The EDGE hypothesis: epigenetically directed genetic errors in repeat-containing proteins (RCPs) involved in evolution, neuroendocrine signaling, and cancer.

Abstract:

:Trans-generational epigenetic phenomena, such as contamination with endocrine-disrupting chemicals (EDCs) that decrease fertility and the global methylation status of DNA in the offspring, are of great concern because they may affect health, particularly the health of children. However, of even greater concern is the possibility that trans-generational changes in the methylation status of the DNA might lead to permanent changes in the DNA sequence itself. By contaminating the environment with EDCs, mankind might be permanently affecting the health of future generations. In this section, we present evidence from our laboratory and others that trans-generational epigenetic changes in DNA might lead to mutations directed to genes encoding amino acid repeat-containing proteins (RCPs) that are important for adaptive evolution or cancer progression. Such epigenetic changes can be induced "naturally" by hormones or "unnaturally" by EDCs or environmental stress. To illustrate the phenomenon, we present new bioinformatic evidence that the only RCP ontological categories conserved from Drosophila to humans are "regulation of splicing," "regulation of transcription," and "regulation of synaptogenesis," which are classes of genes likely to be important for evolutionary processes. Based on that and other evidence, we propose a model for evolution that we call the EDGE (Epigenetically Directed Genetic Errors) hypothesis for the mechanism by which mutations are targeted at epigenetically modified "contingency genes" encoding RCPs. In the model, "epigenetic assimilation" of metastable epialleles of RCPs over many generations can lead to mutations directed to those genes, thereby permanently stabilizing the adaptive phenotype.

journal_name

Front Neuroendocrinol

authors

Ruden DM,Jamison DC,Zeeberg BR,Garfinkel MD,Weinstein JN,Rasouli P,Lu X

doi

10.1016/j.yfrne.2007.12.004

subject

Has Abstract

pub_date

2008-06-01 00:00:00

pages

428-44

issue

3

eissn

0091-3022

issn

1095-6808

pii

S0091-3022(07)00073-8

journal_volume

29

pub_type

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