Research Component 3:
Molecular Genetics Support Core
Director: Kari Buck
The Molecular Genetics Support Core (Component 3) will provide services to all Research Components and Pilot Projects requiring molecular biological and genetic assays.
In the past five years, we identified chromosomal regions (called quantitative trait loci or QTLs) that contain some of the genes involved in behavioral responses to ethanol including preference and withdrawal. Several QTLs were fine mapped to ~1 cM. We identified the quantitative trait gene (QTG) for a withdrawal QTL on chromosome 4 as Mpdz.
Promising candidates were identified for other ethanol-response QTLs using behavioral genetic approaches. We also implicated candidates using microarray analysis. These candidates now require rigorous testing to be accepted as proven QTGs. An important goal of behavioral genomics is to identify the gene underlying QTL phenotypic effects, and to elucidate the mechanism by which the gene influences behavior.
In the next five years of support, complementary strategies will emphasize fine mapping of new QTLs, identification and definitive proof of QTGs for preference, withdrawal, and correlated traits. Proposed genotyping is largely focused on fine mapping of new QTLs. Candidate genes will be tested for differences in expression/function and sequence (coding and regulatory) using appropriate animal models.
Because many genetic markers and almost all genes have been physically mapped in the mouse, rat, monkey, and human genomes, knowing which markers define a chromosomal interval of interest can automatically define which candidate genes are in the interval. Priority for expression/function and sequence comparisons will be determined based on several criteria, including map location, putative biological role, likely relevance to ethanol action, and expression profile (e.g., brain expression).
Database sequence information will be used to design oligonucleotide primers that flank genes of interest for quantitative real-time PCR (QrtPCR) to test for genotype-differences in expression. PCR amplification of the coding and regulatory regions from appropriate strains will be followed by DNA sequencing of PCR products to identify sequence differences.
The Molecular Genetics Support Core will be active in all years of requested Center support. It is responsible for the genotypic, candidate gene sequence, gene and protein expression analyses (QrtPCR, Western blots, and in situ hybridization), and novel transgenic animal model development for Components 5, 6, 7 and pilot project 10D. The Molecular Genetics Support Core will also support candidate gene identification and initial characterization for Component 9, future pilot projects in Component 10, and several RO1 and VA grants.
by Mark Rutledge-Gorman
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