#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Evolutionary Mirages: Selection on Binding Site Composition Creates the Illusion of Conserved Grammars in Enhancers


The clustering of transcription factor binding sites in developmental enhancers and the apparent preferential conservation of clustered sites have been widely interpreted as proof that spatially constrained physical interactions between transcription factors are required for regulatory function. However, we show here that selection on the composition of enhancers alone, and not their internal structure, leads to the accumulation of clustered sites with evolutionary dynamics that suggest they are preferentially conserved. We simulated the evolution of idealized enhancers from Drosophila melanogaster constrained to contain only a minimum number of binding sites for one or more factors. Under this constraint, mutations that destroy an existing binding site are tolerated only if a compensating site has emerged elsewhere in the enhancer. Overlapping sites, such as those frequently observed for the activator Bicoid and repressor Krüppel, had significantly longer evolutionary half-lives than isolated sites for the same factors. This leads to a substantially higher density of overlapping sites than expected by chance and the appearance that such sites are preferentially conserved. Because D. melanogaster (like many other species) has a bias for deletions over insertions, sites tended to become closer together over time, leading to an overall clustering of sites in the absence of any selection for clustered sites. Since this effect is strongest for the oldest sites, clustered sites also incorrectly appear to be preferentially conserved. Following speciation, sites tend to be closer together in all descendent species than in their common ancestors, violating the common assumption that shared features of species' genomes reflect their ancestral state. Finally, we show that selection on binding site composition alone recapitulates the observed number of overlapping and closely neighboring sites in real D. melanogaster enhancers. Thus, this study calls into question the common practice of inferring “cis-regulatory grammars” from the organization and evolutionary dynamics of developmental enhancers.


Vyšlo v časopise: Evolutionary Mirages: Selection on Binding Site Composition Creates the Illusion of Conserved Grammars in Enhancers. PLoS Genet 6(1): e32767. doi:10.1371/journal.pgen.1000829
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1000829

Souhrn

The clustering of transcription factor binding sites in developmental enhancers and the apparent preferential conservation of clustered sites have been widely interpreted as proof that spatially constrained physical interactions between transcription factors are required for regulatory function. However, we show here that selection on the composition of enhancers alone, and not their internal structure, leads to the accumulation of clustered sites with evolutionary dynamics that suggest they are preferentially conserved. We simulated the evolution of idealized enhancers from Drosophila melanogaster constrained to contain only a minimum number of binding sites for one or more factors. Under this constraint, mutations that destroy an existing binding site are tolerated only if a compensating site has emerged elsewhere in the enhancer. Overlapping sites, such as those frequently observed for the activator Bicoid and repressor Krüppel, had significantly longer evolutionary half-lives than isolated sites for the same factors. This leads to a substantially higher density of overlapping sites than expected by chance and the appearance that such sites are preferentially conserved. Because D. melanogaster (like many other species) has a bias for deletions over insertions, sites tended to become closer together over time, leading to an overall clustering of sites in the absence of any selection for clustered sites. Since this effect is strongest for the oldest sites, clustered sites also incorrectly appear to be preferentially conserved. Following speciation, sites tend to be closer together in all descendent species than in their common ancestors, violating the common assumption that shared features of species' genomes reflect their ancestral state. Finally, we show that selection on binding site composition alone recapitulates the observed number of overlapping and closely neighboring sites in real D. melanogaster enhancers. Thus, this study calls into question the common practice of inferring “cis-regulatory grammars” from the organization and evolutionary dynamics of developmental enhancers.


Zdroje

1. StanojevicD

SmallS

LevineM

1991 Regulation of a segmentation stripe by overlapping activators and repressors in the Drosophila embryo. Science 254 1385 1387

2. NibuY

SengerK

LevineM

2003 CtBP-independent repression in the Drosophila embryo. Mol Cell Biol 23 3990 3999

3. KulkarniMM

ArnostiDN

2005 cis-regulatory logic of short-range transcriptional repression in Drosophila melanogaster. Mol Cell Biol 25 3411 3420

4. LebrechtD

FoehrM

SmithE

LopesFJ

Vanario-AlonsoCE

2005 Bicoid cooperative DNA binding is critical for embryonic patterning in Drosophila. Proc Natl Acad Sci U S A 102 13176 13181

5. KulkarniMM

ArnostiDN

2003 Information display by transcriptional enhancers. Development 130 6569 6575

6. ArnostiDN

KulkarniMM

2005 Transcriptional enhancers: Intelligent enhanceosomes or flexible billboards? J Cell Biochem 94 890 898

7. MerikaM

ThanosD

2001 Enhanceosomes. Curr Opin Genet Dev 11 205 208

8. HareEE

PetersonBK

IyerVN

MeierR

EisenMB

2008 Sepsid even-skipped enhancers are functionally conserved in Drosophila despite lack of sequence conservation. PLoS Genet 4 e1000106 doi:10.1371/journal.pgen.1000106

9. KimJ

HeX

SinhaS

2009 Evolution of regulatory sequences in 12 Drosophila species. PLoS Genet 5 e1000330 doi:10.1371/journal.pgen.1000330

10. MakeevVJ

LifanovAP

NazinaAG

PapatsenkoDA

2003 Distance preferences in the arrangement of binding motifs and hierarchical levels in organization of transcription regulatory information. Nucleic Acids Res 31 6016 6026

11. PapatsenkoD

GoltsevY

LevineM

2009 Organization of developmental enhancers in the Drosophila embryo. Nucleic Acids Res

12. LynchM

2007 The frailty of adaptive hypotheses for the origins of organismal complexity. Proc Natl Acad Sci U S A 104 Suppl 1 8597 8604

13. TanayA

SiggiaED

2008 Sequence context affects the rate of short insertions and deletions in flies and primates. Genome Biol 9 R37

14. MacArthurS

BrookfieldJF

2004 Expected rates and modes of evolution of enhancer sequences. Mol Biol Evol 21 1064 1073

15. HeX

LingX

SinhaS

2009 Alignment and prediction of cis-regulatory modules based on a probabilistic model of evolution. PLoS Comput Biol 5 e1000299 doi:10.1371/journal.pcbi.1000299

16. LudwigMZ

PatelNH

KreitmanM

1998 Functional analysis of eve stripe 2 enhancer evolution in Drosophila: rules governing conservation and change. Development 125 949 958

17. DermitzakisET

ClarkAG

2002 Evolution of transcription factor binding sites in Mammalian gene regulatory regions: conservation and turnover. Mol Biol Evol 19 1114 1121

18. MosesAM

PollardDA

NixDA

IyerVN

LiXY

2006 Large-scale turnover of functional transcription factor binding sites in Drosophila. PLoS Comput Biol 2 e130 doi:10.1371/journal.pcbi.0020130

19. DrieverW

Nusslein-VolhardC

1988 A gradient of bicoid protein in Drosophila embryos. Cell 54 83 93

20. StanojevicD

HoeyT

LevineM

1989 Sequence-specific DNA-binding activities of the gap proteins encoded by hunchback and Kruppel in Drosophila. Nature 341 331 335

21. TreismanJ

DesplanC

1989 The products of the Drosophila gap genes hunchback and Kruppel bind to the hunchback promoters. Nature 341 335 337

22. Rivera-PomarR

JackleH

1996 From gradients to stripes in Drosophila embryogenesis: filling in the gaps. Trends Genet 12 478 483

23. SmallS

KrautR

HoeyT

WarriorR

LevineM

1991 Transcriptional regulation of a pair-rule stripe in Drosophila. Genes Dev 5 827 839

24. PetrovDA

2002 DNA loss and evolution of genome size in Drosophila. Genetica 115 81 91

25. BergmanCM

CarlsonJW

CelnikerSE

2005 Drosophila DNase I footprint database: a systematic genome annotation of transcription factor binding sites in the fruitfly, Drosophila melanogaster. Bioinformatics 21 1747 1749

26. LiangHL

NienCY

LiuHY

MetzsteinMM

KirovN

2008 The zinc-finger protein Zelda is a key activator of the early zygotic genome in Drosophila. Nature 456 400 403

27. RastegarS

HessI

DickmeisT

NicodJC

ErtzerR

2008 The words of the regulatory code are arranged in a variable manner in highly conserved enhancers. Dev Biol 318 366 377

28. WonKJ

SandelinA

MarstrandTT

KroghA

2008 Modeling promoter grammars with evolving hidden Markov models. Bioinformatics 24 1669 1675

29. GertzJ

SiggiaED

CohenBA

2009 Analysis of combinatorial cis-regulation in synthetic and genomic promoters. Nature 457 215 218

30. NeafseyDE

PalumbiSR

2003 Genome size evolution in pufferfish: a comparative analysis of diodontid and tetraodontid pufferfish genomes. Genome Res 13 821 830

31. GraurD

ShualiY

LiWH

1989 Deletions in processed pseudogenes accumulate faster in rodents than in humans. J Mol Evol 28 279 285

32. PetrovDA

HartlDL

1998 High rate of DNA loss in the Drosophila melanogaster and Drosophila virilis species groups. Mol Biol Evol 15 293 302

33. PetrovDA

SangsterTA

JohnstonJS

HartlDL

ShawKL

2000 Evidence for DNA loss as a determinant of genome size. Science 287 1060 1062

34. RobertsonHM

2000 The large srh family of chemoreceptor genes in Caenorhabditis nematodes reveals processes of genome evolution involving large duplications and deletions and intron gains and losses. Genome Res 10 192 203

35. BensassonD

PetrovDA

ZhangDX

HartlDL

HewittGM

2001 Genomic gigantism: DNA loss is slow in mountain grasshoppers. Mol Biol Evol 18 246 253

36. HasegawaM

KishinoH

YanoT

1985 Dating of the human-ape splitting by a molecular clock of mitochondrial DNA. J Mol Evol 22 160 174

37. BrownCT

XieY

DavidsonEH

CameronRA

2005 Paircomp, FamilyRelationsII and Cartwheel: tools for interspecific sequence comparison. BMC Bioinformatics 6 70

38. DownTA

BergmanCM

SuJ

HubbardTJ

2007 Large-scale discovery of promoter motifs in Drosophila melanogaster. PLoS Comput Biol 3 e7 doi:10.1371/journal.pcbi.0030007

39. NoyesMB

MengX

WakabayashiA

SinhaS

BrodskyMH

2008 A systematic characterization of factors that regulate Drosophila segmentation via a bacterial one-hybrid system. Nucleic Acids Res 36 2547 2560

40. LiXY

MacArthurS

BourgonR

NixD

PollardDA

2008 Transcription factors bind thousands of active and inactive regions in the Drosophila blastoderm. PLoS Biol 6 e27 doi:10.1371/journal.pbio.0060027

41. De RenzisS

ElementoO

TavazoieS

WieschausEF

2007 Unmasking activation of the zygotic genome using chromosomal deletions in the Drosophila embryo. PLoS Biol 5 e117 doi:10.1371/journal.pbio.0050117

Štítky
Genetika Reprodukčná medicína

Článok vyšiel v časopise

PLOS Genetics


2010 Číslo 1
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Aktuální možnosti diagnostiky a léčby litiáz
nový kurz
Autori: MUDr. Tomáš Ürge, PhD.

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa

#ADS_BOTTOM_SCRIPTS#