Abstract
The IDDM2 type 1 diabetes susceptibility locus was mapped to1–6 and identified as7 allelic variation at the insulin gene (INS) VNTR regulatory polymorphism. In Caucasians, INS VNTR alleles divide into two discrete size classes1. Class I alleles (26 to 63 repeats) predispose in a recessive way to type 1 diabetes, while class III alleles (140 to more than 200 repeats) are dominantly protective8. The protective effect may be explained by higher levels of class III VNTR-associated INS mRNA in thymus such that elevated levels of preproinsulin protein enhance immune tolerance to preproinsulin, a key autoantigen in type 1 diabetes pathogenesis9,10. The mode of action of IDDM2 is complicated, however, by parent-of-origin effects2,7,11–14 and possible allelic heterogeneity within the two defined allele classes7,15. We have now analysed transmission of specific VNTR alleles in 1,316 families and demonstrate that a particular class I allele does not predispose to disease when paternally inherited, suggestive of polymorphic imprinting16. But this paternal effect is observed only when the father's untransmitted allele is a class III. This allelic interaction is reminiscent of epigenetic phenomena observed in plants (for example, paramutation; ref. 17) and in yeast (for example, frans-inactivation; ref. 18). If untransmitted chromosomes can have functional effects on the biological properties of transmitted chromosomes, the implications for human genetics and disease are potentially considerable.
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References
Bell, G.I., Horita, S. & Karam, J.H. A polymorphic locus near the human insulin gene is associated with insulin-dependent diabetes mellitus. Diabetes 33, 176–183 (1984).
Julier, C. et al. lnsulin-IGF2 region on chromosome 11p encodes a gene implicated in HLA-DR4-dependent diabetes susceptibility. Nature 354, 155–159 (1991).
Lucassen, A.M. et al. Susceptibility to insulin dependent diabetes mellitus maps to a 4.1 kb segment of DMA spanning the insulin gene and associated VNTR. Nature Genet. 4, 305–310 (1993).
Owerbach, D. & Gabbay, K.H. Localization of a type 1 diabetes susceptibility locus to the variable tandem repeat region flanking the insulin gene. Diabetes. 42, 1708–1714 (1993).
Julier, C. et al. Multiple DNA variant association analysis: application to the insulin gene region in type 1 diabetes. Am. J. Hum. Genet. 55, 1247–1254 (1994).
Undlien, D.E. et al. Insulin gene region-encoded susceptibility to IDDM maps upstream of the insulin gene. Diabetes 44, 620–625 (1995).
Bennett, S.T. et al. Susceptibility to human type 1 diabetes at IDDM2 is determined by tandem repeat variation at the insulin gene minisatellite locus. Nature Genet. 9, 284–292 (1995).
Bennett, S.T. & Todd, J.A. Human type 1 diabetes and the insulin gene: principles of mapping polygenes. Annu. Rev. Genet. 30, 343–370 (1996).
Vafiadis, P. et al. Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus. Nature Genet. 15, 289–292 (1997).
Pugliese, A. et al. The insulin gene is transcribed in the human thymus and transcription levels correlate with allelic variation at the INS VNTR-/DDM2 susceptibility locus for type 1 diabetes. Nature Genet. 15, 293–297 (1997).
Pugliese, A., Awdeh, Z.L., Alper, C.A., Jackson, R.A. & Eisenbarth, G.S. The paternally inherited insulin gene B allele (1,428 Fokl site) confers protection from insulin-dependent diabetes in families. J. Autoimmun. 7, 687–694 (1994).
PoJychronakos, C., Kukuvitis, A., Giannoukakis, N. & Colle, E. Parental imprinting effect at the INS-IGF2 diabetes susceptibility locus. Diabetologia 38, 715–719 (1995).
Bui, M.M. et al. Paternally transmitted IDDM2 influences diabetes susceptibility despite biallelic expression of the insulin gene in human pancreas. J. Autoimmun. 9, 97–103 (1996).
Bennett, S.T. et al. IDDM2-VNTR-encoded susceptibility to type 1 diabetes: dominant protection and parental transmission of alleles of the insulin gene-linked minisatellite locus. J. Autoimmun. 9, 415–421 (1996).
Bennett, S.T. et al. Insulin expression: is VNTR allele 698 really anomalous? (reply). Nature Genet. 10, 379–380 (1995).
Xu, Y., Grundy, P. & Polychronakos, C. Aberrant imprinting of the insulin-like growth factor II receptor gene in Wilms' tumor. Oncogene 14, 1041–1046 (1997).
Hollick, J., Dorweiler, J. & Chandler, V. Paramutation and related allelic interactions. Trends Genet. 13, 302–308 (1997).
Grewal, S. & Klar, A. Chromosomal inheritance of epigenetic states in fission yeast during mitosis and meiosis. Cell 86, 95–101 (1996).
Todd, J.A. Genetic analysis of type 1 diabetes using whole genome approaches. Proc. Natl. Acad. Sci. USA 92, 8560–8565 (1995).
Barlow, D.P. Gametic imprinting in mammals. Science 270, 1610–1613 (1995).
Neumann, B., Kubicka, P. & Barlow, D.P. Characteristics of imprinted genes. Nature Genet. 9, 12–13 (1995).
LaSalle, J. & Lalande, M. Homologous association of oppositely imprinted chromosomal domains. Science 272, 725–728 (1996).
Xu, Y., Goodyer, C., Deal, C. & Polychronakos, C. Functional polymorphism in the parental imprinting of the human IGF2R gene. Biochem. Biophys. Res. Commun. 197, 747–754 (1993).
Smrzka, O. et al. Conservation of a maternal-specific methylation signal at the human IGF2R locus. Hum. Mol. Genet. 4, 1945–1952 (1995).
Giannoukakis, N., Polychronakos, C., Vafiadis, P., Paquette, J. & Deal, C. The INS 5′ VNTR is associated with IGF2 expression in humans. J. Biol. Chem. (in the press).
Livak, K.J., Marmaro, J. & Todd, J.A. Towards fully automated genome-wide polymorphism screening. Nature Genet. 9, 341–342 (1995).
Bennett, S.T., Lucassen, A.M. & Todd, J.A., in PCR: Essential Techniques (ed. Burke, J.F.) 32–33 (John Wiley & Sons, Chichester, UK, 1996).
Bell, G.I., Seiby, M.J. & Rutter, W.J. The highly polymorphic region near the human insulin gene is composed of simple tandemly repeating sequences. Nature 295, 31–35 (1982).
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Bennett, S., Wilson, A., Esposito, L. et al. Insulin VNTR allele-specific effect in type 1 diabetes depends on identity of untransmitted paternal allele. Nat Genet 17, 350–352 (1997). https://doi.org/10.1038/ng1197-350
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DOI: https://doi.org/10.1038/ng1197-350
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