To address the new generation of problems in molecular genetic epidemiology will require the introduction of new genetic analysis technologies. This will include both the """"""""hardening"""""""" of laboratory instrumentation and the development of new informatics infrastructure and analytic tools. The LPG has explored several new technology platforms and their suitability for high-throughput genetic analysis, and has designed assays for the detection of genetic polymorphisms in genes of interest to molecular epidemiology for each of these technology platforms. Platforms include capillary electrophoresis instruments, the use of photolithographic DNA chips (HuSNP chips), enzymatic cleavage genotyping assays, and MALDI TOF mass spectrometry for genotyping, and more recently single base primer extension (SNaPshot). We have refined the SNaPshot assay to allow us to assess 10 different SNPs in a single reaction. In this manner, we readily tested 200 samples for the presence of 40 potential SNPs. In addition, the LPG has expanded the utilization of the HuSNP technology by mapping the exact chromosomal location of each SNP and then correlating the presence or absence of the SNP with Affymetrix expression data from the same samples. Use of data from HuSNP chips to determine areas associated with loss of heterozygosity (LOH) or allelic imbalance is being explored, and new analysis tools are being developed to allow further integration of polymorphism data and gene expression data. The laboratory is developing novel bioinformatic and analytic tools for genetic/genomic analysis. These include analytical and visualization tools for selecting and prioritizing candidate genes for cancer epidemiology studies, for evaluating the correlation of gene expression and LOH allelic imbalance, and for constructing and analyzing functionally annotated haplotypes using SNP markers. A relational database was developed for managing high throughput laboratory data with easy access via a web interface. In the area of informatics research, significant progress has been made in developing new approaches to address the inherent heterogeneity present in human populations, in analyzing the accuracy and performance of haplotype constructing algorithms, and in developing new algorithms to identify the minimum set of polymorphic markers required for genotype assays.
