We study the genetic and evolutionary mechanisms underlying early embryonic development using a combination of molecular genetic and functional genomics approaches in the animal model C. elegans and related nematodes. One of the main tools we have used is RNA interference (RNAi) followed by time-lapse microscopy to work toward a comprehensive molecular description of early embryogenesis in C. elegans. RNAi offers a powerful way to obtain information about the loss-of-function phenotype of the genes tested, while the early embryo offers a system in which basic cellular and developmental processes can be easily studied.
In collaboration with several other labs, we developed the first genome-wide RNAi inventory of genes required for the first few cell divisions in any animal. By clustering genes based on their phenotypic profiles, we identified groups of genes required for basic processes such as nuclear movements, mitotic spindle formation, cytokinesis, cell cycle progression, and proper asymmetric cell division. These data provided a starting point to study the molecular architecture of specific cellular processes. Most of the genes identified are conserved in humans, and many of their human homologs are associated with genetic diseases, including some that have been previously targeted for anti-cancer drug development. Therefore, our data can be used not only to analyze the C. elegans genome but also to guide the functional examination of the human genome.
Since only around 15% of genes show any phenotype when knocked down on their own, we have extended this work to generate genome-wide genetic interaction maps for essential genes that play important roles in the early embryo. By analyzing the genetic interaction data in combination with other kinds of functional analyses, we are learning how animals coordinate different cellular processes during development. This work will help us understand genetic diseases, most of which are not Mendelian (due to defects in a single gene), but instead arise from interactions between alleles in multiple genes.
We also study the evolution of developmental mechanisms. Comparisons across different nematode species have revealed fundamental differences in modes of reproduction and in developmental patterning. Significantly, in some species the wild-type patterns of early embryonic cell divisions resemble those produced by various C. elegans mutants, indicating plasticity in the underlying molecular networks. We have recently sequenced the genome of a parthogenetic relative of C. elegans that shows an alternate pattern of early cleavages. Strikingly, this species also appears to have a single giant chromosome derived from fusion of six or seven ancestral chromosomes. We are examining these phenotypic differences in conjunction with molecular analyses to identify mechanisms underlying the phenotypic diversity seen in nature.