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DNA methylation profiles in monozygotic and dizygotic twins


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.

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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.

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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.

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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.

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Correspondence to Art Petronis.

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Kaminsky, Z., Tang, T., Wang, SC. et al. DNA methylation profiles in monozygotic and dizygotic twins. Nat Genet 41, 240–245 (2009).

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