Gene Categories Differentially Expressed in C. elegans Age-1 Mutants of Extraordinary Longevity: New Insights From Novel Data-Mining Procedures

Abstract

Two nonsense mutants of age-1, the Caenorhabditis elegans gene encoding phosphoinositide 3-kinase, live nearly 10-fold longer than wild-type controls and are exceptionally resistant to several stresses. Genome-wide expression analyses implicated downregulation of many more genes than were upregulated in second-generation age-1 homozygotes. Functional-annotation analysis, based on Gene Ontology terms, suggested that novel mechanisms may mediate the stronger phenotypes observed for these worms than with milder age-1 disruption. For the current study, the same microarray data were reanalyzed using novel meta-analytic procedures that we developed recently. First, gene p values were corrected for systematic biases based on the observed distribution for nonexpressed genes; these values were then combined to derive an aggregate p value for each functional-annotation term while adjusting for intergene covariance. This resulted in much better coverage of relevant gene categories, including many that were independently supported by other data. The number of nonredundant GO categories significantly distinguishing age-1 alleles of exceptional longevity increased from sevenfold to greater than ninefold, improving both sensitivity and specificity of selection for altered pathways and implicating previously unsuspected longevity mechanisms. Of 150 genes whose differential expression underlay significant GO terms in both comparisons, over half were up-or down-regulated in accord with longevity, whereas one third showed altered expression uniquely in the longest-lived age-1-null strains, consistent with the activation or suppression of pathways peculiar to strong age-1 mutants.