Positional cloning using microarrays September 11, 2006

This article in PLoS Genetics shows how non-sense mediated decay (NMD) can be exploited, in conjunction with limited mapping information and microarrays, to facilitate positional cloning. The authors first show that non-sense mutations constitute a significant fraction (41%) of 941 mutations they examined (in C. elegans). Examining published microarray datasets where single-gene, non-sense, mutant strains were compared to WT, they found several cases where the identity of the mutant genes could have been inferred from differences in expression levels (for the mutant gene) and information about which chromosome the mutated gene is located on. They then use the technique to determine that a mutation in tom-1, the homolog of mammalian tomosyn, is responsible for increased sensitivity to aldicarb through increased secretion of acetycholine in the synaptic cleft of neuromuscular junction. This paper is exciting because it suggests that the time and effort to link a gene to a mutant phenotype can be significantly decreased, while simultaneously obtaining a better understanding of the perturbed molecular networks, through mRNA expression profiling.