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Genomic surveys by methylation-sensitive SNP analysis identify sequence-dependent allele-specific DNA methylation

Abstract

Allele-specific DNA methylation (ASM) is a hallmark of imprinted genes, but ASM in the larger nonimprinted fraction of the genome is less well characterized. Using methylation-sensitive SNP analysis (MSNP), we surveyed the human genome at 50K and 250K resolution, identifying ASM as recurrent genotype call conversions from heterozygosity to homozygosity when genomic DNAs were predigested with the methylation-sensitive restriction enzyme HpaII. Using independent assays, we confirmed ASM at 16 SNP-tagged loci distributed across various chromosomes. At 12 of these loci (75%), the ASM tracked strongly with the sequence of adjacent SNPs. Further analysis showed allele-specific mRNA expression at two loci from this methylation-based screen—the vanin and CYP2A6-CYP2A7 gene clusters—both implicated in traits of medical importance. This recurrent phenomenon of sequence-dependent ASM has practical implications for mapping and interpreting associations of noncoding SNPs and haplotypes with human phenotypes.

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Figure 1: Genotype-dependent ASM in LTF intron 13.
Figure 2: Genotype-dependent ASM and ASE in the CYP2 gene cluster.
Figure 3: Genotype-dependent ASM in the VNN1 gene and allele-specific mRNA expression of all three genes in the vanin cluster.

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References

  1. Chandler, L.A., Ghazi, H., Jones, P.A., Boukamp, P. & Fusenig, N.E. Allele-specific methylation of the human c-Ha-ras-1 gene. Cell 50, 711–717 (1987).

    Article  CAS  PubMed  Google Scholar 

  2. Silva, A.J. & White, R. Inheritance of allelic blueprints for methylation patterns. Cell 54, 145–152 (1988).

    Article  CAS  PubMed  Google Scholar 

  3. Yamada, Y. et al. A comprehensive analysis of allelic methylation status of CpG islands on human chromosome 21q. Genome Res. 14, 247–266 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Yuan, E. et al. A single nucleotide polymorphism chip-based method for combined genetic and epigenetic profiling: validation in decitabine therapy and tumor/normal comparisons. Cancer Res. 66, 3443–3451 (2006).

    Article  CAS  PubMed  Google Scholar 

  5. Lin, M. et al. dChipSNP: significance curve and clustering of SNP-array-based loss-of-heterozygosity data. Bioinformatics 20, 1233–1240 (2004).

    Article  CAS  PubMed  Google Scholar 

  6. Boccaccio, I. et al. The human MAGEL2 gene and its mouse homologue are paternally expressed and mapped to the Prader-Willi region. Hum. Mol. Genet. 8, 2497–2505 (1999).

    Article  CAS  PubMed  Google Scholar 

  7. Lee, S. et al. Expression and imprinting of MAGEL2 suggest a role in Prader-willi syndrome and the homologous murine imprinting phenotype. Hum. Mol. Genet. 9, 1813–1819 (2000).

    Article  CAS  PubMed  Google Scholar 

  8. Saitoh, S. et al. Clinical spectrum and molecular diagnosis of Angelman and Prader-Willi syndrome patients with an imprinting mutation. Am. J. Med. Genet. 68, 195–206 (1997).

    Article  CAS  PubMed  Google Scholar 

  9. Tyndale, R.F. Genetics of alcohol and tobacco use in humans. Ann. Med. 35, 94–121 (2003).

    Article  CAS  PubMed  Google Scholar 

  10. Goring, H.H. et al. Discovery of expression QTLs using large-scale transcriptional profiling in human lymphocytes. Nat. Genet. 39, 1208–1216 (2007).

    Article  PubMed  Google Scholar 

  11. Gimelbrant, A., Hutchinson, J.N., Thompson, B.R. & Chess, A. Widespread monoallelic expression on human autosomes. Science 318, 1136–1140 (2007).

    Article  CAS  PubMed  Google Scholar 

  12. Ohlsson, R., Tycko, B. & Sapienza, C. Monoallelic expression: 'there can only be one'. Trends Genet. 14, 435–438 (1998).

    Article  CAS  PubMed  Google Scholar 

  13. Wang, J., Valo, Z., Smith, D. & Singer-Sam, J. Monoallelic expression of multiple genes in the CNS. PLoS ONE 2, e1293 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Chan, T.L. et al. Heritable germline epimutation of MSH2 in a family with hereditary nonpolyposis colorectal cancer. Nat. Genet. 38, 1178–1183 (2006).

    Article  CAS  PubMed  Google Scholar 

  15. Zogel, C. et al. Identification of cis- and trans-acting factors possibly modifying the risk of epimutations on chromosome 15. Eur. J. Hum. Genet. 14, 752–758 (2006).

    Article  CAS  PubMed  Google Scholar 

  16. Suter, C.M. & Martin, D.I. Inherited epimutation or a haplotypic basis for the propensity to silence? Nat. Genet. 39, 573; author reply 576 (2007).

    Article  CAS  PubMed  Google Scholar 

  17. 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).

    Article  CAS  PubMed  Google Scholar 

  18. von Richter, O. et al. Polymorphic NF-Y dependent regulation of human nicotine C-oxidase (CYP2A6). Pharmacogenetics 14, 369–379 (2004).

    Article  CAS  PubMed  Google Scholar 

  19. Pitarque, M. et al. Identification of a single nucleotide polymorphism in the TATA box of the CYP2A6 gene: impairment of its promoter activity. Biochem. Biophys. Res. Commun. 284, 455–460 (2001).

    Article  CAS  PubMed  Google Scholar 

  20. Pitarque, M. et al. A nicotine C-oxidase gene (CYP2A6) polymorphism important for promoter activity. Hum. Mutat. 23, 258–266 (2004).

    Article  CAS  PubMed  Google Scholar 

  21. Cokus, S.J. et al. Shotgun bisulphite sequencing of the Arabidopsis genome reveals DNA methylation patterning. Nature 452, 215–219 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by grants to B.T. from the US National Institutes of Health, the March of Dimes and the Leukemia and Lymphoma Society in collaboration with the Douglas Kroll Research Program.

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Contributions

Study design: K.K. and B.T. MSNP, molecular validations and analysis of ASE: K.K., A.S., E.Y., J.K., L.J., E.H., K.L. and V.V.M. Bioinformatic analyses: E.H., M.M. and F.H. Statistical analyses: N.S. and F.H. Provision of biological samples: A.S., V.V.M., N.S., E.V. and B.T. Interpretation and writing the paper: K.K., N.S., E.V. and B.T.

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Correspondence to Benjamin Tycko.

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Kerkel, K., Spadola, A., Yuan, E. et al. Genomic surveys by methylation-sensitive SNP analysis identify sequence-dependent allele-specific DNA methylation. Nat Genet 40, 904–908 (2008). https://doi.org/10.1038/ng.174

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