基因组印记与疾病研究进展

基因组印记是一种特别的非孟德尔遗传现象,即来自双亲的等位基因在子代中的差异性表达,是遗传后的基因调控方式,主要与基因组甲基化模式有关,包括去甲基化、重新甲基化及甲基化维持三个过程。印记基因主要通过对启动子、边界元件及非编码RNA的作用来调控基因表达。基因组印记异常与一些先天性疾病相关,也与肿瘤发生和易感性有关,     

Genomic imprinting and cancer

Although we inherit two copies of all genes, except those that reside on the sex chromosomes, there is a subset of these genes in which only the paternal or maternal copy is functional. This phenomenon of monoallelic, parent-of-origin expression of genes is termed genomic imprinting. Imprinted genes are normally involved in embryonic growth and behavioral development, but occasionally they also function inappropriately as oncogenes and tumor suppressor genes. The evidence that imprinted genes play a role in carcinogenesis will be discussed in this review. Additional information about imprinted genes can be found on the Genomic Imprinting Website at: (http://www.geneimprint.com).     

Genomic imprinting and the social brain

Genomic imprinting refers to the parent-of-origin-specific epigenetic marking of a number of genes. This epigenetic mark leads to a bias in expression between maternally and paternally inherited imprinted genes, that in some cases results in monoallelic expression from one parental allele. Genomic imprinting is often thought to have evolved as a consequence of the intragenomic conflict between the parental alleles that occurs whenever there is an asymmetry of relatedness. The two main examples of asymmetry of relatedness are when there is partiality of parental investment in offspring (as is the case for placental mammals, where there is also the possibility of extended postnatal care by one parent), and in social groups where there is a sex-biased dispersal. From this evolutionary starting point, it is predicted that, at the behavioural level, imprinted genes will influence what can broadly be termed bonding and social behaviour. We examine the animal and human literature for examples of imprinted genes mediating these behaviours, and divide them into two general classes. Firstly, mother-offspring interactions (suckling, attachment and maternal behaviours) that are predicted to occur when partiality in parental investment in early postnatal offspring occurs; and secondly, adult social interactions, when there is an asymmetry of relatedness in social groups. Finally, we return to the evolutionary theory and examine whether there is a pattern of behavioural functions mediated by imprinted genes emerging from the limited data, and also whether any tangible predictions can be made with regards to the direction of action of genes of maternal or paternal origin.     

Genomic imprinting in the placenta

Genomic imprinting is an epigenetic mechanism that is important for the development and function of the extra-embryonic tissues in the mouse. Remarkably all the autosomal genes which were found to be imprinted in the trophoblast (placenta) only are active on the maternal and repressed on the paternal allele. It was shown for several of these genes that their paternal silencing is not dependent on DNA methylation, at least not in its somatic maintenance. Rather, recent studies in the mouse suggest that placenta-specific imprinting involves repressive histone modifications and non-coding RNAs. This mechanism of autosomal imprinting is similar to imprinted X chromosome inactivation in the placenta. Although the underlying reasons remain to be explored, this suggests that imprinting in the placenta and imprinted X inactivation are evolutionarily related.     

Genomic imprinting and mammalian reproduction

Among animals, genomic imprinting is a uniquely mammalian phenomenon in which certain genes are monoallelically expressed according to their parent of origin. This silencing of certain alleles often involves differential methylation at regulatory regions associated with imprinted genes and must be recapitulated at every generation with the erasure and reapplication of these epigenetic marks in the germline. Imprinted genes encode regulatory proteins that play key roles in fetal growth and development, but they also exert wider effects on mammalian reproduction. Genetic knockout experiments have shown that certain paternally expressed imprinted genes regulate post-natal behavior in offspring as well as reproductive behaviors in males and females. These deficits involve changes in hypothalamic function affecting multiple areas and different neurochemical pathways. Paternally expressed genes are highly expressed in the hypothalamus which regulates growth, metabolism and reproduction and so are well placed to influence all aspects of reproduction from adults to the resultant offspring. Coadaptation between offspring and mother appears to have played an important role in the evolution of some paternally expressed genes, but the influence of these genes on male reproductive behavior also suggests that they have evolved to regulate their own transmission to successive generations via the male germline.     

Genomic imprinting and Beckwith-Wiedemann syndrome

Genomic imprinting is the parental-allele-specific expression of genes. Beckwith-Wiedemann syndrome (BWS), a congenital overgrowth syndrome with increased risk of childhood tumors, is one of the well-known diseases caused by imprinted genes. The imprinted genes causing BWS are discussed in this review.     

Genomic imprinting and human hereditary disorders

Modern data are reviewed that concern hereditary disorders caused by abnormal expression of imprinted genes rather than mutations and structural aberrations. As an example, the molecular organization of the critical chromosomal region 15(q11.2–q13) and the possible pathogenetic mechanisms are described in detail for Prader-Willi and Angelman syndromes.     

Genomic imprinting and epigenetic control of development

Epigenetic mechanisms are extensively utilized during mammalian development. Specific patterns of gene expression are established during cell fate decisions, maintained as differentiation progresses, and often augmented as more specialized cell types are required. Much of what is known about these mechanisms comes from the study of two distinct epigenetic phenomena: genomic imprinting and X-chromosome inactivation. In the case of genomic imprinting, alleles are expressed in a parent-of-origin-dependent manner, whereas X-chromosome inactivation in females requires that only one X chromosome is active in each somatic nucleus. As model systems for epigenetic regulation, genomic imprinting and X-chromosome inactivation have identified and elucidated the numerous regulatory mechanisms that function throughout the genome during development.     

Genomic imprinting of two antagonistic loci

We present a model that considers the coevolution of genomic imprinting at a growth factor locus and an antagonistic growth suppressor locus. With respect to the two loci considered independently, our model makes the familiar predictions that an imprinted growth factor locus will only be expressed from the paternally derived allele and an imprinted growth suppressor locus only from the maternally derived allele. In addition, our coevolutionary model allows us to make predictions regarding the sequence of evolutionary events necessary for generating such a system. We conclude that imprinting at the growth factor locus preceded the evolution of growth suppressor function at the second locus, which in turn preceded imprinting at that locus. We then discuss the consistency of these predictions with currently available comparative data on the insulin-like growth factor 2 insulin-like growth factor 2 receptor system of mammals.     

Genomic imprinting of chromatin inDrosophila melanogaster

During gametogenesis, chromosomes may become imprinted with information which facilitates proper expression of the DNA in offspring. We have used a position effect variegation mutant as a reporter system to investigate the possibility of imprinting inDrosophila melanogaster. Genetic crosses were performed in which the variegating gene and a strong modifier of variegation were present either within the same parental genome or in opposite parental genomes in all possible combinations. Our results indicate that the presence of the variegating chromosome and a modifier chromosome in the same parental genome can alter the amount of variegation formed in progeny. The genomic imprinting we observed is not determined by the parental origin of the variegating chromosome but is instead determined by the genetic background the variegating chromosome is subjected to during gametogenesis.     

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.