Genomic imprinting in fetal growth and development

Each somatic cell of the human body contains 46 chromosomes consisting of two sets of 23; one inherited from each parent. These chromosomes can be categorised as 22 pairs of autosomes and two sex chromosomes; females are XX and males are XY. Similarly, at the molecular level, two copies of each autosomal gene exist; one copy derived from each parent. Until the mid-1980s, it was assumed that each copy of an autosome or gene was functionally equivalent, irrespective of which parent it was derived from. However, it is now clear from classical experiments in mice and from examples of human genetic disease that this is not the case. The functional activity of some genes or chromosomal regions is unequal, and dependent on whether they have been inherited maternally or paternally. This phenomenon is termed 'genomic imprinting' and the activity or silence of an imprinted gene or chromosomal region is set during gametogenesis. Genomic imprinting involving the autosomes appears to be restricted to eutherian mammals, and has most likely evolved as a result of the conflicting concerns of the parental genomes in the growth and development of their offspring. When the normal pattern of imprinting is disrupted, the phenotypes observed in humans and mice are generally associated with abnormal fetal growth, development and behaviour, illustrating its importance for a normal intrauterine environment. The characteristics of imprinted genes, their regulation and the phenotypes associated with altered imprinting are discussed.     

Uniparentale Disomien

Uniparental disomy (UPD) describes a chromosome aberration with the inheritance of both homologues/both copies of a chromosomal segment (heterodisomy) or two copies of one homologue/one chromosomal segment originating from one parent only. Whole chromosome UPDs can be distinguished from segmental and complex UPDs. UPD-associated problems include trisomy mosaicism, homozygosity of autosomal recessively inherited mutations, father-child and mother-daughter transmission of X-chromosomally inherited mutations and genomic imprinting disorders. Genomic imprinting describes the parent of origin-dependent monoallelic expression of some genes. Well-known imprinting disorders include transient neonatal diabetes mellitus, Silver-Russell syndrome, Beckwith-Wiedemann syndrome, upd(14)mat (Temple syndrome), upd(14)pat, Prader-Willi syndrome, and Angelman syndrome. Mechanisms of UPD formation include trisomic and monosomic rescue, gamete complementation, and postfertilization error. Incidence and prevalence for any UPD are not known, but for some imprinting disorder-associated syndromes frequencies up to 1: 3400 have been calculated. The most frequently applied techniques in routine diagnosis are microsatellite marker analysis, methylation-sensitive polymerase chain reaction (PCR), and methylation-specific multiplex ligation-dependent probe amplification (MLPA).     

哺乳动物印记基因的研究进展

哺乳动物印记基因是指只表达亲本一方的遗传信息,而另一方处于关闭状态的一类基因。约80%的印记基因呈串出现在染色体上;在哺乳动物品种之间,印记基因具有较高的保守性;印记基因的复制通常表现为不同时性;一些印记基因具有印记遗传的时空性;少数印记基因只转录为mRNA而不翻译成蛋白质;印记基因的反意链通常表达,表达产生具有调节印记基因的作用。哺乳动物印记基因的调控序列的DNA甲基化、组蛋白乙酰酸化和组蛋白甲基化等引起其印记表达,其中DNA分子的甲基化是关键,它在生命周期中可被清除,也可被标记。印记基因之间的调控表达通常是相互作用的。克隆动物作为印记基因研究的实验动物模型,已获得许多有意义的研究结果。     

No Evidence for Enrichment in Schizophrenia for Common Allelic Associations at Imprinted Loci

Most genetic studies assume that the function of a genetic variant is independent of the parent from which it is inherited, but this is not always true. The best known example of parent-of-origin effects arises with respect to alleles at imprinted loci. In classical imprinting, characteristically, either the maternal or paternal copy is expressed, but not both. Only alleles present in one of the parental copies of the gene, the expressed copy, is likely to contribute to disease. It has been postulated that imprinting is important in central nervous system development, and that consequently, imprinted loci may be involved in schizophrenia. If this is true, allowing for parent-of-origin effects might be important in genetic studies of schizophrenia. Here, we use genome-wide association data from one of the world’s largest samples (N = 695) of parent schizophrenia-offspring trios to test for parent-of-origin effects. To maximise power, we restricted our analyses to test two main hypotheses. If imprinting plays a disproportionate role in schizophrenia susceptibility, we postulated a) that alleles showing robust evidence for association to schizophrenia from previous genome-wide association studies should be enriched for parent-of-origin effects and b) that genes at loci imprinted in humans or mice should be enriched both for genome-wide significant associations, and in our sample, for parent-of-origin effects. Neither prediction was supported in the present study. We have shown, that it is unlikely that parent-of-origin effects or imprinting play particularly important roles in schizophrenia, although our findings do not exclude such effects at specific loci nor do they exclude such effects among rare alleles.     

Segregation and Recombination of Non-Mendelian Genes in Chlamydomonas

Non-Mendelian genes in Chamydomonas reinhardtii are inherited in a uniparental (UP) fashion. Most zygotes and their progeny receive UP genes only from the mt(+) or maternal parent. However, a few exceptional zygotes are also found in which the mt(-) or paternal UP genome is transmitted. Most of the exceptional zygotes are biparental in that their progeny segregate UP genes transmitted by both parents. As a result, biparental zygotes have been extensively used to study the rules governing UP inheritance.The frequency of biparental zygotes can be greatly increased if the maternal parent is irradiated with ultraviolet light prior to mating. Based principally on studies with ultraviolet-induced biparental zygotes, Sager has argued that a vegetative cell contains two copies of the UP genome and that the progeny of a biparental zygote receive a copy derived from each parent. Results reported in this paper with spontaneous and ultraviolet-induced biparental zygotes do not support the two copy model, but argue for a mulitple copy model with most of the copies normally being transmitted by the maternal parent. A multiple copy model which accounts for both Sager's results and ours is presented.     

A case of segmental paternal isodisomy of chromosome 14

Uniparental disomy of chromosome 14 (UPD 14) results in one of two distinct abnormal phenotypes, depending upon the parent of origin. This discordance may result from the reciprocal over-expression and/or under-expression of one or more imprinted genes. We report a case of segmental paternal isodisomy for chromosome 14 with features similar to those reported in other paternal disomy 14 cases. Microsatellite marker analysis revealed an apparent somatic recombination event in 14q12 leading to proximal biparental inheritance, but segmental paternal uniparental isodisomy distal to this site. Analysis of monochromosomal somatic cell hybrids containing either the paternally inherited or the maternally inherited chromosome 14 revealed no deletion of the maternally inherited chromosome 14 and demonstrated the presence of paternal sequences from D14S121 to the telomere on both chromosomes 14. Thus, the patient has paternal isodisomy for 14q12-14qter. Because the patient shows most of the features associated with paternal disomy 14, this supports the presence of the imprinted domain(s) distal to 14q12 and suggests that the proximal region of chromosome 14 does not contain imprinted genes that contribute significantly to the paternal UPD 14 phenotype.     

Methylation changes of H19 gene in sperms of X-irradiated mouse and maintenance in offspring

The nature of imprinting is just differential methylation of imprinted genes. Unlike the non-imprinted genes, the methylation pattern of imprinted genes established during the period of gametogenesis remains unchangeable after fertilization and during embryo development. It implies that gametogenesis is the key stage for methylation pattern of imprinted genes. The imprinting interfered by exogenous factors during this stage could be inherited to offspring and cause genetic effect. Now many studies have proved that ionizing irradiation could disturb DNA methylation. Here we choose BALB/c mice as a research model and X-ray as interfering source to further clarify it. We discovered that the whole-body irradiation of X-ray to male BALB/c mice could influence the methylation pattern of H19 gene in sperms, which resulted in some cytosines of partial CpG islands in the imprinting control region could not transform to methylated cytosines. Furthermore, by copulating the interfered male mice with normal female, we analyzed the promoter methylation pattern of H19 in offspring fetal liver and compared the same to the pattern of male parent in sperms. We found that the majority of methylation changes in offspring liver were related to the ones in their parent sperms. Our data proved that the changes of the H19 gene methylation pattern interfered by X-ray irradiation could be transmitted and maintained in the first-generation offspring.     

WAMIDEX: A web atlas of murine genomic imprinting and differential expression

The mouse is an established model organism for the study of genomic imprinting. Mice with genetic material originating from only one parent (e.g., mice with uniparental chromosomal duplications) or gene mutations leading to epigenetic deficiencies have proven to be particularly useful tools. In the process of our studies we have accumulated a large set of expression microarray measurements in samples derived from these types of mice. Here, we present the collation of these and third-party microarray data that are relevant to genomic imprinting into a Web Atlas of Murine genomic Imprinting and Differential EXpression (WAMIDEX: https://atlas.genetics.kcl.ac.uk). WAMIDEX integrates the most comprehensive literature-derived catalog of murine imprinted genes to date with a genome browser that makes the microarray data immediately accessible in annotation-rich genomic context. In addition, WAMIDEX exemplifies the use of the self-organizing map method for the discovery of novel imprinted genes from microarray data. The parent-of-origin-specific expression of imprinted genes is frequently limited to specific tissues or developmental stages, a fact that the atlas reflects in its design and data content.     

Analysis of mouse conceptuses with uniparental duplication/deficiency for distal chromosome 12: comparison with chromosome 12 uniparental disomy and implications for genomic imprinting

Distal mouse chromosome 12 is imprinted. Phenotypic analysis of mouse embryos with maternal or paternal uniparental disomy for the whole of chromosome 12 has characterized the developmental defects associated with the altered dosage of imprinted genes on this chromosome. Here we conduct a characterization of maternal and paternal Dp(dist12) mice using the reciprocal translocation T(4;12)47H. This limits the region analysed to the chromosomal domain distal to the T47H breakpoint in B3 on mouse chromosome 12. Both MatDp(dist12)T47H and PatDp(dist12)T47H conceptuses are non-viable and the frequency of recovery of Dp(dist12) conceptuses by 10.5 days post coitum (dpc) was lower than expected after normal adjacent-1 disjunction. A subset of MatDp(dist12) embryos can survive up to one day post partum. In contrast to paternal uniparental disomy 12 embryos, no live PatDp (dist12) embryos were recovered after 16.5 days of gestation. Other phenotypes observed in maternal and paternal chromosome 12 uniparental disomy mice are recapitulated in the Dp(dist12) mice and include placental, muscle and skeletal defects. Additional defects were also noted in the skin of both MatDp(dist12) and maternal uniparental disomy 12 embryos. This study shows that the developmental abnormalities associated with the altered parent of origin for mouse chromosome 12 can be attributed to the genomic region distal to the T47H breakpoint.     

Genomic imprinting at the mammalian Dlk1-Dio3 domain

Genomic imprinting causes genes to be expressed or repressed depending on their parental origin. The majority of imprinted genes identified to date map in clusters and much of our knowledge of the mechanisms, function and evolution of imprinting have emerged from their analysis. The cluster of imprinted genes delineated by the delta-like homolog 1 gene and the type III iodothyronine deiodinase gene (Dlk1-Dio3) is located on distal mouse chromosome 12 and human chromosome 14. Its developmental importance is exemplified by severe phenotypes associated with altered dosage of these genes in mice and humans. The domain contains three imprinted protein-coding genes, Dlk1, Rtl1 and Dio3, expressed from the paternally inherited chromosome and several imprinted large and small noncoding RNA genes expressed from the maternally inherited homolog. Here, we discuss the function and regulation of imprinting at this domain.     

Genetic conflicts in genomic imprinting

The expression pattern of genes in mammals and plants can depend upon the parent from which the gene was inherited, evidence for a mechanism of parent-specific genomic imprinting. Kinship considerations are likely to be important in the natural selection of many such genes, because coefficients of relatedness will usually differ between maternally and paternally derived genes. Three classes of gene are likely to be involved in genomic imprinting: the imprinted genes themselves, trans-acting genes in the parents, which affect the application of the imprint, and trnas-acting genes in the offspring, which recognize and affect the expression of the imprint. We show that coefficients of relatedness will typically differ among these three classes, thus engendering conflicts of interest between Imprinter genes, imprinted genes, and imprint-recognition genes, with probable consequences for the evolution of the imprinting machinery.     

Prader-Willi-Syndrom und Angelman-Syndrom

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are two distinct neurogenetic disorders caused by the loss of function of imprinted genes in the chromosomal region 15q11q13. An approximately 2 Mb region inside 15q11q13 is subject to genomic imprinting. As a consequence the maternal and paternal copies in this region are different in DNA methylation and gene expression. The most frequent genetic lesions in both disorders are an interstitial de novo deletion of the chromosomal region 15q11q13, uniparental disomy 15, an imprinting defect or, in the case of AS, a mutation of the UBE3A gene. Microdeletions in a small number of patients with PWS and AS with an imprinting defect have led to the identification of the chromosome 15 imprinting centre (IC) upstream of the SNURF-SNRPN gene, which acts in cis to regulate imprinting in the whole 15q imprinted domain. The IC consists of two critical elements: one in the more centromeric part which is deleted in patients with AS and which is thought to be responsible for the establishment of imprinting in the female germ line, and one in the more telomeric part which is deleted in patients with PWS and which is required to maintain the paternal imprint.     

A Bayesian method for simultaneously detecting Mendelian and imprinted quantitative trait loci in experimental crosses of outbred species

Genomic imprinting is interpreted as a phenomenon, in which some genes inherited from one parent are not completely expressed due to modification of the genome caused during gametogenesis. Subsequently, the expression level of an allele at the imprinted gene is changed dependent on the parental origin, which is referred to as the parent-of-origin effect. In livestock, some QTL for reproductive performance and meat productivity have been reported to be imprinted. So far, methods detecting imprinted QTL have been proposed on the basis of interval mapping, where only a single QTL was tested at a time. In this study, we developed a Bayesian method for simultaneously mapping multiple QTL, allowing the inference about expression modes of QTL in an outbred F2 family. The inference about whether a QTL is Mendelian or imprinted was made using Markov chain Monte Carlo estimation by comparing the goodness-of-fits between models, assuming the presence and the absence of parent-of-origin effect at a QTL. We showed by the analyses of simulated data sets that the Bayesian method can effectively detect both Mendelian QTL and imprinted QTL.     

Genomic imprinting: male mice with uniparentally derived sex chromosomes

Although it has been known that there is an X-chromosome imprinting effect during early embryogenesis in female mammals, it remains unknown if parental origin of the X chromosome has an effect in males. Furthermore, it has not been possible to produce animals with normal sex chromosomes of uniparental origin to further evaluate such imprinting effects. We have devised a breeding scheme to produce male mice, designated XPYP males, in which both the X and Y chromosomes are paternally inherited. To our knowledge, these are the first mammals produced that have a normal sex chromosome constitution but with both sex chromosomes derived from one parent. Development and reproduction in these XPYP males and the sex ratio and chromosome constitution of their offspring appeared normal; thus there is no apparent effect in males of having both sex chromosomes derive from one parent or of having the X chromosome derived from an inappropriate parent. Although we have detected no X-chromosome imprinting effect in these males, evidence from other sources suggest that the X chromosome is parentally imprinted. Thus detection and definition of an imprint can depend on the assay used.     

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.     

A survey of tissue-specific genomic imprinting in mammals

In mammals, most somatic cells contain two copies of each autosomal gene, one inherited from each parent. When a gene is expressed, both parental alleles are usually transcribed. However, a subset of genes is subject to the epigenetic silencing of one of the parental copies by genomic imprinting. In this review, we explore the evidence for variability in genomic imprinting between different tissue and cell types. We also consider why the imprinting of particular genes may be restricted to, or lost in, specific tissues and discuss the potential for high-throughput sequencing technologies in facilitating the characterisation of tissue-specific imprinting and assaying the potentially functional variations in epigenetic marks.     

Differential regulation of imprinting in the murine embryo and placenta by the Dlk1-Dio3 imprinting control region

Genomic imprinting is an epigenetic mechanism controlling parental-origin-specific gene expression. Perturbing the parental origin of the distal portion of mouse chromosome 12 causes alterations in the dosage of imprinted genes resulting in embryonic lethality and developmental abnormalities of both embryo and placenta. A 1 Mb imprinted domain identified on distal chromosome 12 contains three paternally expressed protein-coding genes and multiple non-coding RNA genes, including snoRNAs and microRNAs, expressed from the maternally inherited chromosome. An intergenic, parental-origin-specific differentially methylated region, the IG-DMR, which is unmethylated on the maternally inherited chromosome, is necessary for the repression of the paternally expressed protein-coding genes and for activation of the maternally expressed non-coding RNAs: its absence causes the maternal chromosome to behave like the paternally inherited one. Here, we characterise the developmental consequences of this epigenotype switch and compare these with phenotypes associated with paternal uniparental disomy of mouse chromosome 12. The results show that the embryonic defects described for uniparental disomy embryos can be attributed to this one cluster of imprinted genes on distal chromosome 12 and that these defects alone, and not the mutant placenta, can cause prenatal lethality. In the placenta, the absence of the IG-DMR has no phenotypic consequence. Loss of repression of the protein-coding genes occurs but the non-coding RNAs are not repressed on the maternally inherited chromosome. This indicates that the mechanism of action of the IG-DMR is different in the embryo and the placenta and suggests that the epigenetic control of imprinting differs in these two lineages.     

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.