Combinatorial RNA interference in Caenorhabditis elegans reveals that redundancy between gene duplicates can be maintained for more than 80 million years of evolution

We established conditions for RNA interference (RNAi) in C. elegans to target multiple genes simultaneously in a high-throughput setting. Using this approach, we can detect the great majority of previously known synthetic genetic interactions. We used this assay to examine the redundancy of duplicated genes in the genome of C. elegans that correspond to single orthologs in S. cerevisiae or D. melanogaster and identified 16 pairs of duplicated genes that have redundant functions. Remarkably, 14 of these redundant gene pairs were duplicated before the divergence of C. elegans and C. briggsae 80-110 million years ago, suggesting that there has been selective pressure to maintain the overlap in function between some gene duplicates.We established a high throughput method for examining genetic interactions using combinatorial RNAi in C. elegans. Using this technique, we demonstrated that many duplicated genes can retain redundant functions for more than 80 million years of evolution. This provides strong support for evolutionary models that predict that genetic redundancy between duplicated genes can be actively maintained by natural selection and is not just a transient side effect of recent gene duplication events.One of the most direct approaches to elucidating the role of any particular gene is to characterize its loss-of-function phenotype. Loss-of-function phenotypes have now been analyzed for almost all of the predicted genes of Saccharomyces cerevisiae [1], Caenorhabditis elegans [2], and Drosophila melanogaster [3], and there are ongoing efforts to make comprehensive collections of mouse knockouts. In all, this gives us an unprecedented level of insight into eukaryotic gene function. However, the loss-of-function phenotype of any individual gene is highly dependent on the genetic context; specifically, variations in the activities of other genes will affect this phenotype (for review [4]). If changes in the activity of one gene affect the loss-of-function phenot