Genomic imprinting in diabetes.
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ABSTRACT:
SUBMITTER: Mitchell BD
PROVIDER: S-EPMC2945012 | biostudies-literature | 2010
REPOSITORIES: biostudies-literature
Publications
Genomic imprinting refers to a class of transmissible genetic effects in which the expression of the phenotype in the offspring depends on the parental origin of the transmitted allele. The DNA from one parent may be epigenetically modified so that only a single allele of the imprinted gene is expressed in the offspring. Although imprinting has an important role in the regulation of growth and development through its role in regulating gene expression, its contribution to susceptibility to commo ...[more]
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Project description:Imprinted genes represent a curious defiance of normal Mendelian genetics. Mammals inherit two complete sets of chromosomes, one from the mother and one from the father, and most autosomal genes will be expressed from both the maternal and the paternal alleles. Imprinted genes, however, are expressed from only one chromosome, in a parent-of-origin-dependent manner. Because silent and active promoters are present in a single nucleus, the differences in activity cannot be explained by transcription-factor abundance. Thus, transcription of imprinted genes represents a clear situation in which epigenetic mechanisms restrict gene expression and, therefore, offers a model for understanding the role of DNA modifications and chromatin structure in maintaining appropriate patterns of expression. Furthermore, because of their parent-of-origin-restricted expression, phenotypes determined by imprinted genes are susceptible not only to genetic alterations in the genes but also to disruptions in the epigenetic programs controlling regulation. Imprinted genes are often associated with human diseases, including disorders affecting cell growth, development, and behavior.
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Project description:Imprinted genes are peculiar in that expression of the two copies differs depending on whether the copy was maternally or paternally inherited. The discovery of this striking pattern of gene expression inspired myriad evolutionary theories, the most successful of which identify scenarios that create an asymmetry between the maternally and paternally inherited gene copies that favors silencing of one of the copies. Most notably, imprinting can evolve when gene dosage affects kin interactions (typically involving conflict) or when silencing enhances coadaptation by coordinating traits expressed by interacting kin. Although we have a well-established theory for the former process (the "Kinship Theory"), the coadaptation process has only been explored for the specific case of interactions between mothers and offspring. Here, we fill this critical gap in our understanding by developing a general "Coadaptation Theory" that explains how imprinting can evolve to coordinate interactions between all types of relatives. Using a simple model in which fitness of an individual is determined by an interaction between its own phenotype (and hence genotype) and that of its social partner(s), we find that when the relatedness of interactants differs through their maternally versus paternally inherited gene copies, then selection favors expression of the allele through which relatedness is higher. The predictions of this Coadaptation Theory potentially apply whenever a gene underlies traits that mediate the outcome of conspecific interactions, regardless of their mechanism or the type of organism, and therefore provide a potential explanation for enigmatic patterns of imprinting, including those underlying adult traits. By providing simple testable predictions that often directly contrast with those derived from alternative theories, our model should play an important role in consolidating our understanding of the evolution of imprinting across genes and species, which will ultimately provide crucial insights into imprinted gene function and dysfunction.
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Project description:BackgroundGenomic imprinting (GI) is a mammalian-specific epigenetic phenomenon that has been implicated in the evolution of the placenta in mammals.MethodsEmbryo transfer procedures and trophoblast stem (TS) cells were used to re-examine mouse placenta-specific GI genes. For the analysis of human GI genes, cytotrophoblast cells isolated from human placental tissues were used. Using human TS cells, the biological roles of human GI genes were examined.Main findings(1) Many previously identified mouse GI genes were likely to be falsely identified due to contaminating maternal cells. (2) Human placenta-specific GI genes were comprehensively determined, highlighting incomplete erasure of germline DNA methylation in the human placenta. (3) Human TS cells retained normal GI patterns. (4) Complete hydatidiform mole-derived TS cells were characterized by aberrant GI and enhanced trophoblastic proliferation. The maternally expressed imprinted gene p57KIP2 may be responsible for the enhanced proliferation. (5) The primate-specific microRNA cluster on chromosome 19, which is a placenta-specific GI gene, is essential for self-renewal and differentiation of human TS cells.ConclusionGenomic imprinting plays diverse and important roles in human placentation. Experimental analyses using TS cells suggest that the GI maintenance is necessary for normal placental development in humans.
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Project description:Genomic imprinting refers to an epigenetic marking of genes that results in monoallelic expression. This parent-of-origin dependent phenomenon is a notable exception to the laws of Mendelian genetics. Imprinted genes are intricately involved in fetal and behavioral development. Consequently, abnormal expression of these genes results in numerous human genetic disorders including carcinogenesis. This paper reviews genomic imprinting and its role in human disease. Additional information about imprinted genes can be found on the Genomic Imprinting Website at http://www.geneimprint.com.
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Project description:Genomic imprinting shapes the genotype-phenotype relationship by creating an asymmetry between the influences of paternally and maternally inherited gene copies. Consequently, imprinting can impact heritable and nonheritable variation, resemblance of relatives, and evolutionary dynamics. Although previous analyses have identified some of the quantitative genetic consequences of imprinting, we lack a framework that cleanly separates the influence of imprinting from other components of variation, particularly dominance. Here we apply a simple orthogonal genetic model to evaluate the roles of genetic (additive and dominance) and epigenetic (imprinting) effects. Imprinting increases the resemblance of relatives who share the expressed allele, and therefore increases variance among families of full or half-siblings. However, only part of this increased variance is heritable and contributes to selection responses. When selection is within, or among, families sharing only a single parent (half-siblings), which is common in selective breeding programs, imprinting can alter overall responses. Selection is more efficient when it acts among families sharing the expressed parent, or within families sharing the parent with lower expression. Imprinting also affects responses to sex-specific selection. When selection is on the sex whose gene copy has lower expression, the response is diminished or delayed the next generation, although the long-term response is unaffected. Our findings have significant implications for understanding patterns of variation, interpretation of short-term selection responses, and the efficacy of selective breeding programs, demonstrating the importance of considering the independent influence of genomic imprinting in quantitative genetics.
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Project description:Purpose of reviewGenomic imprinting refers to preferential allele-specific gene expression. DNA methylation-based molecular mechanisms regulate establishment and maintenance of parental imprints during early embryo development and gametogenesis. Because of the coincident timing, a potential association between assisted reproductive technology (ART) procedures and imprinting defects has been investigated in various studies. In this review, we provide an overview of genomic imprinting and present a summary of the relevant clinical data.Recent findingsART procedures affect DNA methylation pattern, parental imprinting status, and imprinted gene expression in the mouse embryo. In humans, several case series suggested an association between ART and imprinting disorders, with a three-fold to six-fold higher prevalence of ART use among children born with Beckwith-Wiedemann syndrome compared to the general population. However, more recent studies failed to support these findings and could not demonstrate an association between imprinting disorders and ARTs, independent of subfertility.SummaryART procedures may affect methylation status of imprinted regions in the DNA, leading to imprinting disorders. Although the low prevalence of imprinting disorders makes it challenging to perform conclusive clinical trials, further studies in large registries are required to determine the real impact of ARTs on their occurrence.
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Project description:Mammals inherit two complete sets of chromosomes, one from the father and one from the mother, and most autosomal genes are expressed from both maternal and paternal alleles. Imprinted genes show expression from only one member of the gene pair (allele) and their expression are determined by the parent during production of the gametes. Imprinted genes represent only a small subset of mammalian genes that are present but not imprinted in other vertebrates. Genomic imprints are erased in both germlines and reset accordingly; thus, reversible depending on the parent of origin and leads to differential expression in the course of development. Genomic imprinting has been studied in humans since the early 1980's and accounts for several human disorders. The first report in humans occurred in Prader-Willi syndrome due to a paternal deletion of chromosome 15 or uniparental disomy 15 (both chromosome 15s from only one parent) and similar genetic disturbances were reported later in Angelman syndrome.
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Project description:Numerous evolutionary theories have been developed to explain the epigenetic phenomenon of genomic imprinting. Here, we explore a subset of theories wherein non-additive genetic interactions can favour imprinting. In the simplest genic interaction--the case of underdominance--imprinting can be favoured to hide effectively low-fitness heterozygous genotypes; however, as there is no asymmetry between maternally and paternally inherited alleles in this model, other means of enforcing monoallelic expression may be more plausible evolutionary outcomes than genomic imprinting. By contrast, more successful interaction models of imprinting rely on an asymmetry between the maternally and paternally inherited alleles at a locus that favours the silencing of one allele as a means of coordinating the expression of high-fitness allelic combinations. For example, with interactions between autosomal loci, imprinting functionally preserves high-fitness genotypes that were favoured by selection in the previous generation. In this scenario, once a focal locus becomes imprinted, selection at interacting loci favours a matching imprint. Uniparental transmission generates similar asymmetries for sex chromosomes and cytoplasmic factors interacting with autosomal loci, with selection favouring the expression of either maternal or paternally derived autosomal alleles depending on the pattern of transmission of the uniparentally inherited factor. In a final class of models, asymmetries arise when genes expressed in offspring interact with genes expressed in one of its parents. Under such a scenario, a locus evolves to have imprinted expression in offspring to coordinate the interaction with its parent's genome. We illustrate these models and explore key links and differences using a unified framework.
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