CA Semple

Colin A. Semple

CP Ponting

D Graur

E Kenigsberg

Gregory S. Barsh

I Dunham

James G. D. Prendergast

JG Prendergast

MM Hoffman

S Neph

S Roy

WM Fitch

PLoS Genetics

PubMed

James G D Prendergast

Colin A Semple

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Side effects: substantial non-neutral evolution flanking regulatory sites.

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Side Effects: Substantial Non-Neutral Evolution Flanking Regulatory Sites

Prendergast, James G D

Semple, Colin A

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     Edinburgh Research Explorer                                      Side effects: substantial non-neutral evolution flankingregulatory sitesCitation for published version:Prendergast, JGD & Semple, CA 2013, 'Side effects: substantial non-neutral evolution flanking regulatorysites' PLoS Genetics, vol 9, no. 5, pp. e1003528. DOI: 10.1371/journal.pgen.1003528Digital Object Identifier (DOI):10.1371/journal.pgen.1003528Link:Link to publication record in Edinburgh Research ExplorerDocument Version:Publisher's PDF, also known as Version of recordPublished In:PLoS GeneticsPublisher Rights Statement:This is an open-access article distributed under the terms of the Creative Commons Attribution License, whichpermits unrestricted use, distribution, and reproduction in any medium, provided the original author and sourceare credited.General rightsCopyright for the publications made accessible via the Edinburgh Research Explorer is retained by the author(s)and / or other copyright owners and it is a condition of accessing these publications that users recognise andabide by the legal requirements associated with these rights.Take down policyThe University of Edinburgh has made every reasonable effort to ensure that Edinburgh Research Explorercontent complies with UK legislation. If you believe that the public display of this file breaches copyright pleasecontact openaccess@ed.ac.uk providing details, and we will remove access to the work immediately andinvestigate your claim.Download date: 28. Apr. 2017PerspectiveSide Effects: Substantial Non-Neutral Evolution FlankingRegulatory SitesJames G. D. Prendergast, Colin A. Semple*MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United KingdomIn the pre-genome era, most of what weknew about molecular evolution could betraced to our knowledge of the geneticcode, and the impact of DNA sequencevariation on protein structure and, byinference, protein function [1]. But in thepost-genome era, it has become clear thatthe fraction of functional sequence—estimated using comparative approachesto identify residues that ‘‘escape’’ geneticdrift—far exceeds the fraction explainedby protein-coding genes. In mammals,somewhere between 5% and 15% of thegenome is evolutionarily constrained, andis presumably functional [2]. Drosophilaand other invertebrate genomes may havemuch larger proportions (47%–70%) ofconstrained nucleotides [3]; in all cases,the proportions of nucleotides found to beconserved dwarves those encoding pro-teins (around 1% in humans and 20% inflies)—which prompts the question: whataspects of genomic function might explainthese apparent excesses of conservedsequence?Over the past few years, it has becomeclear that the physical organization andstructure of the genome within cells, over arange of scales, also casts discernableshadows on the sequence. This is therealm of chromatin structure (the manycombinations of proteins associated withthe DNA), which adopts an undulatinglandscape along chromosomes associatedwith cellular functions such as transcrip-tion. The binding of a range of proteins toeukaryotic genomes has been shown to belinked to variation in the underlying DNAsequence. The specific regions of thehuman genome known to be bound bytranscription factors often display remark-able patterns of conservation that parallelthe structure of the DNA-binding interfaceof the protein involved [4]. More broadly,characteristic fluctuations in sequencedivergence have been observed corre-sponding to nucleosome cores and inter-vening linker sequences across a variety ofspecies [5], and there is evidence that thisreflects the action of selection [6]. How-ever, recent data from the ENCODEConsortium has suggested that perhaps80% of the human genome is functional,in the sense that it is subject to abiochemical modification in at least onecell type [7]. This substantially exceeds allestimates of the proportion of humannucleotides under constraint, includingthose used by the ENCODE Consortium[8], and the discrepancy has led to somenotably animated discussion [9]. There istherefore a large gap between the propor-tion of the genome thought to be func-tional via evolutionary studies and theproportion that appears functional, ac-cording to the presence of particularchromatin features. This gap also appearsto exist, though to a lesser extent, inDrosophila, where over 90% of the genomehas been assigned a biochemical role ofsome description [10]. In this issue ofPLOS Genetics, Kenigsberg and Tanay [11]have investigated the links between chro-matin and sequence evolution from thepoint of view of conserved noncodingelements (CNEs), and may have found away to begin to bridge the gap. Ratherthan examining DNA sequence conserva-tion at the sites of a particular chromatinstate, they have investigated the charac-teristics of CNEs in the Drosophila genome,within their genomic and chromatincontext.Kenigsberg and Tanay first identifiedapproximately 68,000 short (mean lengthof 50 bp) regions of the genome whoserate of divergence was at least two timeslower than expected. These CNEs wereobserved to coincide with the location of arange of chromatin features, suggestingunderlying DNA sequence conservation isa feature of a range of functional chroma-tin states in Drosophila. Although theseCNEs covered only around 3% of theDrosophila genome, they were found tohave characteristic sequence composition-al biases. The vast majority of these shortelements were centered upon a small (20–30 bp), unusually AT rich, focal region.However, it was found these short AT richregions were embedded in larger (severalhundred base pairs), relatively GC richregions. Surprisingly, these patterns wereobserved at CNEs irrespective of thefunctional chromatin state seen at theCNE, including states associated withpromoters, enhancers, repressed sites,and insulator sites. Compositional biaseshave previously been noted as a commonfeature of some regulatory sites, and thisstudy shows these compositional biases arelinked to the positioning of nucleosomeson either side of such sites. Nucleosomeshave been shown to preferentially associ-ate with GC rich regions of DNA, and, inspecies from yeast to humans, nucleosomepositioning appears to be maintained by abalance in the number of A/T relative toG/C base pair gaining substitutions main-tained by selection [6,12]. Kenigsberg andTanay report a similar balance in the gainand loss of GC dinucleotides, maintainingelevated GC content on either side of therelatively AT rich Drosophila CNEs, andsuggest this balance is also likely to bemaintained by selection. They concludethat although only a small proportion ofthe genome (within CNEs) displays evi-dence for strong evolutionary constraint, asubstantially larger proportion, approxi-mately 25%, is evolving non-neutrally dueto the milder selective constraints imposedto maintain the surrounding local chro-matin structure (Figure 1). This raises thepossibility that large swathes of anyCitation: Prendergast JGD, Semple CA (2013) Side Effects: Substantial Non-Neutral Evolution FlankingRegulatory Sites. PLoS Genet 9(5): e1003528. doi:10.1371/journal.pgen.1003528Editor: Gregory S. Barsh, Stanford University School of Medicine, United States of AmericaPublished May 30, 2013Copyright:  2013 Prendergast and Semple. This is an open-access article distributed under the terms of theCreative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in anymedium, provided the original author and source are credited.Funding: This work was supported by the UK Medical Research Council. The funder had no role in thepreparation of the article.Competing Interests: The authors have declared that no competing interests exist.* E-mail: colin.semple@igmm.ed.ac.ukPLOS Genetics | www.plosgenetics.org 1 May 2013 | Volume 9 | Issue 5 | e1003528genome may be subject to rather modest,and often elusive, levels of constraint onsequence composition as an extended sideeffect of the presence of neighbouringregulatory sites.Kenigsberg and Tanay go on to showthat the rate of base substitutions, asmeasured by population polymorphisms,is also dependent on the base compositionof the region considered. For instance, GCdepleting substitutions were observed to beunderrepresented at GC rich regions. Thiswas found to be the case not only in flies,but also when mouse and human datawere examined. Together, these datasuggest that structural constraints areimpacting the evolutionary dynamics ofcurrent populations across a range ofeukaryotic organisms. They also supporta new worldview in evolutionary geno-mics, where a complete understanding ofsequence variation and its effects onfunction is only possible by consideringthe genome as a physical molecule.Genome evolution may be seen moreclearly seen through the lens of theepigenome.References1. Fitch WM, Margoliash E (1967) Construction ofphylogenetic trees. Science 155: 279–284.2. Ponting CP, Hardison RC (2011) What fractionof the human genome is functional? Genome Res21: 1769–1776.3. Ponting CP, Nellaker C, Meader S (2011) Rapidturnover of functional sequence in human andother genomes. Annu Rev Genomics Hum Genet12: 275–299.4. Neph S, Vierstra J, Stergachis AB, Reynolds AP,Haugen E, et al. (2012) An expansive humanregulatory lexicon encoded in transcription factorfootprints. Nature 489: 83–90.5. Semple CA, Taylor MS (2009) Molecular biolo-gy. The structure of change. Science 323: 347–348.6. Prendergast JG, Semple CA (2011) Widespreadsignatures of recent selection linked to nucleo-some positioning in the human lineage. GenomeRes 21: 1777–1787.7. ENCODE Project Consortium, Dunham I,Kundaje A, Aldred SF, Collins PJ, et al. (2012)An integrated encyclopedia of DNA elements inthe human genome. Nature 489: 57–74.8. Hoffman MM, Ernst J, Wilder SP, Kundaje A,Harris RS, et al. (2013) Integrative annotation ofchromatin elements from ENCODE data. Nu-cleic Acids Res 41: 827–841.9. Graur D, Zheng Y, Price N, Azevedo RB, ZufallRA, et al. (2013) On the immortality of televisionsets: ‘‘function’’ in the human genome accordingto the evolution-free gospel of ENCODE. Ge-nome Biol Evol 5: 578–590.10. modENCODE Consortium, Roy S, Ernst J,Kharchenko PV, Kheradpour P, et al. (2010)Identification of functional elements and regula-tory circuits by Drosophila modENCODE. Sci-ence 330: 1787–1797.11. Kenigsberg E, Tanay A (2013) Drosophila func-tional elements are embedded in structurallyconstrained sequences. PLoS Genet 9:e1003512. doi:10.1371/journal.pgen.100351212. Kenigsberg E, Bar A, Segal E, Tanay A (2010)Widespread compensatory evolution conservesDNA-encoded nucleosome organization in yeast.PLoS Comput Biol 6: e1001039. doi:10.1371/journal.pcbi.1001039Figure 1. Non-neutral evolution within large regions flanking CNEs in Drosophila acts to maintain sequence composition andfavourable nucleosome positioning.doi:10.1371/journal.pgen.1003528.g001PLOS Genetics | www.plosgenetics.org 2 May 2013 | Volume 9 | Issue 5 | e1003528

Side effects: substantial non-neutral evolution flanking regulatory sites

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