Convergent evolution of genomic imprinting in plants and mammals

Parental genomic imprinting is characterized by the expression of a selected panel of genes from one of the two parental alleles. Recent evidence shows that DNA methylation and histone modifications are responsible for this parent-of-origin-dependent expression of imprinted genes. Because similar epigenetic marks have been recruited independently in plants and mammals, the only organisms in which imprinted gene loci have been identified so far, this phenomenon represents a case for convergent evolution. Here we discuss the emerging parallels in imprinting in both taxa. We also describe the significance of imprinting for reproduction and discuss potential models for its evolution.     

Evolution, function, and regulation of genomic imprinting in plant seed development

Genomic imprinting is an epigenetic phenomenon whereby genetically identical alleles are differentially expressed dependent on their parent-of-origin. Genomic imprinting has independently evolved in flowering plants and mammals. In both organism classes, imprinting occurs in embryo-nourishing tissues, the placenta and the endosperm, respectively, and it has been proposed that imprinted genes regulate the transfer of nutrients to the developing progeny. Many imprinted genes are located in the vicinity of DNA-methylated transposon or repeat sequences, implying that transposon insertions are associated with the evolution of imprinted loci. The antagonistic action of DNA methylation and Polycomb group-mediated histone methylation seems important for the regulation of many imprinted plant genes, whereby the position of such epigenetic modifications can determine whether a gene will be mainly expressed from either the maternally or paternally inherited alleles. Furthermore, long non-coding RNAs seem to play an as yet underappreciated role for the regulation of imprinted plant genes. Imprinted expression of a number of genes is conserved between monocots and dicots, suggesting that long-term selection can maintain imprinted expression at some loci.     

Genome-wide survey of imprinted genes

The developmental failure of mammalian parthenogenote has been a mystery for a long time and posed a question as to why bi-parental reproduction is necessary for development to term. In the 1980s, it was proven that this failure was not due to the genetic information itself, but to epigenetic modification of genomic DNA. In the following decade, several studies successfully identified imprinted genes which were differentially expressed in a parent-of-origin-specific manner, and it was shown that the differential expression depended on the pattern of DNA methylation. These facts prompted development of genome-wide systematic screening methods based on DNA methylation and differential gene expression to identify imprinted genes. Recently computational approaches and microarray technology have been introduced to identify imprinted genes/loci, contributing to the expansion of our knowledge. However, it has been shown that the gene silencing derived from genomic imprinting is accomplished by several mechanisms in addition to direct DNA methylation, indicating that novel approaches are further required for comprehensive understanding of genomic imprinting. To unveil the mechanism of developmental failure in mammalian parthenogenote, systematic screenings for imprinted genes/loci have been developed. In this review, we describe genomic imprinting focusing on the history of genome-wide screening.     

Unique patterns of evolutionary conservation of imprinted genes

During mammalian evolution, complex systems of epigenetic gene regulation have been established: Epigenetic mechanisms control tissue-specific gene expression, X chromosome inactivation in females and genomic imprinting. Studying DNA sequence conservation in imprinted genes, it becomes evident that evolution of gene function and evolution of epigenetic gene regulation are tightly connected. Furthermore, comparative studies allow the identification of DNA sequence features that distinguish imprinted genes from biallelically expressed genes. Among these features are CpG islands, tandem repeats and retrotransposed elements that are known to play major roles in epigenetic gene regulation. Currently, more and more genetic and epigenetic data sets become available. In future, such data sets will provide the basis for more complex investigations on epigenetic variation in human populations. Therein, an exciting topic will be the genetic and epigenetic variability of imprinted genes and its input on human disease.     

Multilocus epimutations of imprintome in the pathology of human embryo development

Genomic imprinting is one of the key epigenetic phenomena involved in embryonic development of eutherians and humans. Molecular mechanisms of imprinting disturbances in the pathology of prenatal and postnatal onthogenesis are to a great extent related to methylation abnormalities of the imprinted genes. Over recent years, data are accumulating on multiple abnormalities of methylation simultaneously in several imprinted loci in the development of various pathologies that raises the issue of deciphering the structural and functional organization of imprintome and the interaction of imprinted genes. The present work analyzes DNA methylation of 51 imprinted genes in the placental tissues of human spontaneous abortions. We revealed multiple epimutations in from four to 12 imprinted genes in every embryo. Most of the epimutations (78%) were of a postzygotic origin. It has been established for the first time that the total incidence of methylation disturbance in maternal and paternal alleles of the imprinted genes leading to embryo development suppression is significantly higher than the incidence of epimutations, which stimulate embryogenesis. This fact supports at the epigenetic level the hypothesis of parent-offspring conflict that describes the occurrence of a monoallelic expression of imprinted genes in mammalian evolution.     

Comparative phylogenetic analysis of blcap/nnat reveals eutherian-specific imprinted gene

Imprinted genes are parent-of-origin dependent, monoallelically expressed genes present in marsupials and eutherian mammals. Altered expression of imprinted genes plays a significant role in the etiology of a variety of human disorders and diseases. Nevertheless, the regulatory mechanisms of imprinting remain poorly defined. The imprinted gene Neuronatin (Nnat) is an excellent candidate for studying imprinting because it resides within the 8.5-kb intron of the nonimprinted gene Bladder Cancer-Associated Protein (Blcap) and is the only imprinted gene within the region. A phylogenetic comparison of this micro-imprinted domain in human, mouse, and rat revealed several candidates for imprint control, including tandem repeats and putative binding sites for trans- acting factors known to be involved in chromatin remodeling. Genome-wide phylogenetic comparisons of species from the three major extant mammalian clades failed, however, to show any evidence of Nnat outside the eutherian lineage. Thus, Nnat is the first identified eutherian-specific imprinted gene, demonstrating that imprinted genes did not arise at a single point during evolution. This finding also suggests that the complexity of imprinting regulation observed at other loci may, in part, be directly related to the amount of time they have been imprinted.     

Genomic imprinting mechanisms in mammals

Genomic imprinting is a form of epigenetic gene regulation that results in expression from a single allele in a parent-of-origin-dependent manner. This form of monoallelic expression affects a small but growing number of genes and is essential to normal mammalian development. Despite extensive studies and some major breakthroughs regarding this intriguing phenomenon, we have not yet fully characterized the underlying molecular mechanisms of genomic imprinting. This is in part due to the complexity of the system in that the epigenetic markings required for proper imprinting must be established in the germline, maintained throughout development, and then erased before being re-established in the next generation's germline. Furthermore, imprinted gene expression is often tissue or stage-specific. It has also become clear that while imprinted loci across the genome seem to rely consistently on epigenetic markings of DNA methylation and/or histone modifications to discern parental alleles, the regulatory activities underlying these markings vary among loci. Here, we discuss different modes of imprinting regulation in mammals and how perturbations of these systems result in human disease. We focus on the mechanism of genomic imprinting mediated by insulators as is present at the H19/Igf2 locus, and by non-coding RNA present at the Igf2r and Kcnq1 loci. In addition to imprinting mechanisms at autosomal loci, what is known about imprinted X-chromosome inactivation and how it compares to autosomal imprinting is also discussed. Overall, this review summarizes many years of imprinting research, while pointing out exciting new discoveries that further elucidate the mechanism of genomic imprinting, and speculating on areas that require further investigation.     

Chromatin regulators of genomic imprinting

Genomic imprinting is an epigenetic phenomenon in which genes are expressed monoallelically in a parent-of-origin-specific manner. Each chromosome is imprinted with its parental identity. Here we will discuss the nature of this imprinting mark. DNA methylation has a well-established central role in imprinting, and the details of DNA methylation dynamics and the mechanisms that target it to imprinted loci are areas of active investigation. However, there is increasing evidence that DNA methylation is not solely responsible for imprinted expression. At the same time, there is growing appreciation for the contributions of post-translational histone modifications to the regulation of imprinting. The integration of our understanding of these two mechanisms is an important goal for the future of the imprinting field. This article is part of a Special Issue entitled: Chromatin and epigenetic regulation of animal development.     

Stability of genomic imprinting in embryonic stem cells: lessons from assisted reproductive technology

Imprinted genes are expressed predominantly or exclusively from one allele only. This mode of gene expression makes the regulation of imprinted genes susceptible to epigenetic insults, which may in turn lead to disease. There is compelling experimental evidence that certain aspects of assisted reproductive technology (ART) such as in vitro cell culture may have adverse effects on the regulation of epigenetic information in mammalian embryos, including the disruption of imprinted genes and epigenetic regulators. Moreover, in humans, disorders of genomic imprinting have been reported in children conceived by ART. The derivation and in vitro culture of embryonic stem (ES) cells are potential points of origin for epigenetic abnormalities. There is evidence that defects of genomic imprinting occur in mouse embryonic stem cells, with similar data now emerging in related studies in non-human primate and human ES cells. It is therefore pertinent to rigorously assess the epigenetic status of all stem cells and their derivatives prior to their therapeutic use in humans. Focusing on the stability of genomic imprinting, this review discusses the current evidence for epigenetic disruption in mammalian embryonic stem cells in light of the epigenetic disruption observed in ART-derived mammalian embryos.     

The regulation and biological significance of genomic imprinting in mammals

Genomic imprinting is a system of non-Mendelian inheritance that is unique to mammals. Two types of imprinted genes show parent-of-origin-specific expression patterns: the paternally expressed genes (Pegs), and the maternally expressed genes (Megs). Parental genomic imprinting memory is maintained in the somatic cell lineage and regulates the expression of Pegs and Megs, while it is erased and re-established in the germ cell lineage according to the sex of the individual. The paternal and maternal imprinting mechanisms, which regulate different sets of Pegs and Megs, are essential for establishing the parental expression profiles of imprinted genes that are observed in sperms and eggs. Based on recent evidence, we outline the relationship between parental imprinting and the expression profiles of Pegs and Megs and discuss a novel view of the regulation of genomic imprinting. We also discuss the biological significance of genomic imprinting and propose hypotheses on the essential nature of genomic imprinting and the close relationship between genomic imprinting and the acquisition of placental tissues during mammalian evolution.     

PHLDA2 is an imprinted gene in cattle

Genomic imprinting is an epigenetic non-Mendelian phenomenon found predominantly in placental mammals. Imprinted genes display differential expression in the offspring depending on whether the gene is maternally or paternally inherited. Currently, some 100 imprinted genes have been reported in mammals, and while some of these genes are imprinted across most mammalian species, others have been shown to be imprinted in only a few species. The PHLDA2 gene that codes for a pleckstrin homology-like domain, family A (member 2), protein has to date been shown to be a maternally expressed imprinted gene in humans, mice and pigs. Genes subject to imprinting can have major effects on mammalian growth, development and disease. For instance, disruption of imprinted genes can lead to aberrant growth syndromes in cloned domestic mammals, and it has been demonstrated that PHLDA2 mRNA expression levels are aberrant in the placenta of somatic clones of cattle. In this study, we demonstrate that PHLDA2 is expressed across a range of cattle foetal tissues and stages and provide the first evidence that PHLDA2 is a monoallelically expressed imprinted gene in cattle foetal tissues, and also in the bovine placenta.     

Genomic imprinting in mammals: its life cycle, molecular mechanisms and reprogramming

Genomic imprinting, an epigenetic gene-marking phenomenon that occurs in the germline, leads to parental-origin-specific expression of a small subset of genes in mammals. Imprinting has a great impact on normal mammalian development, fetal growth, metabolism and adult behavior. The epigenetic imprints regarding the parental origin are established during male and female gametogenesis, passed to the zygote through fertilization, maintained throughout development and adult life, and erased in primordial germ cells before the new imprints are set. In this review, we focus on the recent discoveries on the mechanisms involved in the reprogramming and maintenance of the imprints. We also discuss the epigenetic changes that occur at imprinted loci in induced pluripotent stem cells.     

Epimutations of imprinted genes in the human genome: Classification,causes, association with hereditary pathology

Genomic imprinting is an epigenetic phenomenon characterized by monoallelic expression of the genes depending on their parental origin. The molecular basis of this expression is covalent modifications of DNA and histones that are formed during maturation of germline cells. Abnormalities of the establishment of genomic imprinting during gametogenesis or its maintenance at various stages of development, caused by aberrant epigenetic modifications of the chromatin, predominantly disturbance of DNA methylation state, are a form of mutational variability of imprinted genomic loci. In this review, we consider the spectrum of epimutations of imprinted genes, present their classification, and discuss possible causes of their appearance and their role in etiology of hereditary human diseases.     

The origin and evolution of genomic imprinting and viviparity in mammals

Genomic imprinting is widespread in eutherian mammals. Marsupial mammals also have genomic imprinting, but in fewer loci. It has long been thought that genomic imprinting is somehow related to placentation and/or viviparity in mammals, although neither is restricted to mammals. Most imprinted genes are expressed in the placenta. There is no evidence for genomic imprinting in the egg-laying monotreme mammals, despite their short-lived placenta that transfers nutrients from mother to embryo. Post natal genomic imprinting also occurs, especially in the brain. However, little attention has been paid to the primary source of nutrition in the neonate in all mammals, the mammary gland. Differentially methylated regions (DMRs) play an important role as imprinting control centres in each imprinted region which usually comprises both paternally and maternally expressed genes (PEGs and MEGs). The DMR is established in the male or female germline (the gDMR). Comprehensive comparative genome studies demonstrated that two imprinted regions, PEG10 and IGF2-H19, are conserved in both marsupials and eutherians and that PEG10 and H19 DMRs emerged in the therian ancestor at least 160 Ma, indicating the ancestral origin of genomic imprinting during therian mammal evolution. Importantly, these regions are known to be deeply involved in placental and embryonic growth. It appears that most maternal gDMRs are always associated with imprinting in eutherian mammals, but emerged at differing times during mammalian evolution. Thus, genomic imprinting could evolve from a defence mechanism against transposable elements that depended on DNA methylation established in germ cells.     

A phylogenetic approach to test for evidence of parental conflict or gene duplications associated with protein-encoding imprinted orthologous genes in placental mammals

There are multiple theories on the evolution of genomic imprinting. We investigated whether the molecular evolution of true orthologs of known imprinted genes provides support for theories based on gene duplication or parental conflicts (where mediated by amino-acid changes). Our analysis of 34 orthologous genes demonstrates that the vast majority of mammalian imprinted genes have not undergone any subsequent significant gene duplication within placental species, suggesting that selection pressures against gene duplication events could be operating for imprinted loci. As antagonistic co-evolution between imprinted genes can regulate offspring growth, proteins mediating this interaction could be subject to rapid evolution via positive selection. Supporting this, we detect evidence of site specific positive selection for the imprinted genes OSBPL5 (and GNASXL), and detect lineage-specific positive selection for 14 imprinted genes where it is known that the gene is imprinted in a specific lineage, namely for: PLAGL1, IGF2, SLC22A18, OSBPL5, DCN, DLK1, RASGRF1, IGF2R, IMPACT, GRB10, NAPIL4, UBE3A, GATM and GABRG3. However, there is an overall lack of concordance between the known imprinting status of each gene (i.e. whether the gene is imprinted or biallelically expressed in a particular mammalian lineage) and positive selection. While only a small number of orthologs of imprinted loci display evidence of positive selection, we observe that the majority of orthologs of imprinted loci display high levels of micro-synteny conservation and have undergone very few cis- or trans-duplications in placental mammalian lineages.     

Parent-of-origin specific QTL--a possibility towards understanding reciprocal effects in chicken and the origin of imprinting

Reciprocal effects for sexual maturity, egg production, egg quality traits and viability are well known in poultry crosses. They have been used in an optimal way to form profitable production hybrids. These effects have been hypothesized to originate from sex-linked genes, maternal effects or a combination of both. However, these may not be the only explanations for reciprocal effects. Recent mapping of quantitative trait loci (QTL) has revealed autosomal areas with parent-of-origin specific effects in the chicken. In mammals, parental imprinting, i.e. the specifically regulated expression of either maternal or paternal allele in the offspring, is the main cause of such effects. The most commonly accepted hypothesis for the origin of imprinting, the conflict hypothesis, assumes a genetic conflict of interest between the maternal and paternal genomes regarding the allocation of resources to the offspring. It also intrinsically implies that imprinting should not occur in oviparous taxa. However, new molecular genetic information has raised a need to review the possible involvement of imprinting or some related phenomena as a putative cause of reciprocal effects in poultry. Comparative mapping provides strong evidence for the conservation of orthologous imprinted gene clusters on chicken macrochromosomes. Furthermore, these gene clusters exhibit asynchronous DNA replication, an epigenetic mark specific for all imprinted regions. It has been proposed that these intrinsic chromosomal properties have been important for the evolution of imprinted gene expression in the mammalian lineage. Many of the mapped parent-of-origin specific QTL effects in chicken locate in or close to these conserved regions that show some of the basic features involved in monoallelic expression. If monoallelic expression in these regions would be observed in birds, the actual mechanism and cause may be different from the imprinting that evolved later in the mammalian lineage. In this review we discuss recent molecular genetic results that may provide tools for understanding of reciprocal differences in poultry breeding and the evolution of imprinting.     

基因组印记研究进展

基因组印记是由于父源或母源的等位基因受到“标记”而发生的不符合孟德尔遗传定律的特殊遗传现象。父源或母源的等位基因通过某种特异的基因修饰机制,如DNA甲基化,非编码RNA的调节作用和组蛋白修饰等,抑制另一拷贝的表达。哺乳动物中的基因印记影响着其生长发育,正常印记模式的改变在临床上会引起许多疾病。文章总结了自印记现象被发现后二十几年来的研究进展,包括印记的发生机制、发生途径、进化方式和起源理论。目前对基因印记的了解还不完全,后基因组技术的发展也许能够促进对其分子机制的进一步揭示。     

Conserved features of imprinted differentially methylated domains

Genomic imprinting is a conserved epigenetic phenomenon in eutherian mammals, with regards both to the genes that are imprinted and the mechanism underlying the expression of just one of the parental alleles. Epigenetic modifications of alleles of imprinted genes are established during oogenesis and spermatogenesis, and these modifications are then inherited. Differentially methylated domains (DMDs) of imprinted genes are the genomic sites of these inherited epigenetic imprints. We previously showed that CpG-rich imperfect tandem direct repeats within three different mouse DMDs (Snurf/Snrpn, Kcnq1 and Igf2r), each with a unique sequence, play a central role in maintaining the differential methylation. This finding implicates repeat-related DNA structure, not sequence, in the imprinting mechanism. To better define the important features of this signal, we compared sequences of these three DMD tandem repeats among mammalian species. All DMD repeats contain short indirect repeats, many of which are organized into larger unit repeats. Even though the larger repeat units undergo deletion and addition during evolution (most likely through unequal crossovers during meiosis), the size of DMD tandem repeated regions has remained remarkably stable during mammalian evolution. Moreover, all three DMD tandem repeats have a high-CpG content, an ordered arrangement of CpG dinucleotides, and similar predicted secondary structures. These observations suggest that a structural feature or features of these DMD tandem repeats is the conserved DMD imprinting signal.