DEFINING GENES THAT GOVERN LONGEVITY IN CAENORHABDITIS-ELEGANS

We previously identified five regions on the chromosomal map of Caenor habditis elegans, containing genes that help specify life span in this species, by comparing the genotypes of young and long-lived progeny f rom a cross between strains Bristol-N2 and Bergerac-BO [Ebert ef al. ( 1993): Genetics 135:1003-1010]. Analyses of additional crosses, and of putative polymorphisms for the implicated genes, are necessary to cla rify the roles of naturally occurring polymorphic alleles in determini ng longevity. We therefore carried out a second multigenerational cros s, between strains Bristol-N2 and DH424 (both nonmutators at 20 degree s C), to create a different heterogeneous recombinant-inbred populatio n. We again found strong evidence implicating multiple genes, which di ffer between the parental strains, in the determination of life span. Increased variance of survival, for F-2 and homozygous F-25 worms rela tive to F-1 hybrids, is consistent with such alleles asserting randoml y in the cross progeny. Moreover, chromosome mapping data corroborate the polygenic nature of this quantitative trait. Genotypes of young an d very long-lived adult worms from a synchronous F-15 population were determined by polymerase chain reaction, to identify the parental stra in of origin for each of 10 polymorphic loci. Two regions, on chromoso mes II and IV, each contain at least one gene with allelic differences in associated longevity. A recombinant-inbred Bergerac-BO x Bristol-N 2 population, derived from the earlier cross between those strains, wa s exposed to an acute toxic level of hydrogen peroxide. Genotyping of H2O2-resistant worms implicated at least one of the five chromosomal r egions previously identified in the same cross progeny as harboring a longevity-determining gene. Superoxide dismutase and catalase levels, determined for the three parental strains as they aged, confirm the ex istence of polymorphisms in the corresponding genes (or their regulato ry mechanisms) inferred from the chromosome-it mapping data, and are c onsistent with the hypothesis that increased longevity is conferred by high levels of these enzymes late in life. (C) 1996 Wiley-Liss, Inc.