Genomic imprinting and environmental disease susceptibility.

Genomic imprinting is one of the most intriguing subtleties of modern genetics. The term "imprinting" refers to parent-of-origin-dependent gene expression. The presence of imprinted genes can cause cells with a full parental complement of functional autosomal genes to specifically express one allele but not the other, resulting in monoallelic expression of the imprinted loci. Genomic imprinting plays a critical role in fetal growth and behavioral development, and it is regulated by DNA methylation and chromatin structure. This paper summarizes the Genomic Imprinting and Environmental Disease Susceptibility Conference held 8-10 October 1998 at Duke University, Durham, North Carolina. The conference focused on the importance of genomic imprinting in determining susceptibility to environmentally induced diseases. Conference topics included rationales for imprinting: parental antagonism and speciation; methods for imprinted gene identification: allelic message display and monochromosomal mouse/human hybrids; properties of the imprinted gene cluster human 11p15.5 and mouse distal 7; the epigenetics of X-chromosome inactivation; variability in imprinting: imprint erasure, non-Mendelian inheritance ratios, and polymorphic imprinting; imprinting and behavior: genetics of bipolar disorder, imprinting in Turner syndrome, and imprinting in brain development and social behavior; and aberrant methylation: methylation and chromatin structure, methylation and estrogen exposure, methylation of tumor-suppressor genes, and cancer susceptibility. Environmental factors are capable of causing epigenetic changes in DNA that can potentially alter imprint gene expression and that can result in genetic diseases including cancer and behavioral disorders. Understanding the contribution of imprinting to the regulation of gene expression will be an important step in evaluating environmental influences on human health and disease

Maternal Genistein Alters Coat Color and Protects A(vy) Mouse Offspring from Obesity by Modifying the Fetal Epigenome

Genistein, the major phytoestrogen in soy, is linked to diminished female reproductive performance and to cancer chemoprevention and decreased adipose deposition. Dietary genistein may also play a role in the decreased incidence of cancer in Asians compared with Westerners, as well as increased cancer incidence in Asians immigrating to the United States. Here, we report that maternal dietary genistein supplementation of mice during gestation, at levels comparable with humans consuming high-soy diets, shifted the coat color of heterozygous viable yellow agouti (A(vy)/a) offspring toward pseudoagouti. This marked phenotypic change was significantly associated with increased methylation of six cytosine–guanine sites in a retrotransposon upstream of the transcription start site of the Agouti gene. The extent of this DNA methylation was similar in endodermal, mesodermal, and ectodermal tissues, indicating that genistein acts during early embryonic development. Moreover, this genistein-induced hypermethylation persisted into adulthood, decreasing ectopic Agouti expression and protecting offspring from obesity. Thus, we provide the first evidence that in utero dietary genistein affects gene expression and alters susceptibility to obesity in adulthood by permanently altering the epigenome

Paternal obesity is associated with IGF2 hypomethylation in newborns: results from a Newborn Epigenetics Study (NEST) cohort

Data from epidemiological and animal model studies suggest that nutrition during pregnancy may affect the health status of subsequent generations. These transgenerational effects are now being explained by disruptions at the level of the epigenetic machinery. Besides in vitro environmental exposures, the possible impact on the reprogramming of methylation profiles at imprinted genes at a much earlier time point, such as during spermatogenesis or oogenesis, has not previously been considered. In this study, our aim was to determine associations between preconceptional obesity and DNA methylation profiles in the offspring, particularly at the differentially methylated regions (DMRs) of the imprinted Insulin-like Growth Factor 2 (IGF2) gene

IGF2R polymorphisms and risk of esophageal and gastric adenocarcinomas

The mannose 6 phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R) encodes a protein that plays a critical role in tumor suppression, in part by modulating bioavailability of a potent mitogen, insulin-like growth factor-2 (IGF2). We tested the hypothesis that the common non-synonymous genetic variants in M6P/IGF2R c.901C>G (Leu>Val) in exon 6 and c.5002G>A (Gly>Arg) in exon 34 are associated with risk of esophageal and gastric cancers. Study participants in this population-based study comprise 197 controls and 182 cases, including 105 with esophageal-gastric cardia adenocarcinoma (EGA), 57 with non-cardia gastric adenocarcinoma and 20 with esophageal squamous cell carcinoma (ES). Among white males, odds ratios (ORs) were elevated in relation to carrying at least one c.901C>G allele for EGA (OR= 1.9; 95%CI=1.0–3.6) and non-cardia gastric cancer (OR=2.5; 95%CI=1.2–5.5), but not ES. Exploratory subgroup analyses suggested that associations between EGA and this variant were stronger among irregular or non-users of non-steroidal anti-inflammatory drugs (NSAIDs) (OR=2.3; 95%CI=1.2–4.2) and cigarette smokers (OR=2.1; 95%CI=1.0–4.2). An association between carrying the c.5002G>A genotype and EGA was not evident. These findings suggest that non-synonymous polymorphisms in M6P/IGF2R may contribute to the risks of EGA and non-cardia adenocarcinomas. Larger studies are required to confirm these findings

A Model for Transgenerational Imprinting Variation in Complex Traits

Despite the fact that genetic imprinting, i.e., differential expression of the same allele due to its different parental origins, plays a pivotal role in controlling complex traits or diseases, the origin, action and transmission mode of imprinted genes have still remained largely unexplored. We present a new strategy for studying these properties of genetic imprinting with a two-stage reciprocal F mating design, initiated with two contrasting inbred lines. This strategy maps quantitative trait loci that are imprinted (i.e., iQTLs) based on their segregation and transmission across different generations. By incorporating the allelic configuration of an iQTL genotype into a mixture model framework, this strategy provides a path to trace the parental origin of alleles from previous generations. The imprinting effects of iQTLs and their interactions with other traditionally defined genetic effects, expressed in different generations, are estimated and tested by implementing the EM algorithm. The strategy was used to map iQTLs responsible for survival time with four reciprocal F populations and test whether and how the detected iQTLs inherit their imprinting effects into the next generation. The new strategy will provide a tool for quantifying the role of imprinting effects in the creation and maintenance of phenotypic diversity and elucidating a comprehensive picture of the genetic architecture of complex traits and diseases

Association of cord blood methylation fractions at imprinted insulin-like growth factor 2 (IGF2), plasma IGF2, and birth weight

status: publishe