Gene conversion has a central role in the evolutionary fine-tuning of regulatory elements in the fruit fly Drosophila miranda.</jats:p

FAWCETT Jeffrey A

INNAN Hideki

eLife

PubMed

FAWCETT, Jeffrey A

INNAN, Hideki

SOKENDAI  Institutional Repository (Graduate University for Advanced Studies)

elifesciences.orgINSIGHTGENE REGULATIONSpreading good newsGene conversion has a central role in the evolutionary fine-tuning ofregulatory elements in the fruit fly Drosophila miranda.JEFFREY A FAWCETT AND HIDEKI INNANRelated research article Ellison CE,Bachtrog D. 2015. Non-allelic geneconversion enables rapid evolutionarychange at multiple regulatory sitesencoded by transposable elements.eLife 4:e05899. doi: 10.7554/eLife.05899Image Beneficial mutations can spreadquickly via gene conversion to multiplelocations in a genomeNatural selection means that an individualwith a beneficial mutation is more likely topass on its genes to its offspring. This‘vertical’ process means that, eventually, theentire population can share the same beneficialmutation at the same location in the genome.However, beneficial mutations can also spread‘horizontally’ so that they are shared betweentwo (or more) locations in the genome of anindividual (Figure 1). There are only a few ways thatthis horizontal movement can happen in animalsand other eukaryotes. One way involves geneticparasites—called transposable elements—that‘cut’ or ‘copy’ themselves from one locationand then ‘paste’ themselves elsewhere in thegenome. Gene conversion is another mechanismwhereby one region of DNA is copied and usedto replace a different, but highly similar, stretchof DNA. Now, in eLife, Christopher Ellison andDoris Bachtrog—both from the University ofCalifornia, Berkeley—report that a beneficialmutation has spread via these two mechanismsto multiple sites on the X chromosome of the fruitflyDrosophila miranda (Ellison and Bachtrog, 2015).Humans and many other animals have sexchromosomes. Human females are XX andhuman males are XY; this means that femaleshave two copies of every gene on the Xchromosome, but males only have one copy.Many sex chromosomes have a so-called ‘dosagecompensation system’ to counteract this imbal-ance, which makes sure that males and femalesget an equal dose of the molecules made fromthe genes on the sex chromosomes.A dosage compensation system is not some-thing every sex chromosome has from itsbeginning. Instead, it has to be establishedthrough the course of evolution after the sexchromosome has formed. This process appearsto be currently ongoing in Drosophila miranda,which developed a new X chromosome, calledneo-X, about 1.5 million years ago, and providesan excellent opportunity to study how dosagecompensation gets established (Ellison andBachtrog, 2013).In fruit flies, dosage compensation relies ona male-specific molecular complex that binds toa short sequence of DNA found multiple timesacross the X chromosome (Conrad and Akhtar,2011). This complex then acts to increase theexpression of nearby genes, which ensures thatmales receive a full dose of the molecules madefrom these genes. Thus, the most recently formedneo-X chromosome of Drosophila mirandaneeded to somehow develop sequence motifsthat can also recruit this molecular complex.Ellison and Bachtrog previously showed thatsuch sequences are provided, in part, by a familyof transposable elements that had recentlycopied itself across the neo-X chromosome(Ellison and Bachtrog, 2013). In fact, the bindingmotifs of the older X chromosome were alsoderived from transposable elements, and natureoften seems to look to transposable elementsCopyright Fawcett and Innan. Thisarticle is distributed under the terms ofthe Creative Commons AttributionLicense, which permits unrestricted useand redistribution provided that theoriginal author and source are credited.Fawcett and Innan. eLife 2015;4:e07108. DOI: 10.7554/eLife.07108 1 of 3when facing similar challenges. A number ofstudies have shown that transposable elementsoften serve as sources of ready-to-use bindingmotifs that can help regulate the expression ofnetworks of genes (Cowley and Oakey, 2013;Sundaram et al., 2014). However, nature doesnot always get it right first time. Instead, the firstattempt can be more of a ‘quick and dirty’solution that is subject to further improvementover the course of evolution. Ellison and Bach-trog had previously found that the bindingmotifs derived from transposable elements onthe neo-X chromosome are suboptimal (Ellisonand Bachtrog, 2013). This led them to hypothe-size that ‘fine-tuning’ of the process might begoing on.Figure 1. Beneficial mutations can spread through a population both ‘vertically’ and ‘horizontally’. Considera hypothetical population with 10 individuals, each with a single chromosome that has four sites (open circles).(A) When beneficial mutations (red circles) are only passed ‘vertically’ between generations, the best possibleoutcome (shown in bottom dashed circle) is for all the individuals in the population to eventually have the beneficialmutation at the site where it appeared (i.e., the leftmost of the four circles). (B) However, when horizontal events(blue arrows) are involved, it is possible that an individual (marked with a star) can have the beneficial mutation at allfour sites. Over time, the ‘vertical’ spread and natural selection can make it possible for all the individuals in thepopulation to have the beneficial mutation at all four sites (not shown). These horizontal events could be themovement of a transposable element or, as Ellison and Bachtrog report, gene conversion.Fawcett and Innan. eLife 2015;4:e07108. DOI: 10.7554/eLife.07108 2 of 3Insight Gene regulation | Spreading good newsBut, how could this fine-tuning be achieved?We can imagine that a beneficial mutation thatallows the dosage compensation complex tobind more strongly might occur in one copy ofthe transposable element family. Would the onlysolution be for this transposable element to copyand paste itself across the neo-X again? In otherwords, would the entire dosage compensationnetwork have to be rebuilt from scratch eachtime any copy acquires a better mutation?Fortunately, it appears that ‘no’ is the answerto this question. Instead, nature seems to havea far more elegant solution that involves thespread of beneficial mutations via gene conver-sion. Ellison and Bachtrog identified two muta-tions in the transposable element that make itbetter at recruiting the molecular complex thatcarries out dosage compensation. They thenshowed that these two mutations are spreadingacross the different copies of the transposableelement-derived regulatory element on the neo-X by gene conversion. Of course, gene conver-sion can work in both directions; that is to say,the process can spread a mutation or reverse it.However, because the mutations found by Ellisonand Bachtrog are beneficial, natural selectiontend to favor individuals where the mutation hasspread over those where it has been reversed.Gene conversion provides three major advan-tages in spreading beneficial mutations. First,mutations that are closer together, as is the casewith the two mutations identified by Ellison andBachtrog, can be transferred simultaneously. Sec-ond, it allows genetic variation to migrate acrossmultiple sites in the genome, which, in turn, actuallymakes natural selection more efficient (Mano andInnan, 2008). Third, beneficial mutations present indifferent copies, or lineages, can be broughttogether. This may be analogous to the role ofsexual recombination, which is considered as oneof the major reasons why we have two sexes.Although Ellison and Bachtrog only focusedon the two mutations in this study, otherbeneficial mutations might also be present, ormight arise in the future. It is likely that the fine-tuning of the dosage compensation system willcontinue by sharing such mutations across theentire family by gene conversion. It should beinteresting to investigate whether such fine-tuning has occurred throughout the evolution ofother regulatory networks.Jeffrey A Fawcett is in SOKENDAI (The GraduateUniversity for Advanced Studies), Hayama, JapanHideki Innan is in SOKENDAI (The Graduate Universityfor Advanced Studies), Hayama, Japaninnanhk@soken.ac.jpCompeting interests: The authors declare that nocompeting interests exist.Published 02 April 2015ReferencesConrad T, Akhtar A. 2011. Dosage compensation inDrosophila melanogaster: Epigenetic fine-tuning ofchromosome-wide transcription. Nature ReviewsGenetics 13:123–134. doi: 10.1038/nrg3124.Cowley M, Oakey RJ. 2013. Transposable elementsre-wire and fine-tune the transcriptome. PLOS Genetics9:e1003234. doi: 10.1371/journal.pgen.1003234.Ellison CE, Bachtrog D. 2013. Dosage compensationvia transposable element mediated rewiring ofa regulatory network. Science 342:846–850. doi: 10.1126/science.1239552.Ellison CE, Bachtrog D. 2015. Non-allelic geneconversion enables rapid evolutionary change atmultiple regulatory sites encoded by transposableelements. eLife 4:e05899. doi: 10.7554/eLife.05899.Mano S, Innan H. 2008. The evolutionary rate ofduplicated genes under concerted evolution. Genetics180:493–505. doi: 10.1534/genetics.108.087676.Sundaram V, Cheng Y, Ma Z, Li D, Xing X, Edge P,Snyder MP, Wang T. 2014. Widespread contribution oftransposable elements to the innovation of generegulatory networks. Genome Research 24:1963–1976.doi: 10.1101/gr.168872.113.Fawcett and Innan. eLife 2015;4:e07108. DOI: 10.7554/eLife.07108 3 of 3Insight Gene regulation | Spreading good news

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