Zhang:ResearchOverview

Research Overview

The Zhang lab at the UCSD Bioengineering department is interested in developing novel genome technologies towards the applications in personalized genome medicine and stem cell research.

Genome Technology:

We are developing various methods for synthesis, manipulation and sequencing of DNA molecules. Examples include

• large-scale DNA synthesis on programmable DNA chips;
• isolation, amplification and sequencing of single chromosomal molecules;
• digital profiling of gene expression and allele-specific gene expression;
• targeted genome capture and sequencing.
• targeted digital analysis of epigenome.

Genome Informatics:

Almost every single aspect of our genome-scale studies depends on bioinformatics. We do large-scale "manipulation" of DNA molecules in computer before and after processing them in test tubes. Here are some examples:

• designing DNA probes for capturing & sequencing SNPs/Exons, which also includes various simulation;
• mapping and analysis of next-generation DNA sequencing data;
• de novo assembling of single-cell genome sequencing data;
• haplotype assembling and analysis of single molecule sequencing data.

Biology:

Personalized regenerative medicine

Our research interest lies in the genetics of individuality. We ask what are the phenotypic differences among human individuals or cell lines derived from these individuals, and what are the genetic factors that can explain such differences (formally termed as phenotypic variations). We seek to identify functional genetic variations in the human genome, which often contribute to the susceptibility of human complex diseases. We use a system biology approach by combining large-scale genotyping, phenotyping, functional assays, and analysis of gene regulation networks or pathways.

We perform these studies under two different contexts:

• Human embryonic stem cells (hESC) and induced pluripotent stem cells (iPS):
  • We are performing large-scale phenotyping and functional genomic analyses on a panel of hESC lines established at the Harvard Stem Cell Institute (HUES lines).
  • We are also performing genomic analyses of iPS cells to understand the de-differentiation and re-differentiation processes. Our thrust along this line has recently been recognized and supported by the NIH Epigenomics RoadMap program.
• Personal Genome Project: we have received UCSD's IRB approval to perform functional analyses on the samples collected under the Personal Genome Project. Another web site about PGP, which has a link to a video clip of Esther Dyson on the Charlie Rose Show talking about PGP. Here is a recent New York Times article by Steven Pinker on personal genome. We are performing integrative genomic analyses on PGP samples. Some examples are:
  • Exome resequencing: discovery of genetic variations and mutations in 1% of protein coding sequences in the human genome. This project is sponsored by the NHLBI Exome sequencing program;
  • RNA allelome: identification of allele-specific expression and the associated cis-regulatory variants;
  • DNA methylome: genome-wide characterization of DNA methylation in different tissue/cell types; analyses of genomic imprinting and X-chromosome inactivation;

Human microbiome

It has been recognized in the past few years that the distribution and activities of microorganisms in the human body (human microbiome) have profound impacts on the health of the host. Because of the important implications of this research area in public health, NIH recently launched a cross-institutional Human Microbiome Project under its RoadMap Initiatives.

Analyzing the complex communities of these microorganisms has been very challenging, partly because most microorganisms are difficult to grow and maintain in laboratory culturing conditions. Supported by the Human Microbiome Project, we are developing an efficient and scalable method to obtain genome information from single cells in such complex microbial communities. This is a collaborative project with Dr. Yuhwa Lo's laboratory in the UCSD ECE department. It involved seamless integration of methods in several areas including microbiology, genomics, biophotonic, signal processing and nanofabrication.

Potential graduate student rotation projects:

• Design and fabrication of microfluidic devices for single chromosome analysis.
• Development of read mapping strategies for next-generation DNA sequencing data.
• Functional analysis and annotation of genetic variants/mutations identified in exome resequencing.
• Analysis of global epigenetic changes in stem cells.