APPROACHES TO GENE MAPPING DEVELOPMENT AND APPLICATIONS

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The primary focus of this work has been on the development and application of novel gene mapping strategies that incorporate population genetic and evolutionary considerations. Awareness of these principles has allowed us to expand the range of "mappable" genes and traits well beyond those currently being mapped. In particular, we are using these modes of analysis to underpin novel gene mapping strategies that range from the identification and localization of disease and disease susceptibility genes to studies mapping the critical functional and disease-related motifs within alleles of the human major histocompatibility complex (MHC). Classically, mapping has focussed on transmission genetics in pedigrees to monitor distortions in inheritance patterns that reflect linkage. Our principal focus has also been on recombination, but on levels of recombination (5 - 40 cM) that are generally greater than those treated in conventional analyses. We have also used population genetic and phylogenetic principles to deal with much lower levels of recombination ( <1 cM), which is treated in project Z01 BC 05680-06 LGD. In particular, we have been refining MALD (mapping by admixture linkage disequilibrium), as a population-based approach toward mapping genes that are refractory to conventional approaches. Right now, genes involved in progression of infectious disease (e.g., AIDS) and genes involved in multifactorial traits (e.g., the non-BRCA breast cancer genes) are specific targets of our analyses. Work within this project remains primarily theoretical, but is closely allied to other empirical projects in this laboratory and elsewhere that are using MALD. Focus of the theoretical work has shifted to expediting high throughput genotyping, such as microsatellite typing, and the attendant considerations of data of that nature. Especially important considerations for this context are: co-dominant but phase-unknown genotypic data for markers, but potentially all types of transmission for disease loci (dominant, co-dominant, recessive, multiple loci, incomplete penetrance); optimization of cohort collection (e.g., relative size of patient/control samples vs. other strategies); lack of identity-by-descent due to high mutation rates at microsatellite loci; efficient detection of distortions for highly multi-allelic loci. Additionally, a major component of our work is to augment the gene mapping research by other members of the Laboratory of Genomic Diversity.