Functional Elements Are Embedded in Structurally Constrained Sequences
Modern functional genomics uncovered numerous functional elements in metazoan genomes. Nevertheless, only a small fraction of the typical non-exonic genome contains elements that code for function directly. On the other hand, a much larger fraction of the genome is associated with significant evolutionary constraints, suggesting that much of the non-exonic genome is weakly functional. Here we show that in flies, local (30–70 bp) conserved sequence elements that are associated with multiple regulatory functions serve as focal points to a pattern of punctuated regional increase in G/C nucleotide frequencies. We show that this pattern, which covers a region tenfold larger than the conserved elements themselves, is an evolutionary consequence of a shift in the balance between gain and loss of G/C nucleotides and that it is correlated with nucleosome occupancy across multiple classes of epigenetic state. Evidence for compensatory evolution and analysis of SNP allele frequencies show that the evolutionary regime underlying this balance shift is likely to be non-neutral. These data suggest that current gaps in our understanding of genome function and evolutionary dynamics are explicable by a model of sparse sequence elements directly encoding for function, embedded into structural sequences that help to define the local and global epigenomic context of such functional elements.
Vyšlo v časopise:
Functional Elements Are Embedded in Structurally Constrained Sequences. PLoS Genet 9(5): e32767. doi:10.1371/journal.pgen.1003512
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1003512
Souhrn
Modern functional genomics uncovered numerous functional elements in metazoan genomes. Nevertheless, only a small fraction of the typical non-exonic genome contains elements that code for function directly. On the other hand, a much larger fraction of the genome is associated with significant evolutionary constraints, suggesting that much of the non-exonic genome is weakly functional. Here we show that in flies, local (30–70 bp) conserved sequence elements that are associated with multiple regulatory functions serve as focal points to a pattern of punctuated regional increase in G/C nucleotide frequencies. We show that this pattern, which covers a region tenfold larger than the conserved elements themselves, is an evolutionary consequence of a shift in the balance between gain and loss of G/C nucleotides and that it is correlated with nucleosome occupancy across multiple classes of epigenetic state. Evidence for compensatory evolution and analysis of SNP allele frequencies show that the evolutionary regime underlying this balance shift is likely to be non-neutral. These data suggest that current gaps in our understanding of genome function and evolutionary dynamics are explicable by a model of sparse sequence elements directly encoding for function, embedded into structural sequences that help to define the local and global epigenomic context of such functional elements.
Zdroje
1. McvickerG, GordonD, DavisC, GreenP (2009) Widespread Genomic Signatures of Natural Selection in Hominid Evolution. PLoS Genet 5: e1000471 doi:10.1371/journal.pgen.1000471.
2. Raveh-SadkaT, LevoM, ShabiU, ShanyB, KerenL, et al. (2012) Manipulating nucleosome disfavoring sequences allows fine-tune regulation of gene expression in yeast. Nature genetics 44: 743–750 doi:10.1038/ng.2305.
3. LiuX, LeeC-K, GranekJA, ClarkeND, LiebJD (2006) Whole-genome comparison of Leu3 binding in vitro and in vivo reveals the importance of nucleosome occupancy in target site selection. Genome research 16: 1517–28 doi:10.1101/gr.5655606.
4. KaplanN, MooreIK, Fondufe-MittendorfY, GossettAJ, TilloD, et al. (2008) The DNA-encoded nucleosome organization of a eukaryotic genome. Nature 458: 362–366 doi:10.1038/nature07667.
5. TilloD, HughesT (2009) G+C content dominates intrinsic nucleosome occupancy. BMC bioinformatics 10: 442 doi:10.1186/1471-2105-10-442.
6. ValouevA, JohnsonSM, BoydSD, SmithCL, FireAZ, et al. (2011) Determinants of nucleosome organization in primary human cells. Nature 474: 516–20 doi:10.1038/nature10002.
7. GaffneyDJ, McVickerG, PaiAA, Fondufe-MittendorfYN, LewellenN, et al. (2012) Controls of Nucleosome Positioning in the Human Genome. PLoS Genet 8: e1003036 doi:10.1371/journal.pgen.1003036.
8. Schuster-BöcklerB, LehnerB (2012) Chromatin organization is a major influence on regional mutation rates in human cancer cells. Nature 488: 504–7 doi:10.1038/nature11273.
9. KundajeA, Kyriazopoulou-PanagiotopoulouS, LibbrechtM, SmithCL, RahaD, et al. (2012) Ubiquitous heterogeneity and asymmetry of the chromatin environment at regulatory elements. Genome Research 22: 1735–1747 doi:10.1101/gr.136366.111.
10. WarneckeT, BatadaNN, HurstLD (2008) The impact of the nucleosome code on protein-coding sequence evolution in yeast. PLoS Genet 4: e1000250 doi:10.1371/journal.pgen.1000250.
11. WashietlS, MachnéR, GoldmanN (2008) Evolutionary footprints of nucleosome positions in yeast. Trends in genetics: TIG 24: 583–7 doi:10.1016/j.tig.2008.09.003.
12. KenigsbergE, BarA, SegalE, TanayA (2010) Widespread Compensatory Evolution Conserves DNA-Encoded Nucleosome Organization in Yeast. PLoS Comput Biol 6: e1001039 doi:10.1371/journal.pcbi.1001039.
13. AdamsMD (2000) The Genome Sequence of Drosophila melanogaster. Science 287: 2185–2195 doi:10.1126/science.287.5461.2185.
14. RoyS, ErnstJ, KharchenkoPV, KheradpourP, NegreN, et al. (2010) Identification of functional elements and regulatory circuits by Drosophila modENCODE. Science (New York, N.Y.) 330: 1787–97 doi:10.1126/science.1198374.
15. NègreN, BrownCD, MaL, BristowCA, MillerSW, et al. (2011) A cis-regulatory map of the Drosophila genome. Nature 471: 527–31 doi:10.1038/nature09990.
16. SextonT, YaffeE, KenigsbergE, BantigniesF, LeblancB, et al. (2012) Three-Dimensional Folding and Functional Organization Principles of the Drosophila Genome. Cell 148: 458–72 doi:10.1016/j.cell.2012.01.010.
17. AndolfattoP (2005) Adaptive evolution of non-coding DNA in Drosophila. Nature 437: 1149–52 doi:10.1038/nature04107.
18. HalliganDL, KeightleyPD (2006) Ubiquitous selective constraints in the Drosophila genome revealed by a genome-wide interspecies comparison. Genome research 16: 875–84 doi:10.1101/gr.5022906.
19. HaddrillPR, BachtrogD, AndolfattoP (2008) Positive and negative selection on noncoding DNA in Drosophila simulans. Molecular biology and evolution 25: 1825–34 doi:10.1093/molbev/msn125.
20. MackayTFC, RichardsS, StoneEA, BarbadillaA, AyrolesJF, et al. (2012) The Drosophila melanogaster Genetic Reference Panel. Nature 482: 173–8 doi:10.1038/nature10811.
21. MoshkinYM, ChalkleyGE, KanTW, ReddyBA, OzgurZ, et al. (2012) Remodelers organize cellular chromatin by counteracting intrinsic histone-DNA sequence preferences in a class-specific manner. Molecular and cellular biology 32: 675–88 doi:10.1128/MCB.06365-11.
22. MavrichTN, JiangC, IoshikhesIP, LiX, VentersBJ, et al. (2008) Nucleosome organization in the Drosophila genome. Nature 453: 358–62 doi:10.1038/nature06929.
23. ChachickR, TanayA (2012) Inferring Divergence of Context-Dependent Substitution Rates in Drosophila Genomes with Applications to Comparative Genomics. Mol Biol Evol 29: 1769–80 doi: 10.1093/molbev/mss056.
24. MewesHW, AlbermannK, BährM, FrishmanD, GleissnerA, et al. (1997) Overview of the yeast genome. Nature 387: 7–65 doi:10.1038/42755.
25. AertsS, ThijsG, DabrowskiM, MoreauY, Moor BDe (2004) Comprehensive analysis of the base composition around the transcription start site in Metazoa. BMC genomics 5: 34 doi:10.1186/1471-2164-5-34.
26. LiL, ZhuQ, HeX, SinhaS, HalfonMS (2007) Large-scale analysis of transcriptional cis-regulatory modules reveals both common features and distinct subclasses. Genome biology 8: R101 doi:10.1186/gb-2007-8-6-r101.
27. ThomasS, LiX-Y, SaboPJ, SandstromR, ThurmanRE, et al. (2011) Dynamic reprogramming of chromatin accessibility during Drosophila embryo development. Genome biology 12: R43 doi:10.1186/gb-2011-12-5-r43.
28. SaboPJ, HawrylyczM, WallaceJC, HumbertR, YuM, et al. (2004) Discovery of functional noncoding elements by digital analysis of chromatin structure. Proceedings of the National Academy of Sciences of the United States of America 101: 16837–42 doi:10.1073/pnas.0407387101.
29. NephS, VierstraJ, StergachisAB, ReynoldsAP, HaugenE, et al. (2012) An expansive human regulatory lexicon encoded in transcription factor footprints. Nature 489: 83–90 doi:10.1038/nature11212.
30. ThurmanRE, RynesE, HumbertR, VierstraJ, MauranoMT, et al. (2012) The accessible chromatin landscape of the human genome. Nature 489: 75–82 doi:10.1038/nature11232.
31. SaboPJ, HumbertR, HawrylyczM, WallaceJC, DorschnerMO, et al. (2004) Genome-wide identification of DNaseI hypersensitive sites using active chromatin sequence libraries. Proceedings of the National Academy of Sciences of the United States of America 101: 4537–42 doi:10.1073/pnas.0400678101.
32. TilloD, KaplanN, MooreIK, Fondufe-MittendorfY, GossettAJ, et al. (2010) High nucleosome occupancy is encoded at human regulatory sequences. PLoS ONE 5: e9129 doi:10.1371/journal.pone.0009129.
33. AsthanaS, RoytbergM, StamatoyannopoulosJ, SunyaevS (2007) Analysis of sequence conservation at nucleotide resolution. PLoS Comput Biol 3: e254 doi:10.1371/journal.pcbi.0030254.
34. WalterK, AbnizovaI, ElgarG, GilksWR (2005) Striking nucleotide frequency pattern at the borders of highly conserved vertebrate non-coding sequences. Trends in genetics: TIG 21: 436–40 doi:10.1016/j.tig.2005.06.003.
35. VavouriT, WalterK, GilksWR, LehnerB, ElgarG (2007) Parallel evolution of conserved non-coding elements that target a common set of developmental regulatory genes from worms to humans. Genome biology 8: R15 doi:10.1186/gb-2007-8-2-r15.
36. MacdonaldSJ, LongAD (2006) Fine scale structural variants distinguish the genomes of Drosophila melanogaster and D. pseudoobscura. Genome biology 7: R67 doi:10.1186/gb-2006-7-7-R67.
37. SchuettengruberB, GanapathiM, LeblancB, PortosoM, JaschekR, et al. (2009) Functional anatomy of polycomb and trithorax chromatin landscapes in Drosophila embryos. PLoS Biol 7: e13 doi:10.1371/journal.pbio.1000013.
38. ZeitlingerJ, ZinzenRP, StarkA, KellisM, ZhangH, et al. (2007) Whole-genome ChIP-chip analysis of Dorsal, Twist, and Snail suggests integration of diverse patterning processes in the Drosophila embryo. Genes & development 21: 385–90 doi:10.1101/gad.1509607.
39. HaddrillPR, CharlesworthB, HalliganDL, AndolfattoP (2005) Patterns of intron sequence evolution in Drosophila are dependent upon length and GC content. Genome biology 6: R67 doi:10.1186/gb-2005-6-8-r67.
40. GaltierN, BazinE, BierneN (2006) GC-biased segregation of noncoding polymorphisms in Drosophila. Genetics 172: 221–8 doi:10.1534/genetics.105.046524.
41. DuretL, ArndtPF (2008) The impact of recombination on nucleotide substitutions in the human genome. PLoS Genet 4: e1000071 doi:10.1371/journal.pgen.1000071.
42. BerglundJ, PollardKS, WebsterMT (2009) Hotspots of biased nucleotide substitutions in human genes. PLoS Biol 7: e26 doi:10.1371/journal.pbio.1000026.
43. KimuraM (1985) The role of compensatory neutral mutations in molecular evolution. Journal of Genetics 64: 7–19 doi:10.1007/BF02923549.
44. DonigerSW, FayJC (2007) Frequent gain and loss of functional transcription factor binding sites. PLoS Comput Biol 3: e99 doi:10.1371/journal.pcbi.0030099.
45. LiY, VinckenboschN, TianG, Huerta-SanchezE, JiangT, et al. (2010) Resequencing of 200 human exomes identifies an excess of low-frequency non-synonymous coding variants. Nature genetics 42: 969–72 doi:10.1038/ng.680.
46. StoneEA (2012) Joint genotyping on the fly: Identifying variation among a sequenced panel of inbred lines. Genome Res 22: 966–74 doi:10.1101/gr.129122.111.
47. HaddrillPR, CharlesworthB (2008) Non-neutral processes drive the nucleotide composition of non-coding sequences in Drosophila. Biology letters 4: 438–41 doi:10.1098/rsbl.2008.0174.
48. OzdemirA, Fisher-AylorKI, PepkeS, SamantaM, DunipaceL, et al. (2011) High resolution mapping of Twist to DNA in Drosophila embryos: Efficient functional analysis and evolutionary conservation. Genome research 21: 566–577 doi:10.1101/gr.104018.109.
49. NussinovR (1986) Some guidelines for identification of recognition sequences: regulatory sequences frequently contain (T)GTG/CAC(A), TGA/TCA and (T)CTC/GAG(A). Biochimica et biophysica acta 866: 93–108.
50. EdenE, LipsonD, YogevS, YakhiniZ (2007) Discovering motifs in ranked lists of DNA sequences. PLoS Comput Biol 3: e39 doi:10.1371/journal.pcbi.0030039.
51. CrockerJ, PotterN, ErivesA (2010) Dynamic evolution of precise regulatory encodings creates the clustered site signature of enhancers. Nature communications 1: 99 doi:10.1038/ncomms1102.
52. IyerV, StruhlK (1995) Poly(dA:dT), a ubiquitous promoter element that stimulates transcription via its intrinsic DNA structure. The EMBO journal 14: 2570–9.
53. LuskRW, EisenMB (2010) Evolutionary mirages: selection on binding site composition creates the illusion of conserved grammars in Drosophila enhancers. PLoS Genet 6: e1000829 doi:10.1371/journal.pgen.1000829.
54. CaiJJ, MacphersonJM, SellaG, PetrovDA (2009) Pervasive hitchhiking at coding and regulatory sites in humans. PLoS Genet 5: e1000336.
55. BirneyE, StamatoyannopoulosJA, DuttaA, GuigóR, GingerasTR, et al. (2007) Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature 447: 799–816 doi:10.1038/nature05874.
56. PrendergastJGD, SempleCAM (2011) Widespread signatures of recent selection linked to nucleosome positioning in the human lineage. Genome research 21: 1777–87 doi:10.1101/gr.122275.111.
57. FullertonSM, Bernardo CarvalhoA, ClarkAG (2001) Local Rates of Recombination Are Positively Correlated with GC Content in the Human Genome. Molecular Biology and Evolution 18: 1139–1142.
58. WhiteEJ, EmanuelssonO, ScalzoD, RoyceT, KosakS, et al. (2004) DNA replication-timing analysis of human chromosome 22 at high resolution and different developmental states. Proceedings of the National Academy of Sciences of the United States of America 101: 17771–6.
59. CrockerJ, TamoriY, ErivesA (2008) Evolution acts on enhancer organization to fine-tune gradient threshold readouts. PLoS Biol 6: e263 doi:10.1371/journal.pbio.0060263.
60. ErivesA, LevineM (2004) Coordinate enhancers share common organizational features in the Drosophila genome. Proceedings of the National Academy of Sciences of the United States of America 101: 3851–6 doi:10.1073/pnas.0400611101.
61. WorthCL, GongS, BlundellTL (2009) Structural and functional constraints in the evolution of protein families. Nature Reviews Molecular Cell Biology 10: 709–720.
62. SchonesDE, CuiK, CuddapahS, RohT-Y, BarskiA, et al. (2008) Dynamic regulation of nucleosome positioning in the human genome. Cell 132: 887–98 doi:10.1016/j.cell.2008.02.022.
63. Lieberman-AidenE, Berkum NLvan, WilliamsL, ImakaevM, RagoczyT, et al. (2009) Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science (New York, N.Y.) 326: 289–93 doi:10.1126/science.1181369.
64. TolhuisB, PalstraR-J, SplinterE, GrosveldF, LaatW de (2002) Looping and Interaction between Hypersensitive Sites in the Active β-globin Locus. Molecular Cell 10: 1453–1465.
65. LevineM (2010) Transcriptional enhancers in animal development and evolution. Current biology: CB 20: R754–63 doi:10.1016/j.cub.2010.06.070.
66. BantigniesF, RoureV, CometI, LeblancB, SchuettengruberB, et al. (2011) Polycomb-dependent regulatory contacts between distant Hox loci in Drosophila. Cell 144: 214–26 doi:10.1016/j.cell.2010.12.026.
67. RheadB, KarolchikD, KuhnRM, HinrichsAS, ZweigAS, et al. (2010) The UCSC Genome Browser database: update 2010. Nucleic acids research 38: D613–9 doi:10.1093/nar/gkp939.
68. LangmeadB, SalzbergSL (2012) Fast gapped-read alignment with Bowtie 2. Nature Methods 9: 357–359 doi:10.1038/nmeth.1923.
69. WeberCM, HenikoffJG, HenikoffS (2010) H2A.Z nucleosomes enriched over active genes are homotypic. Nature structural & molecular biology 17: 1500–7 doi:10.1038/nsmb.1926.
70. GalloSM, GerrardDT, MinerD, SimichM, SoyeBDes, et al. (2011) REDfly v3.0: toward a comprehensive database of transcriptional regulatory elements in Drosophila. Nucleic acids research 39: D118–23 doi:10.1093/nar/gkq999.
71. CohenNM, KenigsbergE, TanayA (2011) Primate CpG islands are maintained by heterogeneous evolutionary regimes involving minimal selection. Cell 145: 773–786.
72. The International HapMap Project (2003) Nature 426: 789–96.
73. KeaneTM, GoodstadtL, DanecekP, WhiteMA, WongK, et al. (2011) Mouse genomic variation and its effect on phenotypes and gene regulation. Nature 477: 289–94 doi:10.1038/nature10413.
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2013 Číslo 5
- Gynekologové a odborníci na reprodukční medicínu se sejdou na prvním virtuálním summitu
- Je „freeze-all“ pro všechny? Odborníci na fertilitu diskutovali na virtuálním summitu
Najčítanejšie v tomto čísle
- Using Extended Genealogy to Estimate Components of Heritability for 23 Quantitative and Dichotomous Traits
- HDAC7 Is a Repressor of Myeloid Genes Whose Downregulation Is Required for Transdifferentiation of Pre-B Cells into Macrophages
- High-Resolution Transcriptome Maps Reveal Strain-Specific Regulatory Features of Multiple Isolates
- A Compendium of Nucleosome and Transcript Profiles Reveals Determinants of Chromatin Architecture and Transcription