAS Key Laboratory of Genomic and Precision Medicine
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Introduction

 

To integrate rapidly growing approaches of the human genome research into the exploration of complex diseases, Beijing Institute of Genomics (BIG) of Chinese Academy of Sciences (CAS) made the decision to establish the Institute Key Laboratory of Disease Genomics and Individualized Medicine" in 2010. At various administration levels, a key laboratory usually refers to a research center with a few to a couple of tens of research groups leading by principal investigators (PIs). The research of our key lab includes mainly the discovery and functional analysis of genomic and epigenomic variations that contribute to cancer and various diseases. With our exciting achievements on the evolution and selection of somatic mutations in cancer genome as well as the coordination function of genomic and epigenomic alternations in tumor and in metabolic diseases, etc, this center was assigned as the CAS Key Laboratory of Genomic and Precision Medicine (Lab code: 2014DP173034) in summer of 2014.

 

From once the major team and the coordinator of the "China chapter" of the International Haplotype Map (HapMap) Project, till today a CAS Key Laboratory consisting of 14 multidispline research groups, we have our integrated efforts focusing on precision medicine. For the last five years (2011-2015), the key lab published SCI papers of 117 and obtained 79 projects with funding over ?193 million. And in 2015 we published 29 papers and was funded with?44 million from granted projects. Currently the titles or awards among PIs include one awardee of the national Thousand Talents Plan and an academy member (Taiwan), three recipients of the National Science Fund for Distinguished Young Scholars (NSFC), one awardee of the national Thousand Youth Talents Plan, one recipient of Excellent Young Scientists Fund (NSFC), and nine awardees of CAS One Hundred Plan.

 

Research Directions

 

Based on the major research aims in field of public health in CAS 135 plan, as well as taking the advantage of epigenetic research, high throughput sequencing, and data analysis and computation in the institute, the research directions of CAS Key Laboratory of Genomic and Precision Medicine include four categories as briefly stated below.

 

(1)Population genetics and cohort study

As an important approach in field of precision medicine, cohort study will be a major task of the Key Lab activity. Especially as the first precision medicine related project, Chinese Academy of Sciences launched the CAS Precision Medicine Initiative (CASPMI) at the end of 2015. One of the major tasks of CASPMI is to construct a new cohort comprised of thousands of staff members who are working in CAS. Participants will be involved in comprehensive physical and laboratory examinations, which will contribute diverse sources of data at baseline and at follow-up every 5 years including dynamic health records, clinical epidemiological and lifestyle data, and profiles of 杘mics and biomarkers, etc. This prospective cohort was designed to identify genetic variants, epidemiological factors and other biomarkers for the risk of complex traits/diseases, and thus to exploit the immense potential of precision medicine research. We believe that both the near-term and long-term findings from this well-designed study will tremendously benefit people in China and worldwide.

 

(2)Cancer genomics, epigenomics, and evolution

 

1) Evolution of cancers

Although tumorigenesis has been accepted as an evolutionary process, many forces may operate differently in cancers than that in organisms due to vastly different time scales. Among such forces, natural selection is particularly interesting because its action might be thwarted in multicellular organisms. However, the evolutionary forces and their consequences in terms of genetic diversity, changes in fitness, population growth, and the emergence of resistance in cancers are lack of being tested theoretically and empirically, which has been one of the main objects in our research. In addition, as an open complex adaptive system, multiple elements within cancer can change over time and interact with other components in complicated ways. Therapeutic perturbations also apply intense Darwinian selection for resistant clones, which servers as the proximate cause of death in most cancer patients. By exploiting the complex dynamics during the course of leukemia treatment, we aim to apply evolutionary principles to cancer therapy which may lead to prolonged survival.

2) Epigenetic variations and functional importance in tumorigenesis

Recent sequencing studies from cancers genome projects have identified tumor-specific mutations in human genes encoding proteins that function in epigenetic regulation, such as histone modification and DNA methylation. One direction for cancer study is the integrative genomic study to dissect the functional importance of epigenetic mutation in the development of human cancer including acute leukemia, kidney cancer, and cancers of digestive tract.

3) Establishment of Liquid Biopsy platform

Based on previously work on the mutation spectrum, lineage of tumor mutation and epigenetic map in cancers, we will continuously optimize approaches of liquid biopsy to monitor the genetic and epigenetic changes in cancer, and to make our platform applicable for early diagnosis and 損recision therapy?of cancer.

(3)Disease epigenetics

Epigenetics refers to functionally relevant changes to the genome that do not involve a change in the nucleotide sequence. Epigenetics mechanisms include DNA methylation, RNA modification, histone modification, noncoding RNA, and nucleosome positioning, etc., which are critical for regulating gene expression. The recent breakthroughs in high-throughput techniques create possibility for scientists to conduct genome-wide epigenomic studies, and map individual epigenetic marks in health and disease. We aim to dissect epigenetic mechanisms underlying how aberrant alterations and mutations in these epigenetic machineries cause disease.

(4)Omic data interpretation

The dosage of multilayer omics data is increasing in an exponential manner in the current era of big data. Intergrading and transforming these data into valuable knowledge is truly challenging. The efforts of the Key lab also include the methodological and analytical developments to understand the complex relationships among multilayer omics data using the state-of-the-art statistics and deep learning techniques. We synthesize the cutting edge approaches used in population genetics, molecular epidemiology, and bioinformatics to characterize how genomic, transcriptomic, proteomic, and metabolomic changes may contribute to phenomic variations. We also study how these patterns may evolve longitudinally and geographically under continues pressures of natural and artificial selection.

 

Organization

Director: ZENG Changqing

Associate Director: YANG Yungui

Members: CAI Jun, CHEN Hua, CI Weimin, GUO Caixia, LIU Fan, LIU Xin, LU Xuemei, MI Shuangli, SUN Yingli, WANG Qianfei, WU Chung-I, ZHAO Yongliang

 

Academic Committee

Chair: SHEN Yan, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences.

Associate Chair: ZENG Yixin, Chinese Academy of Medical Sciences, Peking Union Medical College.

Members:

CHEN Runsheng, Institute of Biophysics, Chinese Academy of Sciences

JI Jiafu, Peking University Institute of Clinical Oncology

LI Lin, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences

LIN Dongxi, Chinese Academy of Medical Sciences & Peking Union Medical College Tumor Hospital

SHI Yufang, Shanghai Institutes for Biological Sciences; Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine

WANG Qianfei, Beijing Institute of Genomics, Chinese Academy of Sciences

WANG Xiaoning, Chinese PLA General Hospital

WU Hong, Peking University

WU Chung-I, Beijing Institute of Genomics, Chinese Academy of Sciences

XU Guoliang, Professor, Institute of Biochemistryf and Cell Biologu, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences

XU Tao, Institute of Biophysics, Chinese Academy of Sciences

YANG Yungui, Beijing Institute of Genomics, Chinese Academy of Sciences

ZENG Changqing, Beijing Institute of Genomics, Chinese Academy of Sciences

ZHANG Xuemin, Academy of Military Medical Sciences

ZHOU Qi, Institute of Zoology, Chinese Academy of Sciences

 

Recent research progress (since 2014)

 

1. Population genetics and precision medicine

MC1R and facial look. Looking young for one's age has been a desire since time immemorial. Understanding the underlying molecular biology of perceived age is vital for identifying new aging therapies among other purposes, but studies are lacking thus far. As an early attempt, we performed genome-wide association studies of perceived facial age and wrinkling estimated from digital facial images by analyzing over eight million SNPs in over thousands of subjects. The strongest genetic associations with perceived facial age were found for multiple SNPs in the MC1R gene via a compound heterozygosity marker constructed from four pre-selected functional MC1R SNPs (p=1e-12). Individuals carrying the homozygote MC1R risk haplotype looked on average up to 2 years older than non-carriers. A role for MC1R in youthful looks independent of its known melanin synthesis function is suggested. Our study uncovers the first genetic evidence explaining why some people look older for their age and provides new leads for further investigating the biological basis of facial look (Curr Bio, 2016).

 

2. Cancer genomics, epigenomics, and evolution.

Evolution of cancers. The Cancer Genome Atlas (TCGA) data show a low degree of convergent evolution in the evolution between tumors and normal tissues, where genetic changes are not extensively shared among cases. The discovery using TCGA data is that there is almost no net selection in cancer evolution. Both positive and negative selection are evident but they neatly cancel each other out, rendering total selection ineffective in the absence of recombination. The efficacy of selection is even lower in the evolution within tumors, where neutral (non-Darwinian) evolution is increasingly supported by high-density sampling studies (PNAS 2015; Mol Evol Biol, 2016, in revision). Because natural selection is not a strong deterministic force, cancers usually evolve divergently even in similar tissue environments (Annual Rev Genet, 2016, accepted).

 

Novel mutation discovery and clonal evolution of acute myeloid leukemia. We performed high throughput sequencing in AML patients, and for the first time revealed that histone modification abnormality caused by SETD2, as a novel tumor suppressor gene in leukemia, is a critical pathway contributing to leukemogenesis (Leukemia, 2014; Nature Genetics, 2014). Our recent studies showed that leukaemia children treated with low-dose chemotherapy for induction have similar outcomes as those treated with the high-intensity induction regimen. These clinical and genomic analyses suggest that low dose chemotherapy represents a valuable alternative to conventional chemotherapy and can be used in the general pediatric population with AML.

 

5mC and 5hmC in tumorigenesis. Both 5-methylcytosine (5mC) and its oxidized form 5-hydroxymethylcytosine (5hmC) have been proposed to be involved in tumorigenesis. By profiling real 5mC and 5hmC levels simultaneously at single-nucleotide resolution, we demonstrated that loss of 5hmC is both a prognostic marker and an oncogenic event in kidney cancer (Cell Research, 2015, 2016). The ultimate goal of the key lab is to define the genetic and epigenetic changes that occur in cancers, to discover the molecular causes of these changes, and to translate that newly gained knowledge into the clinic in the form of novel, genetic and/or epigenetic-based diagnostics and therapies.

 

3. Variations of epigenetic modifications in disease

DNA methylation and disease progression. We discovered the dynamic patterns in transmission of DNA methylation. The transcription levels of genes are varied during the differentiation progression of stem cells, which was used in the studies to achieve a comprehensive assessment of dynamic patterns and fidelity of methylation. The transcription level is negatively correlated with DNA methylation level during early differentiation, and positively correlated with the methylation fidelity. The methylation fidelity of CpG islands decreases in tumors. In the meanwhile, we developed an analytical procedure to decipher the DNA methylation heterogeneity of mixed cells (Genome Research, 2014; Biomed Research International, 2014; BMC Genomics, 2014). Also, we found vitamin C and quinones have impact on the conversion of 5mC to 5hmC (Nucleic Acids Res, 2014). In the study of prostate cancer, we successfully identified specific DNA methylation variations that can be detected in urine samples from prostate cancer patients as biomarker for diagnosis (Oncotarget, 2015).

 

Mechanisms of RNA modification. We have made a breakthrough point of expanding new research frontiers of RNA methylation-mediated epitranscriptomics by identifying the mammalian RNA N6-Methyladenosine (m6A) methyltransferase complex METTL3/METTL14/WTAP (Cell Research 2014), selective mechanism of m6A site (Cell Stem Cell 2015), m6A demethylase ALKBH5 (Molecular Cell 2013) and direct role of m6A and its nuclear reader YTHDC1 in pre-mRNA splicing (Cell Research 2014; Molecular Cell 2016; RNA Biology 2016). We have shown that in Drosophila melanogaster, new miRNAs are adaptively evolving at birth, which highlights the regulatory of miRNAs (PLoS Genetics, 2014). In an integrative study of biochemistry, stem cell, genomics, and bioinformatics, our findings revealed a brand new role of miRNAs in regulating mRNA epitranscriptomic modification in eukaryotes. The discovery of enzymes catalyzing m6A dynamics and m6A role in RNA processing demonstrates that besides the vital roles of DNA methylations the dynamic and reversible chemical m6A modification on RNA also plays essential roles in epigenetic regulation of basic life processes in mammals and now becomes a novel epitranscriptomic marker of profound biological significance.

 

4. Omic data interpretation Methods to detect CH-like effects in GWAS. Compound Heterozygosity (CH) in classical genetics is the presence of two different recessive mutations at a particular gene locus. A relaxed form of CH alleles may account for an essential proportion of the missing heritability, i.e. heritability of phenotypes so far not accounted for by single genetic variants. Methods to detect CH-like effects in genome-wide association studies (GWAS) may facilitate explaining the missing heritability. CollapsABEL provides a computationally efficient solution for screening general forms of CH alleles in densely imputed microarray or whole genome sequencing datasets. The implemented test provides an improved power over single-SNP based methods in detecting the prevalence of CH in human complex phenotypes, offering an opportunity for tackling the missing heritability problem (BMC Bioinformatics, 2016).

 

 Awards and Honors (since 2014)

 

  • Prof. ZENG Changqing obtained Outstanding Woman Achievement of CAS Beijing Region (2014), was appointed as a Panel Member of the MOST (the Ministry of Science and Technology) for the National Major Research Plan in Precision Medicine (2015), and serves as Associate Chair of Precision Medicine Subcommittee, Chinese Association of Geriatric Research (2016).
  • Prof YANG Yungui obtained "Excellent" in the final review of the CAS "Hundred Talents Program"(2014), was appointed as a CAS Distinguished Professor (2015), received The National Science Fund for Distinguished Young Scholars (2016), and as the Chief Scientist obtained a major funding for National Basic Research Programs in Precision Medicine (2016).
  • Prof. WANG Qianfei received The National Science Fund for Distinguished Young Scholars (2014), was appointed as CAS Distinguished Professor (2015) and as a professor of the National Hundred, Thousand and Ten Thousand Talents Project (2015); received "ZHU-LI Yuehua Excellent Teacher Award" of CAS (2015).
  • Prof. GUO Caixia received "ZHU-LI Yuehua Excellent Teacher Award" of CAS (2016).
  • Prof. CI Weimin received The National Science Fund for Excellent Young Scholars from National Natural Science Foundation of China (2014).
  • Prof. LIU Xin was appointed as a professor of "Hundred Talents Program"of CAS (2015).
  • Prof. LIU Fan was appointed as a professor of "Thousand Youth Talents Program" of CAS (2015).
  • Dr. HOU Yali and Dr. HE Fuhong were elected as members of Youth Innovation Promotion Association of CAS (2015).
  • Dr. SUN Baofa and Dr. ZhANG Dake were elected as the members of Youth Innovation Promotion Association of CAS (2016).