DNA methylation profiles in monozygotic and dizygotic twins

Abstract

Twin studies have provided the basis for genetic and epidemiological studies in human complex traits1,2. As epigenetic factors can contribute to phenotypic outcomes, we conducted a DNA methylation analysis in white blood cells (WBC), buccal epithelial cells and gut biopsies of 114 monozygotic (MZ) twins as well as WBC and buccal epithelial cells of 80 dizygotic (DZ) twins using 12K CpG island microarrays3,4. Here we provide the first annotation of epigenetic metastability of 6,000 unique genomic regions in MZ twins. An intraclass correlation (ICC)-based comparison of matched MZ and DZ twins showed significantly higher epigenetic difference in buccal cells of DZ co-twins (P = 1.2 × 10−294). Although such higher epigenetic discordance in DZ twins can result from DNA sequence differences, our in silico SNP analyses and animal studies favor the hypothesis that it is due to epigenomic differences in the zygotes, suggesting that molecular mechanisms of heritability may not be limited to DNA sequence differences.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Volcano plots of four MZ twin versus co-twin WBC DNA methylation profile comparisons (black), with overlay of four matched twin DNA versus self comparisons (green) for each set of MZ twins.
Figure 2: A chromosomal karyogram depicting degree of MZ co-twin similarity per interrogated locus in the WBC sample.
Figure 3: ICC distributions in buccal epithelial cells of MZ and DZ twins.
Figure 4: A chromosomal karyogram depicting degrees of dichorionic MZ co-twin similarity relative to DZ co-twin similarity per interrogated locus in the buccal sample.
Figure 5: The spot-wise distributions of the within-sibship variance for both inbred (red) and outbred (blue) mice.

References

  1. 1

    Boomsma, D., Busjahn, A. & Peltonen, L. Classical twin studies and beyond. Nat. Rev. Genet. 3, 872–882 (2002).

    CAS  Article  PubMed  Google Scholar 

  2. 2

    Martin, N., Boomsma, D. & Machin, G. A twin-pronged attack on complex traits. Nat. Genet. 17, 387–392 (1997).

    CAS  Article  PubMed  Google Scholar 

  3. 3

    Heisler, L.E. et al. CpG island microarray probe sequences derived from a physical library are representative of CpG islands annotated on the human genome. Nucleic Acids Res. 33, 2952–2961 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. 4

    Schumacher, A. et al. Microarray-based DNA methylation profiling: technology and applications. Nucleic Acids Res. 34, 528–542 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. 5

    Robertson, K.D. & Wolffe, A.P. DNA methylation in health and disease. Nat. Rev. Genet. 1, 11–19 (2000).

    CAS  Article  PubMed  Google Scholar 

  6. 6

    Riggs, A.D., Xiong, Z., Wang, L. & LeBon, J.M. Methylation dynamics, epigenetic fidelity and X chromosome structure. Novartis Found. Symp. 214, 214–225 (1998).

    CAS  PubMed  Google Scholar 

  7. 7

    Ushijima, T. et al. Fidelity of the methylation pattern and its variation in the genome. Genome Res. 13, 868–874 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8

    Jaenisch, R. & Bird, A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat. Genet. 33 (Suppl.), 245–254 (2003).

    CAS  Article  PubMed  Google Scholar 

  9. 9

    Jirtle, R.L. & Skinner, M.K. Environmental epigenomics and disease susceptibility. Nat. Rev. Genet. 8, 253–262 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10

    Wong, A.H., Gottesman & Petronis, A. Phenotypic differences in genetically identical organisms: the epigenetic perspective. Hum. Mol. Genet. 14 (Spec. No. 1), R11–R18 (2005).

    CAS  Article  PubMed  Google Scholar 

  11. 11

    Petronis, A. et al. Monozygotic twins exhibit numerous epigenetic differences: clues to twin discordance? Schizophr. Bull. 29, 169–178 (2003).

    Article  PubMed  Google Scholar 

  12. 12

    Kuratomi, G. et al. Aberrant DNA methylation associated with bipolar disorder identified from discordant monozygotic twins. Mol. Psychiatry 13, 429–441 (2008).

    CAS  Article  PubMed  Google Scholar 

  13. 13

    Heijmans, B.T., Kremer, D., Tobi, E.W., Boomsma, D.I. & Slagboom, P.E. Heritable rather than age-related environmental and stochastic factors dominate variation in DNA methylation of the human IGF2/H19 locus. Hum. Mol. Genet. 16, 547–554 (2007).

    CAS  Article  PubMed  Google Scholar 

  14. 14

    Oates, N.A. et al. Increased DNA methylation at the AXIN1 gene in a monozygotic twin from a pair discordant for a caudal duplication anomaly. Am. J. Hum. Genet. 79, 155–162 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. 15

    Fraga, M.F. et al. Epigenetic differences arise during the lifetime of monozygotic twins. Proc. Natl. Acad. Sci. USA 102, 10604–10609 (2005).

    CAS  Article  PubMed  Google Scholar 

  16. 16

    Hall, J.G. Twinning. Lancet 362, 735–743 (2003).

    Article  PubMed  Google Scholar 

  17. 17

    Falcon, S. & Gentleman, R. Using GOstats to test gene lists for GO term association. Bioinformatics 23, 257–258 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18

    Bruder, C.E. et al. Phenotypically concordant and discordant monozygotic twins display different DNA copy-number-variation profiles. Am. J. Hum. Genet. 82, 763–771 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. 19

    Bouchard, T.J. Jr ., Lykken, D.T., McGue, M., Segal, N.L. & Tellegen, A. Sources of human psychological differences: the Minnesota Study of Twins Reared Apart. Science 250, 223–228 (1990).

    Article  PubMed  Google Scholar 

  20. 20

    Murrell, A. et al. An association between variants in the IGF2 gene and Beckwith-Wiedemann syndrome: interaction between genotype and epigenotype. Hum. Mol. Genet. 13, 247–255 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21

    Flanagan, J.M. et al. Intra- and interindividual epigenetic variation in human germ cells. Am. J. Hum. Genet. 79, 67–84 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 22

    Khulan, B. et al. Comparative isoschizomer profiling of cytosine methylation: the HELP assay. Genome Res. 16, 1046–1055 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. 23

    Kerkel, K. et al. Genomic surveys by methylation-sensitive SNP analysis identify sequence-dependent allele-specific DNA methylation. Nat. Genet. 40, 904–908 (2008).

    CAS  Article  PubMed  Google Scholar 

  24. 24

    Gartner, K. & Baunack, E. Is the similarity of monozygotic twins due to genetic factors alone? Nature 292, 646–647 (1981).

    CAS  Article  PubMed  Google Scholar 

  25. 25

    Wright, M. & Martin, N. Brisbane Adolescent Twin Study: outline of study methods and research projects. Aust. J. Psychol. 56, 65–78 (2004).

    Article  Google Scholar 

  26. 26

    Halfvarson, J., Bodin, L., Tysk, C., Lindberg, E. & Jarnerot, G. Inflammatory bowel disease in a Swedish twin cohort: a long-term follow-up of concordance and clinical characteristics. Gastroenterology 124, 1767–1773 (2003).

    Article  PubMed  Google Scholar 

  27. 27

    Mill, J. et al. Epigenomic profiling reveals DNA-methylation changes associated with major psychosis. Am. J. Hum. Genet. 82, 696–711 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28

    Tost, J., El Abdalaoui, H. & Gut, I.G. Serial pyrosequencing for quantitative DNA methylation analysis. Biotechniques 40, 721–722 724, 726 (2006).

    CAS  Article  PubMed  Google Scholar 

Download references

Acknowledgements

This paper is dedicated to the memory of Professor V.M. Gindilis, an excellent scientist, dedicated teacher and creative twin researcher. We should like to thank S. Ziegler for technical assistance, A. Henders and M. Campbell for selection and preparation of twin DNA samples, and J. Chow for work generating the karyograms. This project was supported by the National Institute of Mental Health (R01 MH074127-01), the Canadian Institutes for Health and Research (CIHR) and the National Alliance for Research on Schizophrenia and Depression (NARSAD). A.P. is Senior Fellow of the Ontario Mental Health Foundation. Z.A.K. was supported by a CIHR graduate fellowship.

Author information

Affiliations

Authors

Contributions

Study design: Z.A.K., S.-C.W., A.H.C.W., A.F.M., P.M.V., N.G.M. and A.P.; sample collection: G.W.M., N.G.M., J.H. and C.T.; animal preparation: L.A.F. and A.H.C.W.; sample preparation: Z.A.K. and C.P.; microarray enrichment and hybridization: Z.A.K. and C.P.; sodium bisulfite–based fine mapping: Z.A.K., C.P. and G.H.T.O.; statistical analysis: Z.A.K., T.T., S.-C.W., C.V., A.F.M. and P.M.V.; manuscript writing: Z.A.K., T.T., S.-C.W., C.P., G.H.T.O., A.H.C.W., L.A.F., C.V., J.H., C.T., A.F.M., P.M.V., G.W.M., I.I.G., N.G.M. and A.P.

Corresponding author

Correspondence to Art Petronis.

Supplementary information

Supplementary Text and Figures

Supplementary Tables 1 and 2, Supplementary Figures 1–6, Supplementary Note and Supplementary Methods (PDF 3775 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Kaminsky, Z., Tang, T., Wang, S. et al. DNA methylation profiles in monozygotic and dizygotic twins. Nat Genet 41, 240–245 (2009). https://doi.org/10.1038/ng.286

Download citation

Further reading