The broad objective of the proposed research is high-resolution genetic dissection of a large number of complex and quantitative traits in the nematode worm C. elegans. Success in understanding the genetic basis of phenotypic variation in a metazoan will provide critical guidance for the design of genotype- phenotype studies in humans and other organisms of medical, biological, and agricultural interest, as well as supply insights into regulatory networks that connect genetic and phenotypic variation and into the evolution of phenotypic variation. Specifically, we will develop and genotype a large set of high-resolution recombinant inbred lines (RILs) from a cross between Bristol and Hawaiian isolates, and genotype a diverse collection of wild isolates. We will then use microarrays to generate expression profiles for the RILs and wild isolates, and carry out linkage and association analysis to define loci that affect gene expression. We will identify individual loci as well as pairs of interacting loci. We will determine which loci affect expression through polymorphisms in the encoding gene or its nearby control regions, and which affect expression of genes at distant locations. We will identify """"""""hot spots""""""""-loci that affect the expression of many genes, and use bioinformatic approaches to integrate the results with regulatory networks. We will also assay behavioral and age-related phenotypes in the RILs, map loci that affect these phenotypes, and integrate these phenotypes with transcript data. Finally, we will identify the genes and polymorphisms that underlie several transcriptional, behavioral and age-related phenotypes and confirm their roles through transgenic and RNAi experiments. We have already successfully carried out similar studies in yeast, and expect that the results will be even richer in C. elegans, given its more complex regulation in the context of multicellularity and development. ? ? Relevance to public health: Genetic factors underlie susceptibility to virtually every human disease. Much of current biomedical research is based on the expectation that identifying these factors is a crucial step in improving diagnosis, prevention, and treatment. Identification is difficult because the genetic basis of common disorders is complex, with disease susceptibility influenced by multiple genes in interaction with each other and with environmental factors. The proposed research will improve our understanding of such interactions and will provide critical guidance for studies of the genetic basis of common human diseases. ? ? ?
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