Skip to main content
SpringerLink
Log in

The correlation of genome size and DNA methylation rate in metazoans

  • Original Paper
  • Published:
Theory in Biosciences Aims and scope Submit manuscript

Abstract

Total DNA methylation rates are well known to vary widely between different metazoans. The phylogenetic distribution of this variation, however, has not been investigated systematically. We combine here publicly available data on methylcytosine content with the analysis of nucleotide compositions of genomes and transcriptomes of 78 metazoan species to trace the evolution of abundance and distribution of DNA methylation. The depletion of CpG and the associated enrichment of TpG and CpA dinucleotides are used to infer the intensity and localization of germline CpG methylation and to estimate its evolutionary dynamics. We observe a positive correlation of the relative methylation of CpG motifs with genome size. We tested this trend successfully by measuring total DNA methylation with LC/MS in orthopteran insects with very different genome sizes: house crickets, migratory locusts and meadow grasshoppers. We hypothesize that the observed correlation between methylation rate and genome size is due to a dependence of both variables from long-term effective population size and is driven by the accumulation of repetitive sequences that are typically methylated during periods of small population sizes. This process may result in generally methylated, large genomes such as those of jawed vertebrates. In this case, the emergence of a novel demethylation pathway and of novel reader proteins for methylcytosine may have enabled the usage of cytosine methylation for promoter-based gene regulation. On the other hand, persistently large populations may lead to a compression of the genome and to the loss of the DNA methylation machinery, as observed, e.g., in nematodes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Notes

  1. Available at http://www.bioinf.uni-leipzig.de/Software/galculator/.

References

  • Arndt PF, Burge CB, Hwa T (2003a) DNA sequence evolution with neighbor-dependent mutation. J Comput Biol 10:313–322

    Article  PubMed  CAS  Google Scholar 

  • Arndt PF, Hwa T (2005) Identification and measurement of neighbor-dependent nucleotide substitution processes. Bioinformatics 21:2322–2328

    Article  PubMed  CAS  Google Scholar 

  • Arndt PF, Petrov DA, Hwa T (2003b) Distinct changes of genomic biases in nucleotide substitution at the time of mammalian radiation. Mol Biol Evol 20:1887–1896

    Article  PubMed  CAS  Google Scholar 

  • Bhutani N, Brady JJ, Damian M, Sacco A, Corbel SY, Blau HM (2010) Reprogramming towards pluripotency requires AID-dependent DNA demethylation. Nature 463:1042–1047

    Article  PubMed  CAS  Google Scholar 

  • Bird AP (1980) DNA methylation and the frequency of CpG in animal DNA. Nucleic Acids Res 8:1499–1504

    Article  PubMed  CAS  Google Scholar 

  • Bird AP, Taggart MH, Smith BA (1979) Methylated and unmethylated DNA compartments in the sea urchin genome. Cell 17:889–901

    Article  PubMed  CAS  Google Scholar 

  • Boerjan B, Sas F, Ernst UR, Tobback J, Lemière F, Vandegehuchte MB, Janssen CR, Badisco L, Marchal E, Verlinden H, Schoofs L, Loof AD (2011) Locust phase polyphenism: Does epigenetic precede endocrine regulation? Gen Comp Endocrinol 173:120–128

    Article  PubMed  CAS  Google Scholar 

  • Bogdanovic O, Veenstra GJC (2009) DNA methylation and methyl-CpG binding proteins: developmental requirements and function. Chromosoma 118:549–565

    Article  PubMed  CAS  Google Scholar 

  • Charlesworth B (2009) Fundamental concepts in genetics: effective population size and patterns of molecular evolution and variation. Nat Rev Genet 10:195–205

    Article  PubMed  CAS  Google Scholar 

  • Chen WJ, Ortí G, Meyer A (2004) Novel evolutionary relationship among four fish model systems. Trends Genet 20:424–431

    Article  PubMed  CAS  Google Scholar 

  • Choi JK, Bae JB, Lyu J, Kim TY, Kim YJ (2009) Nucleosome deposition and DNA methylation at coding region boundaries. Genome Biol 10:R89

    Article  PubMed  Google Scholar 

  • Choy JS, Wei S, Lee JY, Tan S, Chu S, Lee TH (2010) DNA methylation increases nucleosome compaction and rigidity. J Am Chem Soc 132:1782–1783

    Article  PubMed  CAS  Google Scholar 

  • Clark SJ, Harrison J, Frommer M (1995) CpNpG methylation in mammalian cells. Nat Genetics 10:20–27

    Article  PubMed  CAS  Google Scholar 

  • Consortium DG (2007) Evolution of genes and genomes on the Drosophila phylogeny. Nature 450:203–218

    Article  Google Scholar 

  • Conticello S (2008) The AID/APOBEC family of nucleic acid mutators. Genome Biol 9:229

    Article  PubMed  Google Scholar 

  • Conticello SG, Thomas CJ, Petersen-Mahrt SK, Neuberger MS (2005) Evolution of the AID/APOBEC family of polynucleotide (deoxy)cytidine deaminases. Mol Biol Evol 22:367–377

    Article  PubMed  CAS  Google Scholar 

  • Duret L, Galtier N (2000) The covariation between TpA deficiency, CpG deficiency, and G+C content of human isochores is due to a mathematical artifact. Mol Biol Evol 17:1620–1625

    Article  PubMed  CAS  Google Scholar 

  • Elango N, Hunt BG, Goodisman MA, Yi SV (2009) DNA methylation is widespread and associated with differential gene expression in castes of the honeybee, Apis mellifera. Proc Natl Acad Sci USA 106:11206–11211

    Article  PubMed  CAS  Google Scholar 

  • Elango N, Kim SH, Vigoda E, Yi SV (2008) Mutations of different molecular origins exhibit contrasting patterns of regional substitution rate variation. PLoS Comput Biol 4:e1000015

    Google Scholar 

  • Elango N, Yi SV (2008) DNA methylation and structural and functional bimodality of vertebrate promoters. Mol Biol Evol 25:1602–1608

    Article  PubMed  CAS  Google Scholar 

  • Eyre-Walker A, Keightley PD, Smith NGC, Gaffney D (2002) Quantifying the slightly deleterious mutation model of molecular evolution. Mol Biol Evol 19:2142–2149

    Article  PubMed  CAS  Google Scholar 

  • Feng S, Cokus SJ, Zhang X, Chen PY, Bostick M, Goll MG, Hetzel J, Jain J, Strauss SH, Halpern ME, Ukomadu C, Sadler KC, Pradhan S, Pellegrini M, Jacobsen SE (2010) Conservation and divergence of methylation patterning in plants and animals. Proc Natl Acad Sci USA 107:8689–8694

    Article  PubMed  CAS  Google Scholar 

  • Feschotte C, Keswani U, Ranganathan N, Guibotsy ML, Levine D (2009) Exploring repetitive DNA landscapes using REPCLASS, a tool that automates the classification of transposable elements in eukaryotic genomes. Genome Biol Evol 1:205–220

    Article  PubMed  Google Scholar 

  • Feuerbach L, Lyngsø RB, Lengauer T, Hein J (2011) Reconstructing the ancestral germline methylation state of young repeats. Mol Biol Evol 470:1777–1784

    Article  Google Scholar 

  • FitzGerald PC, Sturgill D, Shyakhtenko A, Oliver B, Vinson C (2006) Comparative genomics of Drosophila and human core promoters. Genome Biol 7:R53

    Article  PubMed  Google Scholar 

  • Gertz EM, Yu YK, Agarwala R, Schäffer AA, Altschul SF (2006) Composition-based statistics and translated nucleotide searches: improving the TBLASTN module of BLAST. BMC Biol 4:41

    Article  PubMed  Google Scholar 

  • Goll MG, Bestor TH (2005) Eukaryotic cytosine methyltransferases. Annu Rev Biochem 74:481–514

    Article  PubMed  CAS  Google Scholar 

  • Gregory TR (2010) Animal genome size database. http://www.genomesize.com/

  • Grunau C, Renault E, Rosenthal A, Roizes G (2001) MethDB–a public database for DNA methylation data. Nucleic Acids Res 29:270–274. http://www.methdb.de

    Google Scholar 

  • Guindon S, Gascuel O (2003) A simple, fast, and accurate algorithm to estimate large phylogenies by maximum likelihood. Syst Biol 52:696–704

    Article  PubMed  Google Scholar 

  • Hardeland U, Bentele M, Jiricny J, Schär P (2003) The versatile thymine DNA-glycosylase: a comparative characterization of the human, Drosophila and fission yeast orthologs. Nucleic Acids Res 31:2261–2271

    Article  PubMed  CAS  Google Scholar 

  • Hejnol A, Obst M, Stamatakis A, Ott M, Rouse GW, Edgecombe GD, Martinez P, Baguñà J, Bailly X, Jondelius U, Wiens M, Müller WEG, Seaver E, Wheeler WC, Martindale MQ, Giribet G, Dunn CW (2009) Assessing the root of bilaterian animals with scalable phylogenomic methods. Proc Biol Sci 276:4261–4270

    Article  PubMed  Google Scholar 

  • Ho KL, McNae IW, Schmiedeberg L, Klose RJ, Bird AP, Walkinshaw MD (2008) MeCP2 binding to DNA depends upon hydration at methyl-CpG. Mol Cell 29:525–531

    Article  PubMed  CAS  Google Scholar 

  • Hodges C, Bintu L, Lubkowska L, Kashlev M, Bustamante C (2009) Nucleosomal fluctuations govern the transcription dynamics of RNA polymerase II. Science 325:626–628

    Article  PubMed  CAS  Google Scholar 

  • Holterman M, van der Wurff A, van den Elsen S, van Megen H, Bongers T, Holovachov O, Bakker J, Helder J (2006) Phylum-wide analysis of SSU rDNA reveals deep phylogenetic relationships among nematodes and accelerated evolution toward crown clades. Mol Biol Evol 23:1792–1800

    Article  PubMed  CAS  Google Scholar 

  • Hu TT, Pattyn P, Bakker EG, Cao J, Cheng JF, Clark RM, Fahlgren N, Fawcett JA, Grimwood J, Gundlach H, Haberer G, Hollister JD, Ossowski S, Ottilar RP, Salamov AA, Schneeberger K, Spannagl M, Wang X, Yang L, Nasrallah ME, Bergelson J, Carrington JC, Gaut BS, Schmutz J, Mayer KFX, Peer YVD, Grigoriev IV, Nordborg M, Weigel D, Guo YL (2011) The Arabidopsis lyrata genome sequence and the basis of rapid genome size change. Nat Genet 43:476–481

    Google Scholar 

  • Jurka J, Kapitonov VV, Pavlicek A, Klonowski P, Kohany O, Walichiewicz J (2005) Repbase Update, a database of eukaryotic repetitive elements. Cytogenet Genome Res 110:462–467

    Article  PubMed  CAS  Google Scholar 

  • Karlin S, Cardon LR (1994) Computational DNA sequence analysis. Annu Rev Microbiol 48:619–654

    Article  PubMed  CAS  Google Scholar 

  • Kondrashov AS (2003) Direct estimates of human per nucleotide mutation rates at 20 loci causing Mendelian diseases. Hum Mutat 21:12–27

    Article  PubMed  CAS  Google Scholar 

  • Krauss V, Eisenhardt C, Unger T (2009) The genome of the stick insect Medauroidea extradentata is strongly methylated within genes and repetitive DNA. PLoS ONE 4:e7223

    Article  PubMed  Google Scholar 

  • Krauss V, Reuter G (2011) DNA methylation in Drosophila—a critical evaluation. Prog Mol Biol Transl Sci 101:177–191

    Google Scholar 

  • Kriegs JO, Churakov G, Kiefmann M, Jordan U, Brosius J, Schmitz J (2006) Retroposed elements as archives for the evolutionary history of placental mammals. PLoS Biol 4:e91

    Article  PubMed  Google Scholar 

  • Laurent L, Wong E, Li G, Huynh T, Tsirigos A, Ong CT, Low HM, Kin Sung KW, Rigoutsos I, Loring J, Wei CL (2010) Dynamic changes in the human methylome during differentiation. Genome Res 20:320–331

    Article  PubMed  CAS  Google Scholar 

  • Lister R, Pelizzola M, Dowen RH, Hawkins RD, Hon G, Tonti-Filippini J, Nery JR, Lee L, Ye Z, Ngo QM, Edsall L, Antosiewicz-Bourget J, Stewart R, Ruotti V, Millar AH, Thomson JA, Ren B, Ecker JR (2009) Human DNA methylomes at base resolution show widespread epigenomic differences. Nature 462:315–322

    Article  PubMed  CAS  Google Scholar 

  • Lynch M (2006) The origins of eukaryotic gene structure. Mol Biol Evol 23:450–468

    Article  PubMed  CAS  Google Scholar 

  • Lynch M (ed) (2007) The origins of genome architecture. Sinauer Associates, Sunderland

  • Maddison WP, Maddison DR (2001) Mesquite: a modular system for evolutionary analysis. http://mesquiteproject.org

  • Maksakova IA, Romanish MT, Gagnier L, Dunn CA, van de Lagemaat LN, Mager DL (2006) Retroviral elements and their hosts: insertional mutagenesis in the mouse germ line. PLoS Genet 2:e2

    Article  PubMed  Google Scholar 

  • Marhold J, Rothe N, Pauli A, Mund C, K K, Brueckner B, Lyko F (2004) Conservation of DNA methylation in dipteran insects. Insect Mol Biol 13:117–123

    Article  PubMed  CAS  Google Scholar 

  • Maunakea AK, Nagarajan RP, Bilenky M, Ballinger TJ, D’Souza C, Fouse SD, Johnson BE, Hong C, Nielsen CB, Zhao Y, Turecki G, Delaney A, Varhol R, Thiessen N, Shchors K, Heine VM, Rowitch DH, Xing X, Fiore C, Schillebeeckx M, Jones SJM, Haussler D, Marra MA, Hirst M, Wang T, Costello JF (2010) Conserved role of intragenic DNA methylation in regulating alternative promoters. Nature 466:253–257

    Article  PubMed  CAS  Google Scholar 

  • Meissner A, Mikkelsen TS, Gu H, Wernig M, Hanna J, Sivachenko A, Zhang X, Bernstein BE, Nusbaum C, Jaffe DB, Gnirke A, Jaenisch R, Lander ES (2008) Genome-scale DNA methylation maps of pluripotent and differentiated cells. Nature 454:766–770

    PubMed  CAS  Google Scholar 

  • Midford PE, Garland T, Maddison WP (2010) PDAP:PDTREE: a translation of the PDTREE application of Garland et al.’s phenotypic diversity analysis programs, version1.14

  • Molaro A, Hodges E, Fang F, Song Q, McCombie WR, Hannon GJ, Smith AD (2011) Sperm methylation profiles reveal features of epigenetic inheritance and evolution in primates. Cell 146:1029–1041

    Article  PubMed  CAS  Google Scholar 

  • Morgan MT, Bennett MT, Drohat AC (2007) Excision of 5-halogenated uracils by human thymine DNA glycosylase. robust activity for DNA contexts other than cpg. J Biol Chem 282:27578–27586

    Article  PubMed  CAS  Google Scholar 

  • Nanty L, Carbajosa G, Heap GA, Ratnieks F, van Heel DA, Down TA, Rakyan VK (2011) Comparative methylomics reveals gene-body H3K36me3 in Drosophila predicts DNA methylation and CpG landscapes in other invertebrates. Genome Res 21:1841–1850

    Article  PubMed  CAS  Google Scholar 

  • Neafsey DE, Palumbi SR (2003) Genome size evolution in pufferfish: a comparative analysis of diodontid and tetraodontid pufferfish genomes. Genome Res 13:821–830

    Article  PubMed  CAS  Google Scholar 

  • Okamura K, Matsumoto KA, Nakai K (2010) Gradual transition from mosaic to global DNA methylation patterns during deuterostome evolution. BMC Bioinforma 11(Suppl 7):S2

    Google Scholar 

  • Popp C, Dean W, Feng S, Cokus SJ, Andrews S, Pellegrini M, Jacobsen SE, Reik W (2010) Genome-wide erasure of DNA methylation in mouse primordial germ cells is affected by AID deficiency. Nature 463:1101–1115

    Article  PubMed  CAS  Google Scholar 

  • Pruesse E, Quast C, Knittel K, Fuchs BM, Ludwig W, Peplies J, Glöckner FO (2007) SILVA: a comprehensive online resource for quality checked and aligned ribosomal RNA sequence data compatible with ARB. Nucleic Acids Res 35:7188–7196

    Article  PubMed  CAS  Google Scholar 

  • Rai K, Huggins IJ, James SR, Karpf AR, Jones DA, Cairns BR (2008) DNA demethylation in zebrafish involves the coupling of a deaminase, a glycosylase, and gadd45. Cell 135:1201–1212

    Article  PubMed  CAS  Google Scholar 

  • Regev A, Lamb M, Jablonka E (1998) The role of DNA methylation in invertebrates: Developmental regulation or genome defense? Mol Biol Evol 15:880–891

    Article  CAS  Google Scholar 

  • Robinson KL, Tohidi-Esfahani D, Lo N, Simpson SJ, Sword GA (2011) Evidence for widespread genomic methylation in the migratory locust, Locusta migratoria (Orthoptera: Acrididae). PLos One 6:e28167

    Article  PubMed  CAS  Google Scholar 

  • Rogozin IB, Iyer LM, Liang L, Glazko GV, Liston VG, Pavlov YI, Aravind L, Pancer Z (2007) Evolution and diversification of lamprey antigen receptors: evidence for involvement of an AID-APOBEC family cytosine deaminase. Nat Immunol 8:647–656

    Article  PubMed  CAS  Google Scholar 

  • Rollins RA, Haghighi F, Edwards JR, Das R, Zhang MQ, Ju J, Bestor TH (2006) Large-scale structure of genomic methylation patterns. Genome Res 16:157–163

    Article  PubMed  CAS  Google Scholar 

  • Sasai N, Defossez PA (2010) Many paths to one goal? The proteins that recognize methylated DNA in eukaryotes. Int J Dev Biol 53:323–334

    Article  Google Scholar 

  • Shoemaker R, Deng J, Wang W, Zhang K (2010) Allele-specific methylation is prevalent and is contributed by CpG-SNPs in the human genome. Genome Res 20:883–889

    Article  PubMed  CAS  Google Scholar 

  • Simmen MW (2008) Genome-scale relationships between cytosine methylation and dinucleotide abundances in animals. Genomics 92:33–40

    Article  PubMed  CAS  Google Scholar 

  • Simmen MW, Leitgeb S, Charlton J, Jones SJ, Harris BR, Clark VH, Bird A (1999) Nonmethylated transposable elements and methylated genes in a chordate genome. Science 283:1164–1167

    Article  PubMed  CAS  Google Scholar 

  • Suzuki MM, Bird AP (2008) Dna methylation landscapes: provocative insights from epigenomics. Nat Rev Genet 9:465–476

    Article  PubMed  CAS  Google Scholar 

  • Thalhammer A, Hansen AS, El-Sagheer AH, Brown T, Schofield CJ (2011) Hydroxylation of methylated CpG dinucleotides reverses stabilisation of DNA duplexes by cytosine 5-methylation. Chem Commun Camb 47:5325–5327

    Article  CAS  Google Scholar 

  • The Human Genome International Sequencing Consortium (2001) Initial sequencing and analysis of the human genome. Nature 409:860–921

    Article  Google Scholar 

  • Varriale A, Bernardi G (2006a) DNA methylation and body temperature in fishes. Gene 385:111–121

    Article  PubMed  CAS  Google Scholar 

  • Varriale A, Bernardi G (2006b) DNA methylation in reptiles. Gene 385:122–127

    Article  PubMed  CAS  Google Scholar 

  • Walsh CP, Bestor TH (1999) Cytosine methylation and mammalian development. Genes Dev 13:26–34

    Article  PubMed  CAS  Google Scholar 

  • Walsh TK, Brisson JA, Robertson HM, Gordon K, Jaubert-Possamai S, Tagu D, Edwards OR (2010) A functional dna methylation system in the pea aphid, Acyrthosiphon pisum. Insect Mol Biol 19 Suppl 2:215–228

    Article  PubMed  CAS  Google Scholar 

  • Wang Y, Jorda M, Jones PL, Maleszka R, Ling X, Robertson HM, Mizzen CA, Peinado MA, Robinson GE (2006) Functional CpG methylation system in a social insect. Science 314:645–647

    Article  PubMed  CAS  Google Scholar 

  • Wu SC, Zhang Y (2010) Active DNA demethylation: many roads lead to rome. Nat Rev Mol Cell Biol 11:607–620

    Article  PubMed  CAS  Google Scholar 

  • Yoder JA, Walsh CP, Bestor TH (1997) Cytosine methylation and the ecology of intragenomic parasites. Trends Genet 13:335–340

    Article  PubMed  CAS  Google Scholar 

  • Zemach A, McDaniel IE, Silva P, Zilberman D (2010) Genome-wide evolutionary analysis of eukaryotic DNA methylation. Science 328:916–919

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported in part by DFG GRK-1384 and MA5082/1-1.

Author information

Authors and Affiliations

  1. Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marbacher Weg 6, 35037, Marburg, Germany

    Marcus Lechner

  2. RNA Bioinformatics and High Throughput Analysis, Friedrich Schiller University, Leutragraben 1, 07743, Jena, Germany

    Manja Marz

  3. Department of Pharmaceutical Chemistry and Bioanalytics, Institute of Pharmacy, Martin-Luther-University Halle-Wittenberg, Wolfgang-Langenbeck-Straße 4, 06120, Halle, Germany

    Christian Ihling & Andrea Sinz

  4. Bioinformatics Group, Department of Computer Science and Interdisciplinary Center for Bioinformatics, University of Leipzig, Härtelstraße 16-18, 04107, Leipzig, Germany

    Peter F. Stadler

  5. Max Planck Institute for Mathematics in the Sciences, Inselstraße 22, 04103, Leipzig, Germany

    Peter F. Stadler

  6. RNomics Group, Fraunhofer Institut für Zelltherapie und Immunologie, Deutscher Platz 5e, 04103, Leipzig, Germany

    Peter F. Stadler

  7. Department of Theoretical Chemistry, University of Vienna, Währingerstraße 17, 1090, Wien, Austria

    Peter F. Stadler

  8. Center for Non-coding RNA in Technology and Health, University of Copenhagen, Grønnegårdsvej 3, 1870, Frederiksberg, Denmark

    Peter F. Stadler

  9. Santa Fe Institute, 1399 Hyde Park Rd, Santa Fe, NM, 87501, USA

    Peter F. Stadler

  10. Bioinformatics Group, Department of Computer Science, University of Leipzig, Härtelstraße 16-18, 04107, Leipzig, Germany

    Veiko Krauss

  11. Group of Developmental Genetics, Institute for Biology, Martin Luther University Halle-Wittenberg, Weinbergweg 10, 06120, Halle, Germany

    Veiko Krauss

Authors
  1. Marcus Lechner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Manja Marz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Christian Ihling
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Andrea Sinz
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Peter F. Stadler
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Veiko Krauss
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Peter F. Stadler or Veiko Krauss.

Electronic supplementary material

Supplementary figures are available from the journal website. Machine readable supplementary data, including methylation rate data, genome size data, tree and the used genome versions are available at http://www.bioinf.uni-leipzig.de/supplements/10-026

PDF (287 KB)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lechner, M., Marz, M., Ihling, C. et al. The correlation of genome size and DNA methylation rate in metazoans. Theory Biosci. 132, 47–60 (2013). https://doi.org/10.1007/s12064-012-0167-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12064-012-0167-y

Keywords

Search

Navigation