Research
CAS Key Laboratory of Genomic and Precision Medicine
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1. 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 in summer of 2014.

 

2. 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) Heterogeneity and genome evolution in cancer


Based on previously important results on the mutation spectrum and lineage of tumor mutation and improved analytical approaches by integrating population genetics and evolutionary theory, we will investigate the mutational patterns and their influence on tumor development, and further explore more therapies.


(2) Epigenetic variations and their roles in disease development


Based on previous important results on various levels of epigenomics studies, we will focus to understand the function and mechanism of epigenetic variations including histone modification and their roles in leukemia development, RNA methylation mechanism and their influences in the development and diseases, the dynamic patterns of DNA methylation during development and tumor genesis.


(3) Integrative analysis of big data and construction of precision medical data platform


Through interpreting and integrating multi-level data of genome and phenotype from large-scale prospective cohort and clinical samples, we attempt to construct precision medical data platform based on human genome records and previous relevant research achievements for diagnosis, therapeutics, and precision medicine, which supported by the advantages of the institute and CAS.


(4) Functional annotation for complex physiological traits and individualized patterns


The ultimate goal of human genome research is to maintain the state of health, and to achieve early prevention, early diagnostic, and accurate treatment for diseases. By precision and functional annotation in certain genes of several complex traits in our previous results, our future studies involves in two main directions: the impacts of alterations in the genome stability on tumor development and drug resistance and the functional annotation of genes associated with hypoxia adaptation and tumor microenvironment.

 

3. Organization


The laboratory implements director responsibility system which under the direction of the institute and the academic advisory committee:

 

Director: ZENG Changqing
Deputy Director: YANG Yungui

Academic Committee

Director: SHEN Yan, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences
Deputy Director: ZENG Yixin, Chinese Academy of Medical Sciences, Peking Union Medical College

 

Members (ordered alphabetically):


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, Institute of Biochemistry and Cell Biology, 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

 

4. Annual research progress


(1) Cancer genomics and evolution


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. Because natural selection is not a strong deterministic force, cancers usually evolve divergently even in similar tissue environments (Annual Review of Genetics, 2016). We creatively developed Droplet-CirSeq for relatively efficient, low-bias and ultra-sensitive identification of variations by combining millions of picoliter uniform-sized droplets with Cir-seq. Droplet-CirSeq is entitled with an incredibly low error rate of 3~5*10-6. Our findings indicated that 30 pg DNA input accommodated in 5~10 million droplets resulted in maximal detection of authentic mutations compared to 3 pg (BMC Genomics, 2016).


(2) Variations of epigenetic modifications in disease


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 and direct role of m6A and its nuclear reader YTHDC1 in pre-mRNA splicing (Molecular Cell, 2016; RNA Biology, 2016). 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. 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, 2016). By comparing their respective DNA methylation level of the Y chromosome from 72 donors, we found that the DNA methylation pattern on the Y chromosome was stable among family members and haplogroups. Interestingly, two haplogroup-specific methylation sites were found, which were both genotype-dependent. Moreover, the African and Asian samples also had similar DNA methylation pattern with a remote divergence time. Our findings indicated that the DNA methylation pattern on the Y chromosome was conservative during human male history (PLoS One, 2016).

 

(3) The mechanism of genomic variations and their functions in disease progressions


We found that TLS polymerase REV1 can promote TLS after UV radiation through the enhanced interaction between REV1 and ubiquitylated RAD18, which facilitates the release of non-ubiquitylated RAD18 from ubiquitylated RAD18 trapping, after which RAD18 is recruited to chromatin for its TLS function (Journal of Cell Science, 2016a). We also found that human helicases RecQL4 involved in many DNA repair pathways drives cisplatin resistance in gastric cancer by activating an AKT-YB1-MDR1signaling pathway (Cancer Research, 2016). We developed an exquisite ultra-sensitive NGS platform to screen regulators of TLS and monitor environmental genotoxic substances (Scientific Reports, 2016). We generated a Human Huntingtin (HTT) testis conditional knockout mouse and found that spermatogenesis is impaired. Using an iTRAQ-based quantitative proteomic assay, we found that knockout of Htt significantly altered the testis protein profile (Journal of Cell Science, 2016b). Our findings identify a novel molecular link between ATX-3 and p53-mediated cell death and provide an explanation for the direct involvement of p53 in SCA3 disease pathogenesis (PLoS Biology, 2016).


(4) Functional annotation for complex physiological traits


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). 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 (Current Biology, 2016). A logistic regression model considering the genotypes of 25 SNPs from 12 genomic loci was highly informative (probability>0.80) for up to 19% of receivers, thus may assist decision making on early MPB intervention actions and in forensic investigations (European Journal of Human Genetics, 2016). Through analysis of de novo whole-genome sequence of R. bieti and genomic sequences for the four other species, eight shared substitutions were found in six genes related to lung function, DNA repair, and angiogenesis in the high-altitude snub-nosed monkeys, which provide valuable insights into the adaptation to high altitude in the snub-nosed monkeys (Nature Genetics, 2016). 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).


5. Talents, awards and honors


ZENG Changqing, CAS Distinguished Research Fellow.
ZENG Changqing, Associate Chair of Precision Medicine Subcommittee, Chinese Association of Geriatric Research.
YANG Yungui, The National Science Fund for Distinguished Young Scholars.
YANG Yungui, Vice Director of CSBMB RNA Society
YANG Yungui, Head of Educational Programme (HEP) for SDC Omics, UCAS
WANG Qianfei, Special Government Allowances of the State Council.
GUO Caixia, “ZHU-LI Yuehua Excellent Teacher Award” of CAS.