Most human disease, production traits of agriculturally important species, and fitness-related characters in natural populations, are controlled by multiple interacting genes with small, and environmentally sensitive effects. Determining what loci contribute to variation in complex traits, how they interact with each other and the environment, and what molecular polymorphisms cause the variation in phenotypes, are of fundamental importance for human health, agriculture, and understanding the evolutionary process. The long-term goal of this project is to understand the genetic architecture of quantitative traits in terms of phenotypic and molecular variation of alleles at individual quantitative trait loci (QTLs), using the numbers of abdominal and sternopleural bristles of Drosophila melanogaster as a model system. During this project period, the investigators shall map the molecular polymorphisms, or quantitative trait nucleotides (QTNs), at five candidate bristle number loci: the achaete-scute complex (ASC), daughterless (da), scabrous (sca), extramacrochaetae (emc) and hairy (h). A sample of 250 alleles from an African and from a US population will be typed for all polymorphisms at the ASC using denaturing high performance liquid chromatography to detect variants, followed by sequencing to determine polymorphic sites. This technique is highly efficient for loci like the ASC where low levels of polymorphism are expected, but not for the other candidate loci, which will harbor higher levels of diversity. For these loci, common polymorphic sites will be determined from nucleotide sequences of 10 alleles from each population; the remaining 480 alleles will be genotyped for these common single nucleotide polymorphisms (SNPs). The association between polymorphic sites and bristle number phenotypes will be evaluated using a statistical method that accounts for the large number of tests performed and the correlation among sites. Having determined putative QTNs by the population association study, they shall infer homozygous, heterozygous and epistatic effects of the QTNs in multiple laboratory environments. The investigators shall also assess the relative roles of selection and genetic drift in maintaining the well-known cline in bristle number along the east coast of North America, by testing for heterogeneity in a measure of population subdivision between the QTNs and putative neutral polymorphic sites in the candidate genes. Finally, they shall fine-map QTLs causing response to selection from segregating variation and from new mutations, using a set of overlapping deficiencies covering 70 percent of the Drosophila genome.
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