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Host defenses to transposable elements and the evolution of genomic imprinting.
Genomic imprinting is the differential expression of maternally and paternally inherited alleles of specific genes. Several organismic level hypotheses have been offered to explain the evolution of genomic imprinting. We argue that evolutionary explanations of the origin of imprinting that focus exclusively on the organismic level are incomplete. We propose that the complex molecular mechanisms that underlie genomic imprinting originally evolved as an adaptive response to the mutagenic potential of transposable elements (TEs). We also present a model of how these mechanisms may have been co-opted by natural selection to evolve molecular features characteristic of genomic imprinting.
Intralocus sexual conflict can drive the evolution of genomic imprinting.
Genomic imprinting is a phenomenon whereby the expression of an allele differs depending upon its parent of origin. There is an increasing number of examples of this form of epigenetic inheritance across a wide range of taxa, and imprinting errors have also been implicated in several human diseases. Various hypotheses have been put forward to explain the evolution of genomic imprinting, but there is not yet a widely accepted general hypothesis for the variety of imprinting patterns observed. Here a new evolutionary hypothesis, based on intralocus sexual conflict, is proposed. This hypothesis provides a potential explanation for much of the currently available empirical data, and it also makes new predictions about patterns of genomic imprinting that are expected to evolve but that have not, as of yet, been looked for in nature. This theory also provides a potential mechanism for the resolution of intralocus sexual conflict in sexually selected traits and a novel pathway for the evolution of sexual dimorphism.
Igf2r and Igf2 gene expression in androgenetic, gynogenetic, and parthenogenetic preimplantation mouse embryos: absence of regulation by genomic imprinting.
Genomic imprinting in mammals is believed to result from modifications to chromosomes during gametogenesis that inactivate the paternal or maternal allele. The genes encoding the insulin-like growth factor type 2 (Igf2) and its receptor (Igf2r) are reciprocally imprinted and expressed from the paternal and maternal genomes, respectively, in the fetal and adult mouse. We find that both genes are expressed in androgenetic, gynogenetic, and parthenogenetic preimplantation mouse embryos. These results indicate that inactivation of imprinted genes occurs postfertilization (most likely postimplantation) and that genomic imprinting and gene inactivation are separate processes. We propose that imprinting marks the chromosome so that regulatory factors expressed in cells at later times can recognize the imprint and selectively inactivate the maternal or paternal allele. For these genes, this finding invalidates models of genomic imprinting that require them to be inactive from the time of fertilization.
Methylated DNA sequences in genomic imprinting.
Genomic imprinting is a special form of epigenetic system that determines the parent-of-origin-specific, or monoallelic, expression of a small number of genes, termed "imprinted" genes. Considerable sequence and methylation analysis of imprinted genes has revealed a common theme: Regions of allele-specific methylation inherited from the gametes, or primary differentially methylated regions (DMRs), are associated with CpG islands and repeat elements, and this overall structure suggests functional significance. For at least three imprinted genes the sequence of the primary DMR constitutes an element able to regulate gene activity in cis--a chromatin insulator and a promoter of an antisense transcript. In these cases the unique feature of imprinting appears to be in the ability to switch the regulatory capacity of these elements on or off by the absence or presence of inherited methylation. Increasing evidence therefore suggests that genomic imprinting for at least some genes constitutes the regulation of gene regulatory elements by methylation. An important challenge now is to determine how the differential methylation of primary DMR sequences is established in the germ line. If methylation is the primary imprint, then the processes establishing it are the primary imprinting mechanisms. Trans-acting factors that are expressed in one sex of germ line and not the other are likely to be involved, and their ability to methylate may be mediated through repeat elements associated with the sequence of primary DMRs.
[Syndromes with manifestations of genomic imprinting].
Genomic imprinting is one of epigenetic factors, which influences expression of genes. It represents specific marking of some chromosome segments depending on the parental origin of the mutation. Imprinted genes are for some time inactive; such period varies in different developmental stage and in different tissues. Such inactivation is manifested as expriming genes and represents an exception to the 3rd Mendel's rule. In the last 10 years, a large group of disorders was recognised, the clinical manifestation of which depends on the parental origin of the mutation, such as Albright's hereditary osteodystrophy, progressive osseous hyperplasia. Curschmann-Steinert myotonic dystrophy, Huntington disease, Beckwith-Wiedemann EMG syndrome, Silver-Russell syndrome, Angelman syndrome, Prader-Willi syndrome. Genomic imprinting contributes to the clarification of mechanisms of the variable expressivity, incomplete penetration, generation anticipation etc.
Competitive signal discrimination, methylation reprogramming and genomic imprinting.
Genomic imprinting (parent-of-origin-dependent gene regulation) is associated with intra-genomic evolutionary conflict over the optimal pattern of gene expression. Most theoretical models of imprinting focus on the conflict between the maternally and paternally derived alleles at an imprinted locus. Recently, however, more attention has been focused on multi-directional conflicts involving not only the imprinted gene itself, but also the genes that encode the regulatory machinery responsible for establishing and maintaining imprinted gene expression. In this paper, I examine the conflict involved in epigenetic reprogramming of imprinted genes in early mammalian embryonic development. In the earliest phase of development, maternal-store proteins are responsible for most regulatory activity in the embryo. These proteins are under selection to maximize the mother's inclusive fitness, which is not identical to that of either of the sets of genes present in the embryo. Both the maternally and paternally derived genomes in the embryo favor maintenance of the epigenetic modifications established in the female and male germlines, respectively. Maternal-store proteins favor maintenance of some of these modifications, but erasure of others. Here I consider the logical structure of the machinery responsible for these two activities. Methylation maintenance is most effectively performed by AND-linked architectures, which may explain the unusual trafficking behavior of the oocyte-specific DNA methyltransferase, Dnmt1o. By contrast, demethylation is better supported by OR-linked architectures, which may explain the difficulty in identifying the factor(s) responsible for the active demethylation of the paternal genome following fertilization.
Genomic imprinting.
Genomic imprinting is the modification of gene expression depending on whether the genetic material is inherited from the mother or the father. The article reviews the concept and its implications in various human disorders such as the chromosomal deletion syndromes, human cancers, endocrine disorders, and various other diseases which show parent-of-origin effects.
[Epigenetics and development: genomic imprinting].
Genomic imprinting leads to parent-of-origin-specific monoallelic expression of about 60 known genes in the mammalian genome. It was discovered 20 years ago and the aim of this review is to summarize its main characteristics. The nature of the imprint, still unknown, is characterized by differential chromatin structure and DNA methylation. The imprint is reset at each generation during gametogenesis, which can be observed by demethylation in the PGCs, then gamete-specific remethylation. The imprinted genes are usually located in clusters and regulated by cis sequences such as imprinting centres, trans factors such as the insulator protein CTCF and/or large non coding antisense RNAs. Genetic and epigenetic abnormalities of the imprinted clusters can lead to human diseases such as Prader-Willi, Angelman or Beckwith-Wiedemann syndromes.
Impact of genomic imprinting on genomic instability and radiation-induced mutation.
PURPOSE: The purpose of this review is to assess the effect of radiation-induced mutation on genes subject to genomic imprinting, and the consequences of this on the understanding of genomic instability. Genomic imprinting is the phenomenon in which one of the two alleles of a gene is expressed or suppressed depending on the gamete from which it was inherited, thus effectively rendering a cell hemizygous for the expression of certain key genes. The consequence of this is that such loci are potentially more likely targets for mutagenesis since one allele is normally inactive. This is not only important in the recognition of a subgroup of target genes for radiation-induced damage, but also raises the possibility of mutations affecting the epigenotype of key tumour suppressor or tumour promoting genes. Such mutations may in principle affect the stability of imprinting and may fall into a novel class of 'epimutation', where the DNA sequence is not affected, but post-transcriptional mechanisms of epigenotype maintenance are stably altered. These novel mechanisms are discussed in relation with radiation-induced genomic instability and the heritability of tumour predisposition from radiation-exposed parents. CONCLUSIONS: As yet there is only circumstantial evidence that the targets for radiation-induced DNA and epigenetic damage are imprinted genes, or genes involved in the maintenance of the epigenotype. However, the potential consequences of such genes being important targets for the generation of genomic instability or other forms of damage are serious and could affect the interpretation of the risks of low dose radiation exposure and of epidemiological data.
Imprinting the genome: imprinted genes, imprinting genes, and a hypothesis for their interaction.
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The novel gene, gamma2-COP (COPG2), in the 7q32 imprinted domain escapes genomic imprinting.
The gene MEST (or PEG1) on chromosome 7q32 is paternally expressed in human fetal tissues as a result of genomic imprinting. Since some imprinted genes are clustered, we speculated that an imprinted gene cluster might exist at 7q32. We have sought to isolate additional human genes close to MEST and to characterize their allelic expression patterns. Here, we report the biallelic expression of the gene, gamma2-COP (coatomer protein complex, subunit gamma 2, HUGO-approved symbol COPG2), and monoallelic expression of the transcript, CIT1, which is located in intron 20 of gamma2-COP. Recently, gamma2-COP was reported to be a novel imprinted gene that overlaps the 3'-untranslated region (3'-UTR) of MEST in a tail-to-tail orientation. However, our results revealed biallelic expression in all fetal tissues and adult blood lymphocytes. On the other hand, CIT1 was an antisense transcript of gamma2-COP intron 20 and was expressed from the paternal allele in all fetal tissues examined. Adult blood lymphocytes showed biallelic expression. We identified additional MEST 3'-UTR sequence, which overlaps the last four exons and introns of gamma2-COP. This additional MEST 3'-UTR may complicate analysis of gamma2-COP imprinting. Our data indicate that the region containing MEST at 7q32 is an imprinted domain, but gamma2-COP adjacent to MEST escapes genomic imprinting.
The evolution of X-linked genomic imprinting.
We develop a quantitative genetic model to investigate the evolution of X-imprinting. The model compares two forces that select for X-imprinting: genomic conflict caused by polygamy and sex-specific selection. Genomic conflict can only explain small reductions in maternal X gene expression and cannot explain silencing of the maternal X. In contrast, sex-specific selection can cause extreme differences in gene expression, in either direction (lowered maternal or paternal gene expression), even to the point of gene silencing of either the maternal or paternal copy. These conclusions assume that the Y chromosome lacks genetic activity. The presence of an active Y homologue makes imprinting resemble the autosomal pattern, with active paternal alleles (X- and Y-linked) and silenced maternal alleles. This outcome is likely to be restricted as Y-linked alleles are subject to the accumulation of deleterious mutations. Experimental evidence concerning X-imprinting in mouse and human is interpreted in the light of these predictions and is shown to be far more easily explained by sex-specific selection.
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.
Genomic imprinting and reproduction.
Genomic imprinting is the parent-of-origin specific gene expression which is a vital mechanism through both development and adult life. One of the key elements of the imprinting mechanism is DNA methylation, controlled by DNA methyltransferase enzymes. Germ cells undergo reprogramming to ensure that sex-specific genomic imprinting is initiated, thus allowing normal embryo development to progress after fertilisation. In some cases, errors in genomic imprinting are embryo lethal while in others they lead to developmental disorders and disease. Recent studies have suggested a link between the use of assisted reproductive techniques and an increase in normally rare imprinting disorders. A greater understanding of the mechanisms of genomic imprinting and the factors that influence them are important in assessing the safety of these techniques.
Two novel genes in the center of the 11p15 imprinted domain escape genomic imprinting.
We previously reported the isolation of a 2.5 Mb tumor-suppressing subchromosomal transferable fragment (STF) from human chromosome 11p15 and the identification of nine known genes and four novel genes within this STF. We now report the isolation of two novel cDNAs, designated here as TSSC4 and TSSC6 (tumor-suppressing STF cDNA 4 and 6), located within the STF. TSSC4 and TSSC6 encode predicted proteins of 329 and 290 amino acids, respectively, with no close similarity to previously reported proteins. TSSC4 and TSSC6 are both located in the center of a 1 Mb imprinted domain, which contains the imprinted genes TSSC3, TSSC5, p57(KIP2), KVLQT1, ASCL2, IGF2 and H19. However, we found that neither TSSC4 nor TSSC6 was significantly imprinted in any of the fetal or extra-embryonic tissues examined. Based on this result, the imprinted gene domain of 11p15 appears to contain at least two imprinted subdomains, between which TSSC4 and TSSC6 substantially escape imprinting, due either to lack of initial silencing or to an early developmental relaxation of imprinting.
Atp10a, the mouse ortholog of the human imprinted ATP10A gene, escapes genomic imprinting.
The mouse Atp10a gene is located at the border of an imprinted domain distal to the p-locus on mouse chromosome 7. The localization of Atp10a neighboring the maternally expressed gene Ube3a in the imprinted domain and an unusual inheritance pattern of the obesity phenotype with a p-locus deletion have suggested that Atp10a might be imprinted and associated with body fat. Recently, its human ortholog, ATP10A, was identified as the second imprinted gene with maternal expression in the human chromosome 15q11-q13 imprinted domain. To elucidate the imprinting status of Atp10a, we performed expression analysis in various tissues from reciprocal crosses between C57BL/6 and PWK (divergent strains of Mus musculus) mice. The results revealed that Atp10a was biallelically expressed in all tissues examined. Furthermore, there was no differential methylation in the CpG island and no antisense transcripts of the gene. These findings suggest that the mouse Atp10a gene escapes genomic imprinting.
The gene TSGA14, adjacent to the imprinted gene MEST, escapes genomic imprinting.
We identified the gene TSGA14, encoding the testis-specific protein A14 and located 50 kb proximal to the imprinted gene MEST in a head-to-head orientation. TSGA14 has at least two transcripts: a long-type (l-type) transcript, and a short-type (s-type) transcript. Since the COPG2IT1 gene in the vicinity of MEST has been reported to be imprinted, we presumed that TSGA14 might also be imprinted. We thus analyzed the imprinting status of TSGA14 l-type and s-type transcripts in various fetal tissues. TSGA14 l-type transcript, which consists of 11 exons and encodes a l-type isoform with 373 amino acids, is biallelically expressed in the fetal tissues including the testis. TSGA14 s-type transcript, which consists of three exons and encodes a s-type isoform with 54 amino acids, also showed biallelic expression in the fetal brain and liver. No allele-specific methylation in the TSGA14 CpG island was detected. The fact that COPG2 and TSGA14, both neighbors of MEST, escape genomic imprinting suggests that the 7q32 imprinted region may be small and not similar to other imprinted domains, such as those at 15q11-13 and 11p15.5.