This research will characterize cryptic genetic variation for early embryogenesis in the nematode Caenorhabditis elegans. Cryptic genetic variation includes alleles that confer functional effects on phenotype, but which are detectable only after genetic or environmental perturbation. Few of the genes that underly heritable human diseases have been identified, and because complex diseases are heavily influenced by epistatic and environmental interactions, it makes sense that a majority of the causal loci behave cryptically. Provoking a biological system to identify cryptic genetic variation can uncover the very determinants that other approaches, such as linkage or association mapping, miss. C. elegans is an excellent model for exploring cryptic genetic variation, because resources and tractability make determination of the complete network of genes involved in metazoan development a realizable goal in the nematode system. Characterization of cryptic genetic variation relies on detecting phenotypic differences from allelic variation that originated in wild populations. To provoke the system to uncover cryptic functional alleles that produce phenotypic differences, RNA interference (RNAi) will induce genetic perturbation;to map the alleles to precise regions of the genome, the experiments will be performed on recombinant inbred lines (RILs).
The specific aims of this work include:
Aim 1. Generate C. elegans RILs.
Aim 2. Characterize the architecture of cryptic genetic variation in early embryogenesis.
Aim 3. Identify new genes and nucleotides that affect embryogenesis. By taking advantage of easy genetic manipulation and implementing recently developed high throughput assays for embryonic phenotypes, this work has the potential to contribute new insight into the genomic architecure of complex traits, as well as identify novel genetic determinants for an important developmental process. Identifying the genes that underly heritable disease is a major aim in public health research. However, the complexity of most diseases prevents traditional approaches from identifying more than a fraction of those causal genes. This research implements an alternate approach to uncovering complex trait genes, using C. elegans embryogenesis as a model system.
|Paaby, Annalise B; Rockman, Matthew V (2013) The many faces of pleiotropy. Trends Genet 29:66-73|