RESEARCH PLAN

With my experience in physical mapping, SNP marker discovery, and genotyping method development, I intend to pursue a research program in 3 directions - development of mutation detection methods, development of genotyping methods, and apply these tools in the study of complex disease traits, pharmacogenetics and population genetics.

1. Development of homogeneous and robust mutation scanning methods.

Current approaches for mutation scanning include single strand conformation polymorphism (SSCP) scanning, denaturing gradient gel electrophoresis (DGGE), denaturing high performance liquid chromatography (DHPLC), and direct DNA sequencing. All of these methods are based on separation of DNA fragments on various platforms. A promising approach to distinguish between mismatched heteroduplex and homoduplex DNA is to compare their melting temperatures. By monitoring the fluorescence intensity of an intercalating dye such as SYBR Green I along a temperature gradient, one can construct melting curves for any DNA mixture and identify the presence of homo- and heteroduplexes. No separation or other manipulations are necessary once the initial PCR amplification is accomplished. I will also explore the use of mismatch-specific cleavage enzymes to magnify the difference in melting temperatures

2. Development of cost-effective, high throughput, homogeneous genotyping assays.

There are currently no methods that are capable of genotyping SNPs at the level required in functional genomic studies. By one estimation, a typical project involves genotyping 1,000 subjects with 60,000 SNP markers at a rate of 1 million assays per day. I will devise different ways to utilize homogeneous and chip-based approaches to help make genotyping large numbers of samples with numerous markers possible. I will pursue several promising ideas including the use of FP in allele-specific PCR. The goal is to develop methods that will enable laboratories of any size and budget to genotype with robust methods.

3. Study of complex traits, pharmacogenetics and  population genetics with SNP markers.

I will actively seek collaboration with other investigators and apply the many tools I have developed to study complex traits and population genetics. With methods that can identify SNPs in any population and genotype large numbers of individuals with large numbers of markers, one can begin to ask interesting questions regarding population movements in ancient times, identify genetic factors involved in complex traits, and reconstruct evolutionary history.

Similarly, I can apply SNP and genotyping methods to study the effectiveness of drug treatment, and estabolish correlation between genetic background and drug treatment and procedures. This will help to accomplish goals of individual and predictive medicine.

Since these methods can be applied universally to any organism, I will also collaborate with investigators studying model organisms and help define the genes involved in different pathways by a molecular genetic approach.

Home | Experience | Research Plan | Qualification | Contact

Last revised: January 13, 2004.