Genome evolution: Making sense of antisense transcription

252 | APRIL 2005 | VOLUME 6 www.nature.com/reviews/genetics

R E S E A R C H H I G H L I G H T S

and Bruno van Swinderen show that geneticnetworks can, in fact, be remarkably flexible.

The approaches that are generally used toreconstruct biological networks rely on informa-tion about specific types of readily definableinteractions, such as protein–protein interactionsor co-expression. But this doesn’t capture infor-mation about interactions in a broader sense, interms of how they contribute to a particularphenotype. As an alternative approach, theauthors defined a network of genes involved ina simple behaviour in Drosophila melanogaster.They first took flies that were heterozygous for amutation in the Syntaxin 1A (Syx1A) gene, whichshow a behavioural phenotype at increased tem-peratures, and carried out a screen for alleles ofother genes that suppress the phenotype.

The genes identified were then tested forepistatic interactions as a measure of their par-ticipation in a common network. This wasdone by quantifying the behavioural pheno-types in flies that carried overexpression allelesof each possible pair of genes, and was carried

out both in the presence and absence of theSyx1A mutant allele. In both cases, severalstrong epistatic relationships were seen, indi-cating functional interactions between genes.Strikingly, however, the set of epistatic interac-tions within the network was changed markedlybetween the two genetic backgrounds: someinteractions that were seen in one backgrounddisappeared completely in the other, and inother cases a positive interaction in one contextbecame negative in the other.

So, instead of a strictly defined set of interac-tions within a network, the functional relation-ships among genes can undergo significantchanges in different contexts. This has importantimplications for future studies of gene networks,suggesting that models of gene interactions thatare built up from data on molecular interac-tions or expression data might not be providingus with the whole picture.

Louisa Flintoft

References and linksORIGINAL RESEARCH PAPER van Swinderen, B. &Greenspan, R. J. Flexibility in a gene network affecting a simplebehaviour in Drosophila melanogaster. Genetics 31 January2005 (doi:10.1534/genetics.104.032631)FURTHER READING Greenspan, R. J. The flexible genome.Nature Rev. Genet. 2, 383–387 (2001) | Kitano, H. Biologicalrobustness. Nature Rev. Genet. 5, 826–837 (2004)WEB SITEThe Neurosciences Institute web site: www.nsi.edu

The flexible network G E N E N E T W O R K S

The increasing trend towards a systemsapproach to biology has fuelled great interest inhow genes interact with each other in networks.Although networks show robustness, in thatthey can often compensate for the loss of one ormore component, the set of interactions thatcan occur between components is generallythought to fairly rigid. Now, using Drosophilagenetics to probe interactions between genes indifferent genetic contexts, Ralph Greenspan

The biological relevance of naturallyoccuring antisense transcription (NAT) haslong been debated. Is this transcriptionalplasticity really intentional or is it simply amanifestation of leaky RNA transcriptionmachinery? By comparing the genomicorganization of genes with or withoutantisense transcripts between humans andthe pufferfish Fugu rubripes (or Takifugurubripes), Dahary et al. now show thatantisense overlap seen in the human genomeis real and remarkably conserved throughoutvertebrate evolution.

They reason that separation between two neighbouring overlapping genes with a sense–antisense relationship would benegatively selected through evolution.Database searches and Antisensor algorithms allowed the authors to identify236 sense–antisense gene pairs in humanwith orthologues in pufferfish. Of these,23.3% remained consecutive and preservedtheir orientation in pufferfish.Sense–antisense pairs tend to maintain theirgene order significantly more often than

genes that originate from the same strand,which implies that NAT constrains gene-orderrearrangements.

Intriguingly, the authors found that theaverage distance between ‘same-strand’ genepairs is 11-fold larger in humans than inpufferfish, in contrast to a 2.5-fold differencefor antisense gene pairs. Could antisensetranscription affect genome expansion?Further comparisons between mammaliangenomes support the view that NAT sets arigorous control on genome expansion andaffects mammalian evolution in a mannersimilar to that observed for humans and fish.

As it has been estimated that antisense genepairs might comprise ~10% of all humangenes, the authors point out that antisensetranscription might impose a significantrestriction on the gene order and genomeexpansion throughout vertebrate evolution.With its involvement in gene-expressionmechanisms and various human diseases,who can now say that antisense transcriptiondoesn’t make any sense?

Ekat Kritikou

References and linksORIGINAL RESEARCH PAPER Dahary, D. et al. Naturallyoccuring antisense: transcriptional leakage or real overlap?Genome Res. March 2005 (doi:10.1011/gr3308405)WEB SITESLEADS-Antisensor: http://www.labonweb.com/antisenseCompugen Research and Development:http://www.cgen.com/research

Making sense of antisense transcription

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