Multifactorial genetics

Genetic mapping of quantitative trait loci governing longevity of Caenorhabditis elegans in recombination-inbred progeny of a Bergerac-BO x RC301 interstrain cross. Ayyadevara, S. et al. Genetics 157, 655–666 (2001) [PubMed]

This paper goes some way towards uncovering the natural polymorphisms that contribute to variation in longevity between two worm strains, C. elegans RC301 and Bergerac-BO. Seven highly significant quantitative trait loci (QTL) were identified from the progeny of these two strains, which were tested for QTL associations with lifespan after seven generations of inbreeding. All seven loci, which were identified using single-marker analysis, were confirmed and mapped more precisely by nonparametric interval mapping. Furthermore, making animals that were congenic for two candidate QTL had a significant impact on their survival.

Cancer genetics

A candidate prostate cancer susceptibility gene at chromosome 17p. Tavitagan, S. V. et al. Nature Genet. 27, 172–180 (2001) [PubMed]

Pten and p27KIP1 cooperate in prostate cancer tumor suppression in the mouse. Di Cristafano, A. et al. Nature Genet. 27, 222–224 (2001) [PubMed]

Previous mapping studies have failed to reveal highly penetrant alleles to account for prostate cancer in high-risk families. But now Tavitagan et al. report the cloning of a putative prostate cancer susceptibility gene, ELAC2, from a genome-wide screen of several such families. This screen led to a locus on chromosome 17p, from which the researchers positionally cloned ELAC2. Mutation analysis identified a frameshift and a non-conservative substitution in ELAC2 in two independent prostate cancer families, but the gene's association with the disease was not clear cut — not all male family members with the frameshift mutation have prostate cancer and the substitution was present in some but not all individuals with the disease. Whether these non-carriers are sporadic cases remains to be resolved, as does the role of ELAC2 in DNA repair and prostate cancer susceptibility. In the second paper, Di Cristafano et al. report on the cooperation between Pten and one of its targets, p27KIP1 (encoded by Cdkn1b), in suppressing prostate cancer. Pten+/− mice die of cancer by ∼51 weeks of age. This survival rate rapidly decreases with the loss of one or both alleles of Cdkn1b. By the age of three months, all Pten+/− /Cdkn1b−/− mice develop prostate cancer that histologically and pathologically resembles the human disease. Cell proliferation, but not cell survival, is increased in these mice, indicating that Pten and p27KIP1 cooperate to suppress tumour formation through the control of cell-cycle progression.