HIGHLIGHTS HIGHLIGHT ADVISORS WENDY BICKMORE FUNCTIONAL GENOMICS MRC HUMAN GENETICS UNIT, UK SEAN B. CARROLL UNIVERSITY OF WISCONSIN, Elegant tour de force USA ADAM EYRE-WALKER UNIVERSITY OF SUSSEX, UK When the draft human genome genes, for example, those that JANE GITSCHIER sequence was published it was encode essential components of the UNIVERSITY OF CALIFORNIA, referred to as the blueprint. But, as basal cellular machinery. By con- SAN FRANCISCO, USA with any design plan, the challenge trast, most of the genes in the Vpep RALPH J. GREENSPAN is in establishing how the plan is class probably represent animal- THE NEUROSCIENCES executed. This task lies at the heart specific genes, and their products INSTITUTE, CALIFORNIA, USA of functional genomics, and now affect processes such as behaviour YOSHIHIDE HAYASHIZAKI Kamath et al. provide an important or body shape. RIKEN GENOMIC SCIENCES contribution to this field with their A closer look at the genomic dis- CENTER, JAPAN tour de force systematic RNAi tribution of genes in each class PETER KOOPMAN analysis of the Caenorhabditis revealed that genes with similar UNIVERSITY OF QUEENSLAND, AUSTRALIA elegans genome. Not only do they functions tend to be co-localized in LEONID KRUGLYAK uncover the function of scores of large domains of the genome and FRED HUTCHINSON CANCER worm genes, but they also provide are co-transcribed. The size of these RESEARCH CENTER, USA important information on the clusters, however, suggests that any BARBARA MEYER worm genome structure and its large-scale transcriptional co-regu- UNIVERSITY OF CALIFORNIA, evolution. lation must be mediated by a mech- BERKELEY, USA To determine RNAi phenotypes anism other than the previously LEE NISWANDER for as many C. elegans genes as pos- described open-looped chromatin. SLOAN-KETTERING INSTITUTE, sible, the authors constructed a Another interesting finding con- NEW YORK, USA library of 16,757 bacterial strains cerns the X chromosome. The fact genes that have mammalian homo- CHRISTOS OUZOUNIS (equivalent to 86% of all currently that Nonv genes are underrepre- logues, some of which have already THE EUROPEAN predicted worm open reading sented on the X chromosome, been implicated in fat metabolism. BIOINFORMATICS INSTITUTE, frames; ORFs), each of which whereas those that encode compo- The worm fat-regulating genes fall UK expressed double-stranded RNA nents of signalling pathways and into three main pathways (insulin, NORIYUKI SATOH (dsRNA) corresponding to a single transcription factors are overrepre- serotonin and tubby) confirming KYOTO UNIVERSITY, JAPAN worm gene. When worms feed on sented, suggests that very different that fat metabolism is conserved in MARC VIDAL these bacteria (Escherichia coli selection pressures operate on genes metazoans and that the worm can DANA-FARBER CANCER is their normal diet) the dsRNA on the sex chromosomes compared be used as a model of human fat INSTITUTE, BOSTON, USA is internalized and mediates with genes on the autosomes. metabolic disorders. VIRGINIA WALBOT sequence-specific knock down of Two other studies, in which the The authors of the second report, STANFORD UNIVERSITY, USA the endogenous gene. One by one, same approach was used to address published in Nature Genetics, sought DETLEF WEIGEL the phenotypes were scored, and more specific biological questions, genes that, when inactivated, MAX PLANCK INSTITUTE FOR 10.3% of the analysed ORFs gave have also been recently published. increased the C. elegans lifespan. Lee DEVELOPMENTAL BIOLOGY, consistent phenotypes, which the Ashrafi et al. used the same RNAi et al. followed up their RNAi screen GERMANY authors grouped into three classes: library to look for genes that regu- with a classic forward genetics screen LEONARD I. ZON nonviable (Nonv), growth defects late fat storage and mobilization. and, together, the results showed that CHILDREN’S HOSPITAL, (Gro) and viable post-embryonic Among the 305 genes that reduce worms with impaired mitochondrial BOSTON, USA phenotypes (Vpep). The first class body fat stores and the 112 that and certain metabolic functions tend ▲ contains many universal eukaryotic increase them, they identified those to be long-lived. NATURE REVIEWS | GENETICS VOLUME 4 | FEBRUARY 2003 | 79 © 2003 Nature Publishing Group HIGHLIGHTS ▲ Apart from the important bio- more complete picture of individual Caenorhabditis elegans genome using RNAi. IN THE NEWS Nature 421, 231–237 (2003) | Ashrafi K. et al. logical insights, Kamath et al. have biological processes. The hope is Genome-wide RNAi analysis of Caenorhabditis Clone baby? given the community an important that, as RNAi technology improves, elegans fat regulatory genes. Nature 421, Doubts have started to resource — the bacterial RNAi similar systematic screens will also 268–272 (2003) | Lee, S. S. et al. A systematic surface over the truth of library that can be used over and be feasible in mammalian cells. RNAi screen identifies a critical role for claims that the first human mitochondria in C. elegans longevity. Nature over again. Many more reports of Magdalena Skipper Genet. 33, 40–48 (2003) clone has been born, after screens such as those by Ashrafi et al. FURTHER READING Dillin, A. et al. Rates of Clonaid — the company that References and links behavior and aging specified by mitochondrial made the original 27 and Lee et al. are bound to follow, ORIGINAL RESEARCH PAPERS Kamath, R. S. function during development. Science 298, December announcement — the results of which will provide a et al. Systematic functional analysis of the 2398–2401 (2002) backed away from an independent verification by genetic tests. The New York Times EVOLUTIONARY GENOMICS reported that Clonaid’s self- imposed one-week deadline expired with no evidence forthcoming. Clonaid’s chief executive Brigitte Boisselier Compensation or innovation said “The parents told me that they needed 48 hours to decide yes or no — if they Gene duplications are often seen experimental conditions. These to perform a new function. The would do it” (New York Times). as an opportunity to evolve new observations indicated that buffering effect of duplicates is The credibility of the claims functions through the duplicated genes compensate largely caused by their partially took another hit when accumulation of mutations for each other, a conclusion that overlapping function. Axel Meyer Michael Guillen — the leading to functional was supported by the fact that argues for a dual role for duplicate freelance science journalist diversification. But, they can deletions of either gene from a genes, but further whole-genome- organizing the genetic tests also be thought of as a back-up duplicate pair showed similar sequence comparisons and — pointedly distanced or a buffer against loss-of- fitness effects. Furthermore, the functional genetic analyses are himself from Clonaid after the tests did not go ahead. function mutations in one of smaller the divergence between needed before we can really “It’s entirely possible [that] the duplicates. Using yeast as a the duplicates, the better they address this question. Clonaid’s announcement is working example, Gu et al. have compensate for each other. It also Magdalena Skipper part of an elaborate hoax to shown that gene duplications turns out that deleting duplicate References and links bring publicity to the Raelian considerably contribute to genetic genes with higher expression levels ORIGINAL RESEARCH PAPER Gu, Z. et al. movement,” he said robustness against null has a greater effect on fitness than Role of duplicate genes in genetic robustness (The Guardian). mutations. deleting those that are not as against null mutations. Nature 421, 63–22 Claude Vorhilon (aka ‘Rael’), (2003) A previous study of genetic highly expressed. leader of the pseudoscientific FURTHER READING Meyer, A. Duplication, duplication. Nature 421, 31–32 (2003) sect that funds Clonaid, robustness — the ability to These data provide strong suggests that a Florida court withstand null mutations — evidence for the role of gene action aimed at placing the concluded that it was redundant duplication in genetic robustness baby under the court’s metabolic pathways and networks, against null mutations. Whether protection might explain the rather than duplicate genes, that this contribution is more or less company’s reticence. “…to mainly fulfil this function. important than the interactions take away this poor baby However, these conclusions were between unduplicated genes that from a mother, I think this is based only on a few genes, so Gu function in alternative pathways completely crazy, just because she was cloned. et al. revisited this problem — this remains to be seen. The role of So I called Doctor Boisselier, time addressing it on a genome- duplicates in genetic buffering and I said, ‘If I was you, I wide scale. They made use of a might explain why these genes would not test anything.’” previous study in which almost do not ‘decay’ into pseudogenes (The Washington Times). all of the genes of Saccharomyces as quickly as expected. But, Axel The increasing scepticism cerevisae were knocked out and the Meyer — the author of the of the media has not fitness of the mutants was assessed accompanying News and Views — prevented Clonaid from expanding their claims: under five different conditions suggests that their incorporation according to them a further (see Highlights section in into new networks and pathways three human clones will be September 2002 issue). When the also prevents such decay. So, does born in