A surprise of functional genomics in worms and yeast is the extent to which gene knockouts confer no obvious phenotype. Such genes may contribute to fitness in subtle ways, but they may also contribute to essential functions redundantly. Adding to the confusion, genes with overlapping or redundant functions need not be related by DNA sequence. We are using classical genetics and the
mec-8 gene to explore the issue of gene redundancy. MEC-8 is a putative RNA-binding protein that is required for processing of
unc-52 mRNA. Null mutations in
mec-8 confer mechanosensory and chemosensory defects but not highly-penetrant lethality. The combination of a
mec-8 loss-of-function mutation, however, with a viable mutation in any of six sym ( sy nthetic lethal with m ec-8 ) genes (or with a viable allele of
unc-52 , the prototype analysis for this study) results in embryonic or early larval lethality.
sym-1 X has been previously shown to encode a hypodermally-secreted, leucine-rich repeat protein that, in the absence of MEC-8, is required for attachment of body muscles to the cuticle. Thus,
sym-1 and
mec-8 compose an example of redundant genes whose products are not related in structure and function, leading to the suggestion that
sym-1 overlaps in function with a gene whose mRNA needs to be processed by MEC-8 (Davies et al. 1999; Genetics 153: 117). With the aim of identifying the hypothesized
mec-8 target and other genes that overlap functionally with
sym-1 , we have been screening for mutations that are s ynthetically l ethal with s y m-1
(mn601). Candidate sly mutations are being genetically characterized. We are interested in understanding the nature of the overlap between
sym-2 II and
mec-8 . Rescue experiments have suggested that ZK1067.6 is
sym-2 . DNA sequence analysis has now confirmed this supposition:
sym-2(
mn617) correlates with a change of a tyrosine to an asparagine codon at position 163 in the 618-codon open reading frame. SYM-2 contains three copies of an RNA recognition motif, suggesting that SYM-2 is an RNA binding protein that overlaps with MEC-8 in the processing of an unknown gene transcript that is essential for viability. The structure of SYM-2 will be compared with MEC-8 and with heterogeneous nuclear ribonucleoproteins (hnRNPs) from mammals.