I have a broad interest in Human Genetics, Cancer Genomics, Population Genetics, and System Biology.
I use comprehensive approaches, especially genomic tools, to study micro-evolution issues in cancer cells, including dynamics of tumor cell evolution, tumor growth pattern and mutation rate in this process. The study of the intrinsic attribute of cancer cells not only provide a genetic basis of cancer but also expand the framework of evolutionary theory in cellular level. Right now, I adopt transdisciplinary tools to study the aerobic issue with rat model, including microarray, genome sequencing genotyping and massive behavior study, aiming to provide a better understanding the genetics of aerobic capacity and an excellent mode for therapy of human metabolic disease.
Diversification and evolution of tumor cells
My Ph.D. thesis focuses on the evolutionary issue of the cancer genome, including the diversification of tumor cells and evolution of mutation rate. We aim to expand our knowledge of macro-level population genetics to micro-level tumor cells in order to extend the framework of classical evolutionary theory to the cellular level.
In 1976, Peter Nowell proposed a remarkable perspective on cancers as an evolutionary process at the cellular level. The analogy to modern Darwinian Theory, the most important issue is whether the accumulated mutations adaptive for the cellular process. Our research is based on the diversification between metastasis and primary tumors, aiming to reveal whether cellular heterogeneity an adaptive or drift biological process. We have paired hepatocellular carcinoma samples and validate at a small number of cells. My work includes 1) identify rapid clones and its causing mutations 2) simulate population dynamics between adenoma and carcinoma. Our results show a strong phenomenon of selection for certain mutations during metastasis. Besides this, further results in adenoma and paired carcinoma indicate a pathway selection during the evolution of cancer cells.
Evolution of Mutation Rate in vivo
I consider mutation rate as one of my long-term interest, as the essential and basic position in population genetics. Mutation rate is a product with multiple effects, and the evolution of mutation rate in cancerous cells is a representative issue, not only demonstrates the genetic basis of cancer but also tests the hypothesis in cellular level. With the analysis of cancer genomic data, I describe the profiling of mutation rate and identify the significance of mutator effect. My work includes 1) the effect of the internal factor on mutation number variations, namely “intrinsic mutator”, 2) reveal the evolution of time-series mutation rate. My results show that the existence of internal driving factors and “mutator” effect could contribute largely to the accumulation of somatic mutations.
Diversification of Cultivate Rice
Today, rice is one of the most important grain with regard to human nutrition and feeds more than half the world's population. It is widely grown on every continent in the world except Antartica and feed people over a longer period of time than any other crop, since 7000 year BC. But do you know where rice comes from and why they are so important? There are numerous debates on the origins of cultivated rice, especially the two most popular strain: japonica and indica. One idea is separate origin: fossil and archaeological evidence points that these two strains are separately cultivated in two areas. While the other idea is shared the origin: some important cultivated genes are shared by two strains.
In 2011, we used next-generation sequencing technology to solve the original problem of rice: 1) know the history of cultivating rice; 2) identify important cultivated traits. This is the first time to use dual-platform sequencing technology (Illumina + SOLID) on rice genome, and enable us to get much more precise data. In total, we sequenced 66 pooled samples from rufipogon (wild rice) and indica and japonica (cultivated rice) and covered more than 50,000 genes of rice. We then detected the difference between cultivated (japonica and indica) and wild rice and reach a striking result: 40% of two cultivated rice genome have shared history, while others have separated history. That is, for most of the genes, indica and japonica are indeed no closers to each other in kinship than each to wild rice, supporting the view that the two cultivars were independently domesticated. However, when the gene influenced by selection were examined, indica and japonica appear to share a surprisingly strong kinship. In light of our new data, the story of rice may need to be revisited. Early farmers from different regions may have cultivated rice independently but it seems that they also borrowed desired traits extensively from rice farmed by others, resulting in the opposing kinships reported.
Genetic mechanism of aerobic capacity in Rat Model
My current research is the metabolic disease on rat disease model. We aim to provide a better understanding of the metabolic disease and a model for therapy.
Aerobic capacity refers to the max amount ability of oxygen-consuming during exercise. It is a function of the overall performance of the cardiorespiratory system and has a strong association of risks of obesity, hypertension, and type-2 diabetes. We adopted a rat model system, comprising two lines with well-established phenotype on running ability. After directional selection on running ability for >= 30 generations, two lines, HCR (high capability runners) and LCR (low capability runners), display a distinguished heterogeneous phenotype and dramatic diversified physical features, although sharing with common ancestors. Combine with transdisciplinary approaches, with massive microarray and sequencing tools, we are now deciphering the genetic basis of aerobic capacity.
Group I intron Database (GISSD)
DNA, RNA and protein comprise the central dogma: “DNA makes RNA, and RNA makes protein”. During the process from DNA to RNA, introns self-spliced and are removed from precursor RNA. Among all types of introns, the group I introns constitute a major class that catalyzes their own excision from the precursor RNA. They are widely spread across different species, including bacteria, lower eukaryotes, and higher plants, and are incorporated into different tRNA rRNA, and mRNA. The self-splicing is a key process of central dogma and occurs by two coupled transesterification reactions involving a guanosine cofactor in the first step. Next, group I introns fold into a secondary structure and assemble different functional core domain, then excise itself from precursor RNA.
The secondary structure, folding and autocatalysis of group I introns have been rigorously studied in a few species, but not globally. Thus, a specialized and comprehensive study on the secondary structure of group I introns is essential for understanding from a systemic level. Our research aims to provide a comprehensive annotation for the group I intron and infer the subgroup of different group I introns. For each subgroup, we will call consensus structure based on high-quality alignments. At first, we collected all 1789 introns with the complete record, including the nucleotide sequence of each annotated intron plus 15 nt of the upstream and downstream exons. Then, we infer the secondary structure of each record by combining the minimal free energy algorithms and comparative sequence alignment. By clustering those key component from the secondary structure, we clustered group I introns into 13 known minor subgroups and identify a new group which has never been reported. For each group, they have a distinct functional domain. More strikingly, we identify for the first time group I intron from Cordyceps sobolifera ( fungi) and eukaryotic virus.
Previous Lab Experience
During my fantastic campus life in Wuhan University from 2003 to 2007, I worked mainly on two aspects, group-I intron and Metarrhizium anisopliae in labs of Dr. Zhang Yi and Dr. Hu Yuanyang. I received my first published paper in 2006 in Zhang's lab, which is a milestone in my scientific career. Dr. Zhang had a beneficial influence on my scientific life with her scientific spirit. Then, I stepped into CAS(Chinese Academy of Sciences) for senior scientific training from 2007 to 2012. In 2008, I studied in BGI, supervised by Dr.Wang Jun, who showed me another view of scientific view, which is a large fortune for me. From 2009 on, Dr. Wu Chung-I guided me to the world of evolution and population genetics.