DEVELOPMENTAL GENETICS OF CAENORHABDITIS ELEGANS

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The overall goal of the proposed research is to further the art of genetic analysis of the small free-living nematode Caenorhabditis elegans, which has been chosen as a model for elucidating the genetic basis of development and behavior because of its relative cellular simplicity and its inherent advantages for classical and molecular genetic analysis. An understanding of the genetic basis of development may well be fundamental to much of medicine and may ultimately contribute important information to many problems, ranging from congenital defects to senescence. The first specific aim is to extend and refine the duplication-loss method of generating C. elegans genetic mosaics, which are used to elucidate cell- specific gene function. C. elegans mosaics are generated by the spontaneous somatic loss of a free chromosome fragment or duplication, which is present in addition to the normal chromosome complement. Methods are proposed for tagging various free duplications with a cell autonomous marker that allows one to identify cells that carry the duplication. Methods for manipulating the frequency of somatic duplication loss are also proposed. The second aim is to conduct mosaic analyses of genes that affect patterns of cell lineage, cell migration and nerve process outgrowth as well as essential genes, defined by recessive lethal mutations; the structures and functions of homozygous lethal cells in mosaic animals will be analyzed. The third aim is to identify and characterize recessive lethal mutations balanced by a free duplication that is well suited for high resolution mosaic analysis. Overlapping deficiencies in the region covered by this free duplication will be generated to facilitate the mapping and complementation testing of the lethals. Terminal arrest phenotypes will be characterized. The fourth aim is to study further mec-8, a gene originally defined by mutations that confer touch insensitivity but which is now represented by zygotic embryonic lethal alleles. New alleles are to be identified and characterized, and extragenic suppressor mutations will be studied. The fifth aim is to clone and sequence mec-8 and at least one essential embryonic gene represented by interesting genetic mosaics. The sixth aim is to generate, identify, and characterize new chromosome duplications, which should prove useful both for balancing recessive lethal mutations and for mosaic analysis.