APPROACHES TO GENE MAPPING DEVELOPMENT AND APPLICATIONS

点击翻译按钮获取中文摘要

Population genetics, molecular evolution, and phylogenetic reconstruction are a continuum of disciplines that provide different perspectives on some of the more interesting questions of human genetic disease. Refinements in both the theory and the application of these disciplines are now possible with the exquisitely detailed understanding of human and other genomes that is emerging. The research objectives of this project primarily concern the development and application of demographic, genetic, and phylogenetic analyses. In particular, we are using these modes of analysis to underpin novel gene mapping strategies that range, in terms of their genomic scale, 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. These strategies are currently being applied to find genes underpinning various etiologies in LGD collaborations on AIDS, breast cancer, prostate cancer, hypertension, and kidney disease. Concomittant with these studies are related molecular studies on patterns of human molecular variation at both short (allelic) and long (haplotypes and multi-locus genotypes) genomic ranges. Our early work on mapping by admixture linkage disequilibrium (MALD) demonstrated its feasibility as a mapping strategy by the direct detection of linkage disequilibrium in admixed populations. The work on MALD implementation has recently been expanded to include different transmission modalities (e.g., recessive, dominant, and codominant disease phenotypes), optimized sampling of patients and controls, incomplete penetrance, and disease genetic heterogeneity. Furthermore, now the tests for linkage are much easier and more amenable to high- throughput analysis in a clinical setting. Explicit results were obtained by i) solving for expected levels of disequilibrium (D) due to admixture; ii) translating D into a measurable effect (in this case, an allele frequency difference between patients and appropriate controls) under different models of admixture, transmission modality, and allele frequency; and iii) determination of patient/control sample sizes required to statistically detect the effect.