A MODEL FOR GENOMIC IMPRINTING IN THE SOCIAL BRAIN: ADULTS

Genomic imprinting refers to genes that are silenced when inherited via sperm or via egg. The silencing of genes conditional upon their parental origin requires an evolutionary explanation. The most widely accepted theory for the evolution of genomic imprinting—the kinship theory—argues that conflict between maternally inherited and paternally inherited genes over phenotypes with asymmetric effects on matrilineal and patrilineal kin results in self‐imposed silencing of one of the copies. This theory has been applied to imprinting of genes expressed in the placenta, and infant brain determining the allocation of parental resources being the source of conflict parental promiscuity. However, there is growing evidence that imprinted genes are expressed in the postinfant brain where parental promiscuity per se is no longer a source of conflict. Here, we advance the kinship theory by developing an evolutionary model of genomic imprinting in adults, driven by intragenomic conflict over allocation to parental versus communal care. We consider the role of sex differences in dispersal and variance in reproductive success as sources of conflict. We predict that, in hominids and birds, parental care will be expressed by maternally inherited genes. In nonhominid mammals, we predict more diversity, with some mammals showing the same pattern and other showing the reverse. We use the model to interpret experimental data on imprinted genes in the house mouse: specifically, paternally expressed Peg1 and Peg3 genes, underlying maternal care, and maternally expressed Gnas and paternally expressed Gnasxl genes, underlying communal care. We also use the model to relate ancestral demography to contemporary imprinting disorders of adults, in humans and other taxa.     

A model for genomic imprinting in the social brain: elders

Genomic imprinting refers to the process whereby genes are silenced when inherited via sperm or egg. The most widely accepted theory for the evolution of genomic imprinting-the kinship theory-argues that conflict between maternally inherited and paternally inherited genes over phenotypes with asymmetric effects on matrilineal and patrilineal kin results in self-imposed silencing of one of the copies. This theory was originally developed in the context of fitness interactions within nuclear families, to understand intragenomic conflict in the embryo and infant, but it has recently been extended to encompass interactions within wider social groups, to understand intragenomic conflict over the social behavior of juveniles and adults. Here, we complete our model of genomic imprinting in the social brain by considering age-specific levels of expression in a society were generations overlap, to determine how intragenomic conflict plays out in older age. We determine the role of sex bias in juvenile dispersal, reproductive success, and adult mortality in mediating the direction and intensity of conflict over the competing demands of parental and communal care as the individual ages. We discover that sex-specific asymmetries in these demographic parameters result in intragenomic conflict at early age but this conflict gradually decays with age. Although individuals are riven by internal conflict in their youth and middle age, they put their demons to rest in later life.     

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.     

Do social insects support Haig's kin theory for the evolution of genomic imprinting?

Although numerous imprinted genes have been described in several lineages, the phenomenon of genomic imprinting presents a peculiar evolutionary problem. Several hypotheses have been proposed to explain gene imprinting, the most supported being Haig's kinship theory. This theory explains the observed pattern of imprinting and the resulting phenotypes as a competition for resources between related individuals, but despite its relevance it has not been independently tested. Haig's theory predicts that gene imprinting should be present in eusocial insects in many social scenarios. These lineages are therefore ideal for testing both the theory's predictions and the mechanism of gene imprinting. Here we review the behavioral evidence of genomic imprinting in eusocial insects, the evidence of a mechanism for genomic imprinting and finally we evaluate recent results showing parent of origin allele specific expression in honeybees in the light of Haig's theory.     

Intragenomic conflict over queen determination favours genomic imprinting in eusocial Hymenoptera

Colonies of eusocial Hymenoptera, such as ants, bees and wasps, have long been recognized as candidates for the study of genomic imprinting on the grounds of evolutionary conflicts that arise from close interactions among colony members and relatedness asymmetry owing to haplodiploidy. Although a general kinship theory of genomic imprinting predicts its occurrence under various circumstances of the colony life cycle, new theoretical approaches are required to account for the specifics of real colonies based on recent advances in molecular-level understanding of ants and honeybees. Using a multivariate quantitative genetic model, we examined the potential impact of genomic imprinting on genes that determine the carrier female's propensity to develop into the queen caste. When queen overproduction owing to the increased propensity comes at a colony-level cost, the conflict between maternally and paternally inherited genes in polyandrous (queen multiple mating) colonies favours genomic imprinting. Moreover, we show that the genomic imprinting can occur even under monandry (queen single mating), once incorporating the costs differentially experienced by new males and new queens. Our model predicts the existence of imprinted 'genetic royal cheats' with patriline-specific expression in polyandrous colonies, and seems consistent with the paternal effect on queen determination in monandrous Argentine ants.     

Complementation hypothesis: the necessity of a monoallelic gene expression mechanism in mammalian development

Gene expression from both parental alleles (biallelic expression) is beneficial in minimizing the occurrence of recessive genetic disorders in diploid organisms. However, imprinted genes in mammals display parent of origin-specific monoallelic expression. As some imprinted genes play essential roles in mammalian development, the reason why mammals adopted the genomic imprinting mechanism has been a mystery since its discovery. In this review, based on the recent studies on imprinted gene regulation we discuss several advantageous features of a monoallelic expression mechanism and the necessity of genomic imprinting in the current mammalian developmental system. We further speculate how the present genomic imprinting system has been established during mammalian evolution by the mechanism of complementation between paternal and maternal genomes under evolutionary pressure predicted by the genetic conflict hypothesis.     

Imprinting evolution and the price of silence

In contrast to the biallelic expression of most genes, expression of genes subject to genomic imprinting is monoallelic and based on the sex of the transmitting parent. Possession of only a single active allele can lead to deleterious health consequences in humans. Aberrant expression of imprinted genes, through either genetic or epigenetic alterations, can result in developmental failures, neurodevelopmental and neurobehavioral disorders and cancer. The evolutionary emergence of imprinting occurred in a common ancestor to viviparous mammals after divergence from the egg-laying monotremes. Current evidence indicates that imprinting regulation in metatherian mammals differs from that in eutherian mammals. This suggests that imprinting mechanisms are evolving from those that were established 150 million years ago. Therefore, comparing genomic sequence of imprinted domains from marsupials and eutherians with those of orthologous regions in monotremes offers a potentially powerful bioinformatics approach for identifying novel imprinted genes and their regulatory elements. Such comparative studies will also further our understanding of the molecular evolution and phylogenetic distribution of imprinted genes.     

Evolution of genomic imprinting with biparental care: implications for Prader-Willi and Angelman syndromes

The term “imprinted gene” refers to genes whose expression is conditioned by their parental origin. Among theories to unravel the evolution of genomic imprinting, the kinship theory prevails as the most widely accepted, because it sheds light on many aspects of the biology of imprinted genes. While most assumptions underlying this theory have not escaped scrutiny, one remains overlooked: mothers are the only source of parental investment in mammals. But, is it reasonable to assume that fathers'' contribution of resources is negligible? It is not in some key mammalian orders including humans. In this research, I generalize the kinship theory of genomic imprinting beyond maternal contribution only. In addition to deriving new conditions for the evolution of imprinting, I have found that the same gene may show the opposite pattern of expression when the investment of one parent relative to the investment of the other changes; the reversion, interestingly, does not require that fathers contribute more resources than mothers. This exciting outcome underscores the intimate connection between the kinship theory and the social structure of the organism considered. Finally, the insight gained from my model enabled me to explain the clinical phenotype of Prader-Willi syndrome. This syndrome is caused by the paternal inheritance of a deletion of the PWS/AS cluster of imprinted genes in human Chromosome 15. As such, children suffering from this syndrome exhibit a striking biphasic phenotype characterized by poor sucking and reduced weight before weaning but by voracious appetite and obesity after weaning. Interest in providing an evolutionary explanation to such phenotype is 2-fold. On the one hand, the kinship theory has been doubted as being able to explain the symptoms of patients with Prader-Willi. On the other hand, the post-weaning symptoms remain as one of the primary concern of pediatricians treating children with Prader-Willi. In this research, I reconcile the clinical phenotype of Prader-Willi syndrome with the kinship theory, contending that paternal investment relative to maternal investment increases after weaning. I also propose a genetic composition of the PWS/AS cluster, discuss the effects of new types of mutations, and contemplate the potential side effects of reactivating silent genes for medical purposes.     

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.     

Kin recognition in Aleochara bilineata could support the kinship theory of genomic imprinting

Genomic imprinting corresponds to the differential expression of a gene according to its paternal or maternal origin. The kinship theory of genomic imprinting proposes that maternally or paternally inherited genes may be in conflict over their effects on kin differently related along the paternal or maternal line. Most examples supporting the kinship theory of imprinting deal with competition between offspring for maternal resources. However, genomic imprinting may also explain differential behavioral expression toward kin whenever sibs are more related to each other via one parental sex than the other. Unfortunately, nothing is currently known about imprinting associated with a behavioral phenotype in insects. Here we report the first evidence of such a maternally imprinted behavior. We show that the solitary parasitoid larvae of Aleochara bilineata Gyll (Coleoptera; Staphylinidae), which avoid superparasitizing their full sibs, also avoid their cousins when they are related to them through their father, but not when they are related to them through their mother. A genetic kin recognition mechanism is proposed to explain this result and we conclude that genomic imprinting could control the avoidance of kin superparasitism in this species and have a profound influence on decision-making processes.     

Theory of genomic imprinting conflict in social insects

Background  

Genomic imprinting refers to the differential expression of genes inherited from the mother and father (matrigenes and patrigenes). The kinship theory of genomic imprinting treats parent-specific gene expression as products of within-genome conflict. Specifically, matrigenes and patrigenes will be in conflict over treatment of relatives to which they are differently related. Haplodiploid females have many such relatives, and social insects have many contexts in which they affect relatives, so haplodiploid social insects are prime candidates for tests of the kinship theory of imprinting.     

Base-resolution analyses of sequence and parent-of-origin dependent DNA methylation in the mouse genome

Differential methylation of the two parental genomes in placental mammals is essential for genomic imprinting and embryogenesis. To systematically study this epigenetic process, we have generated a base-resolution, allele-specific DNA methylation (ASM) map in the mouse genome. We find parent-of-origin dependent (imprinted) ASM at 1,952 CG dinucleotides. These imprinted CGs form 55 discrete clusters including virtually all known germline differentially methylated regions (DMRs) and 23 previously unknown DMRs, with some occurring at microRNA genes. We also identify sequence-dependent ASM at 131,765 CGs. Interestingly, methylation at these sites exhibits a strong dependence on the immediate adjacent bases, allowing us to define a conserved sequence preference for the mammalian DNA methylation machinery. Finally, we report a surprising presence of non-CG methylation in the adult mouse brain, with some showing evidence of imprinting. Our results provide a resource for understanding the mechanisms of imprinting and allele-specific gene expression in mammalian cells.     

Genomic imprinting in mammals-epigenetic parental memories

Genomic imprinting is an epigenetic phenomenon that brings the difference of expression between paternally or maternally derived alleles and is specific for mammals in vertebrates. This imprint is established in the parental germlines and then inherited to the next generation to regulate expression of imprinted genes that are essential to support proper embryonic development. More than one hundred imprinted genes have been identified in mice and humans. Some are essential for embryonic development, especially placental formation, and others regulate metabolism, behavior and physiological functions. In humans, disruption of genomic imprinting causes several diseases, including cancer. Recently, the molecular mechanisms of genomic imprinting are getting clarified. How do parents regulate gene expression of their children? Why and how is genomic imprinting evolved in mammals? The review offers a handful of recent progress in this area.     

Genomic imprinting in ruminants: allele-specific gene expression in parthenogenetic sheep

Studies in the mouse have established that both parental genomes are essential for normal embryonic development. Parthenogenetic mouse embryos (which have two maternal genomes and no paternal genome), for example, are growth-retarded and die at early postimplantation stages. The distinct maternal and paternal contributions are mediated by genomic imprinting, an epigenetic mechanism by which the expression of certain genes is dependent on whether they are inherited from mother or father. Although comparative studies have established that many imprinted mouse (and rat) genes are allele-specifically expressed in humans as well (and vice versa), so far imprinting studies have not been performed in other mammalian species. When considering evolutionary theories of genomic imprinting, it would be important to know how widely it is conserved among placental mammals. We have investigated its conservation in a bovid ruminant, the domestic sheep, by comparing parthenogenetic and normal control embryos. Our study establishes that, like in the mouse, parthenogenetic development in sheep is associated with growth-retardation and does not proceed beyond early fetal stages. These developmental abnormalities are most likely caused by imprinted genes. We demonstrate that, indeed, like in mice and humans, the growth-related PEG1/MEST and Insulin-like Growth Factor 2 (IGF2) genes are expressed from the paternal chromosome in sheep. These observations suggest that genomic imprinting is conserved in a third, evolutionarily rather diverged group of placental mammals, the ruminants. Received: 13 May 1998 / Accepted: 16 July 1998     

Genomic imprinting in plants: observations and evolutionary implications

The epigenetic phenomenon of genomic imprinting occurs among both plants and animals. In species where imprinting is observed, there are parent-of-origin effects on the expression of imprinted genes in offspring. This review focuses on imprinting in plants with examples from maize, where gene imprinting was first described, and Arabidopsis. Our current understanding of imprinting in plants is presented in the context of cytosine methylation and imprinting in mammals, where developmentally essential genes are imprinted. Important considerations include the structure and organization of imprinted genes and the role of regional, differential methylation. Imprinting in plants may be related to other epigenetic phenomena including paramutation and transgene silencing. Finally, we discuss the role of gene structure and evolutionary implications of imprinting in plants.     

Balance between maternal and paternal alleles sets the timing of resource accumulation in the maize endosperm

Key aspects of seed development in flowering plants are held to be under epigenetic control and to have evolved as a result of conflict between the interests of the male and female gametes (kinship theory). Attempts to identify the genes involved have focused on imprinted sequences, although imprinting is only one mechanism by which male or female parental alleles may be exclusively expressed immediately post-fertilization. We have studied the expression of a subset of endosperm gene classes immediately following interploidy crosses in maize and show that departure from the normal 2 : 1 ratio between female and male genomes exerts a dramatic effect on the timing of expression of some, but not all, genes investigated. Paternal genomic excess prolongs the expression of early genes and delays accumulation of reserves, while maternal genomic excess foreshortens the expression period of early genes and dramatically brings forward endosperm maturation. Our data point to a striking interdependence between the phases of endosperm development, and are consonant with previous work from maize showing progression from cell proliferation to endoreduplication is regulated by the balance between maternal and paternal genomes, and from Arabidopsis suggesting that this ‘phasing’ is regulated by maternally expressed imprinted genes. Our findings are discussed in context of the kinship theory.     

What Are Imprinted Genes Doing in the Brain?

As evidence for the existence of brain?expressed imprinted genes accumulates, we need to address exactly what they are doing in this tissue, especially in terms of organizational themes and the major challenges posed by reconciling imprinted gene action in brain with current evolutionary theories attempting to explain the origin and maintenance of genomic imprinting. We are at the beginning of this endeavor and much work remains to be done but already it is clear that imprinted genes have the potential to influence diverse behavioral processes via multiple brain mechanisms. There are also grounds to believe that imprinting may contribute to risk of mental and neurological disease. As well as being a source of basic information about imprinted genes in the brain (e.g., via the newly established website, www.bgg.cardiff.ac.uk/imprinted_tables/index.html), we have used this chapter to identify and focus on a number of key questions. How are brain?expressed imprinted genes organized at the molecular and cellular levels? To what extent does imprinted action depend on neurodevelopmental mechanisms? Do imprinted gene effects interact with other epigenetic influences, especially early on in life? Are imprinted effects on adult behaviors adaptive or just epiphenomena? If they are adaptive, what areas of brain function and behavior might be sensitive to imprinted effects? These are big questions and, as shall become apparent, we need much more data, arising from interactions between behavioral neuroscientists, molecular biologists and evolutionary theorists, if we are to begin to answer them.     

Post-natal imprinting: evidence from marsupials

Genomic imprinting has been identified in therian (eutherian and marsupial) mammals but not in prototherian (monotreme) mammals. Imprinting has an important role in optimising pre-natal nutrition and growth, and most imprinted genes are expressed and imprinted in the placenta and developing fetus. In marsupials, however, the placental attachment is short-lived, and most growth and development occurs post-natally, supported by a changing milk composition tailor-made for each stage of development. Therefore there is a much greater demand on marsupial females during post-natal lactation than during pre-natal placentation, so there may be greater selection for genomic imprinting in the mammary gland than in the short-lived placenta. Recent studies in the tammar wallaby confirm the presence of genomic imprinting in nutrient-regulatory genes in the adult mammary gland. This suggests that imprinting may influence infant post-natal growth via the mammary gland as it does pre-natally via the placenta. Similarly, an increasing number of imprinted genes have been implicated in regulating feeding and nurturing behaviour in both the adult and the developing neonate/offspring in mice. Together these studies provide evidence that genomic imprinting is critical for regulating growth and subsequently the survival of offspring not only pre-natally but also post-natally.