Epigenetics of Complex Diseases: From General Theory to Laboratory Experiments
- 1.2k Downloads
Despite significant effort, understanding the causes and mechanisms of complex non-Mendelian diseases remains a key challenge. Although numerous molecular genetic linkage and association studies have been conducted in order to explain the heritable predisposition to complex diseases, the resulting data are quite often inconsistent and even controversial. In a similar way, identification of environmental factors causal to a disease is difficult. In this article, a new interpretation of the paradigm of “genes plus environment” is presented in which the emphasis is shifted to epigenetic misregulation as a major etiopathogenic factor. Epigenetic mechanisms are consistent with various non-Mendelian irregularities of complex diseases, such as the existence of clinically indistinguishable sporadic and familial cases, sexual dimorphism, relatively late age of onset and peaks of susceptibility to some diseases, discordance of monozygotic twins and major fluctuations on the course of disease severity. It is also suggested that a substantial portion of phenotypic variance that traditionally has been attributed to environmental effects may result from stochastic epigenetic events in the cell. It is argued that epigenetic strategies, when applied in parallel with the traditional genetic ones, may significantly advance the discovery of etiopathogenic mechanisms of complex diseases. The second part of this chapter is dedicated to a review of laboratory methods for DNA methylation analysis, which may be useful in the study of complex diseases. In this context, epigenetic microarray technologies are emphasized, as it is evident that such technologies will significantly advance epigenetic analyses in complex diseases.
KeywordsComplex Disease Monozygotic Twin Angelman Syndrome Epigenetic Difference Restriction Landmark Genomic Scanning
Unable to display preview. Download preview PDF.
- Deb-Rinker P, O’Reilly RL, Torrey EF, Singh SM (2002) Molecular characterization of a 2.7 kb, 12q13-specific, retroviral related sequence isolated by RDA from monozygotic twins discordant for schizophrenia. Genome 45:1–10Google Scholar
- Ehrlich M, Ehrlich K (1993) Effect of DNA methylation and the binding of vertebrate and plant proteins to DNA. In: Jost J, Saluz P (eds) DNA methylation: molecular biology and biological significance. Birkhauser Verlag, Basel, 145–168Google Scholar
- Jablonka E, Lamb M (1995) Epigenetic inheritance and evolution. Oxford University Press, New York, pp 1–360Google Scholar
- Mueller K, Doerfler W (2000) Methylation-sensitive amplicon subtraction: a novel method to isolate differentially methylated DNA sequences in complex genomes. Gene Funct Dis 1:154–160Google Scholar
- Riggs A, Porter T (1996) Overview of epigenetic mechanisms. In: Russo VEA MR, Riggs AD (eds) Epigenetic mechanisms of gene regulation. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, pp 29–45Google Scholar
- Riggs A, Xiong Z, Wang L, JM L (1998) Methylation dynamics, epigenetic fidelity and X chromosome structure. In: Wolffe A (ed) Epigenetics. John Wiley and Sons, Chichester, pp 214–227Google Scholar
- Saluz HP, Jiricny J, Jost JP (1986) Genomic sequencing reveals a positive correlation between the kinetics of strand-specific DNA demethylation of the overlapping estradiol/glucocorticoid-receptor binding sites and the rate of avian vitellogenin mRNA synthesis. Proc Natl Acad Sci U S A 83:7167–7171PubMedGoogle Scholar
- Schumacher A (2001) Mechanisms and brain specific consequences of genomic imprinting in Prader-Willi and Angelman syndromes. Gene Funct Dis 1:7–25Google Scholar
- Ushijima T, Morimura K, Hosoya Y, et al (1997) Establishment of methylation-sensitive-representational difference analysis and isolation of hypo-and hypermethylated genomic fragments in mouse liver tumors. ProcNatl Acad Sci U S A 94:2284–2289Google Scholar
- Yang AS JP, Shibata A (1996) The mutational burden of 5-methylcytosine. In: Russo V, Riggs A (eds) Epigenetic mechanisms of gene regulation. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, pp 77–94Google Scholar
- Zubenko GS, Maher B, Hughes HB 3rd, et al (2003) Genome-wide linkage survey for genetic loci that influence the development of depressive disorders in families with recurrent, early-onset, major depression. Am J Med Genet 123B:1–18Google Scholar