RESEARCH NOTES

Pseudogenes get some respect adenoviral entry is mediated by interaction between RGD motifs and integrins, they went on to engineer a virus with an RGD peptide. This are the non-functional remnants of genes that have version of the modified virus specifically infected tumor cells and repli- been thought to do nothing more than take up space. A new cated more effectively than Delta-24. When injected directly into report by Shinji Hirotsune and colleagues provides evidence that human gliomas xenografted into mice, Delta-24-RGD allowed signifi- at least one such has an essential role as a regulator of cantly longer survival than did Delta-24 or an inactivated virus control. gene expression (Nature 423, 91–96; 2003). A fortuitous insertion More impressively, 60% of mice treated with Delta-24-RGD were long- of a into the Makorin1-p1 locus generated a mouse term survivors (compared with 15% of those treated with Delta-24 with a bone deformity and polycystic kidneys. Makorin1-p1 is a characterized by complete tumor regression). MH pseudogene that is normally transcribed, although no functional protein product can be produced. Strikingly, the transgene insertion reduced not only the of Makorin1-p1, but RNAi on or off target? that of its functional homolog, Makorin1, as well. In vitro Two new reports examine the specificity of RNA interference (RNAi) in experiments show that an intact Makorin1-p1 locus stabilizes the human cells using -wide expression profiling. Targeting exoge- Makorin1 mRNA, and a rescue of the original transgenic mouse nous GFP in human embryonic kidney cells, Jen-Tsan Chi and col- with Makorin1-p1 proves that the pseudogene is required for leagues report efficient and specific knockdown using two different normal expression of Makorin1. The authors postulate that siRNAs (Proc. Natl. Acad. Sci USA10.1073/pnas.1037853100). Analysis Makorin1-p1 may titrate out a factor that destabilizes the of approximately 20,000 genes identified no consistent gene expression Makorin1 transcript, thereby increasing Makorin1 expression in profile and no statistically significant difference in global gene expres- a developmentally regulated manner. With about 20,000 sion patterns associated with the two siRNAs. Further analyses did not pseudogenes in the human genome, further examples of this kind identify spreading of the RNAi effect to similar exogenous sequences, no doubt await discovery. AP leading the authors to conclude that the RNAi effect is on target in mammalian cells. In a related paper, Peter Linsley and colleagues tar- http://www.nature.com/naturegenetics geted endogenous genes (Nat. Biotechnol. 10.1038/nbt831). They exam- Flyin’ pain free ined the effect of 16 different siRNAs against IGF1R and 8 different Nociception, the sensing of painful stimuli, has been studied in mam- siRNAs targeted against MAPK14. In each case, the gene expression pro- mals for decades, but there has not been a robust model system to file was siRNA-specific. A group of 9 genes with partial sequence iden- study the of pain. W. Daniel Tracey, Jr. and colleagues have tity to the siRNA duplex targeted against MAPK14 were downregulated now described an assay in Drosophila larvae for the detection of pain with similar kinetics. The authors conclude that at least some cross- (Cell 113, 261–273; 2003). They show that in response to a hot probe hybridization of siRNAs to transcripts of similar sequences occurs. or mechanical pinching of the cutical, wild-type larvae roll in a char- These results suggest that ensuring siRNA-specific effects requires well acteristic sideways corkscrew motion. A forward genetic screen of controlled experiments. DG 1,500 previously isolated P-element lines resulted in the isolation of the first Drosophila mutant for pain sensation, appropriately named painless. The painless gene encodes a new member of the transient History to the rescue receptor potential ion channel family, which had been previously The analysis of sequence variation on the Y © Group 2003 Nature Publishing implicated in nociception and mechanosensory transduction. Suction chromosome provides a powerful tool for electrode recordings of sectioned abdominal nerves showed that spike studying a population’s genetic ancestry. frequencies in painless mutants did not change dramatically as the Matthew Hurles and colleagues have now temperature was raised to 42 oC, as opposed to wild-type embryos, used it to uncover the genetic impact of a whose firing rate nearly doubled. Characterization of the 48 additional historical episode during the Polynesian slave nociception-defective lines identified in the screen will certainly add trade (Am. J. Hum. Genet. 72, 1282–1287; new dimensions to our understanding of pain. MS 2003). Genetic evidence suggests that Polynesians originally came from South East Asia. But an earlier study by the authors Can a virus outsmart glioma? indicated that inhabitants of one Polynesian Glioma is a lethal brain cancer that can resist radiation and chemother- island, called Rapa, had Y-chromosomal markers specific for Native apy. Adenovirus-based treatment has been difficult, but a new viral sys- Americans. A closer look at Rapan Y chromosomes and tem has now shown unprecedented success. Juan Fueyo and colleagues mitochondrial DNA shows that this population, unlike those of other genetically manipulated an adenovirus to effectively destroy a tumor Polynesian islands, contains substantial levels of European and Native from the inside out (J. Natl. Cancer Inst. 95, 652–660; 2003). First, they American admixture. To explain this, Hurles et al. hit the history developed a tumor-selective adenovirus, Delta-24, with a deletion in books. The Peruvian slave trade caused depopulation of many E1A that disrupts its ability to bind retinoblastoma (Rb) protein. In nor- Polynesian islands from 1862 to 1863. In 1863, Rapans captured the mal cells, Rb prevents viruses from entering, so Delta-24 can replicate Peruvian slave ship Cora. Most members of the crew were sailed to only when Rb is inactivated, as in cancer cells. Delta-24 killed the Tahiti for trial, but five remained on Rapa. These five men were tumors but had low infectivity, possibly owing to the low concentration probably of Native American origin, possibly with European of coxsackie-adenovirus receptors on the surface of cancer cells. Because admixture. If these men had children, we could expect to see their genetic contributions in the Rapan population, especially because shortly after their arrival on the island, Rapans were devastated by an Research Notes written by Laura Bonetta, David Gresham, Monica epidemic of dysentery or smallpox, to which the marooned sailors Harrington, Alan Packer and Michael Stebbins. may have been more resistant. LB

NATURE GENETICS VOLUME 34 | NUMBER 2 | JUNE 2003 133