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Perspective Origins of imprinting Natural selection and the function of genome imprinting: beyond the silenced minority Most hypotheses of the evolutionary origin of genome imprinting assume that the biochemical character on which natural selection has operated is the expression of the allele from only one parent at an affected locus. We propose an alternative – that natural selection has operated on differences in the chromatin structure of maternal and paternal chromosomes to facilitate pairing during meiosis and to maintain the distinction between homologues during DNA repair and recombination in both meiotic and mitotic cells. Maintenance of differences in chromatin structure in somatic cells can sometimes result in the transcription of only one allele at a locus. This pattern of transcription might be selected, in some instances, for reasons that are unrelated to the original establishment of the imprint. Differences in the chromatin structure of homologous chromosomes might facilitate pairing and recombination during meiosis, but some such differences could also result in non-random segregation of chromosomes, leading to parental-origin-dependent transmission ratio distortion. This hypothesis unites two broad classes of parental origin effects under a single selective force and identifies a single substrate through which Mendel’s first and second laws might be violated. enome imprinting has come to be defined as the transcription of only one allele at a locus, dependent on the parental origin of the allele1. The term is often restricted further to describe a process that occurs only in mammals1. Although the term was used first to describe meiotic and mitotic chromosome segregation in insects2, neither the casual reader of recent imprinting literature, nor most investigators in the field, would take issue with the notion that the true gist of the imprinting process is parental-origin-dependent transcription in mammals. This consensus of opinion is surprising given the range of biological phenomena and the phylogenetically diverse collection of organisms in which epigenetic parental origin effects occur (Table 1). Curiously, the exclusion of these ‘other’ parental origin effects (i.e. those that are nonmammalian or do not affect gene expression) from the definition of imprinting has occurred in the absence of any relevant data. It is as though one of two opposing armies, realizing their superiority of number, decided to declare victory and withdraw without ever engaging in battle. Scientific decisions are not often made in this way, and it is instructive to examine the circumstances surrounding the consensus on the present use of the term. G 0168-9525/00/$ – see front matter © 2000 Elsevier Science Ltd. All rights reserved. PII: S0168-9525(00)02134-X The voice of gene silencing The confluence of three factors probably led to the definition of imprinting as parental-origin-dependent transcription in mammals: • the developmental failure of mouse embryos that are gynogenetic (containing only maternal germline-derived chromosomes) or androgenetic (containing only paternal germline-derived chromosomes)3; • the parental conflict hypothesis4; • the demonstration of differences in DNA methylation between maternal and paternal alleles at imprinted loci (reviewed in Ref. 1). This combination of a marked effect of the parental origin of the genome on phenotype, a powerful argument for how natural selection might exploit differences between maternal and paternal genomes to result in parentalorigin-dependent gene expression, and the existence of a strong candidate for the molecular identification mark by which the transcriptional machinery might distinguish the parental origin of an allele, drove most investigators straight into the waiting arms of allele-specific DNA methylation and RT–PCR. In retrospect, the field moved so quickly in this direction that there was little serious consideration of alternatives to the view that the primary TIG December 2000, volume 16, No. 12 Fernando PardoManuel de Villena* fernando@ unix.temple.edu Elena de la CasaEsperón* elena@ unix.temple.edu Carmen Sapienza*† sapienza@ unix.temple.edu * Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, 3307 North Broad Street, Philadelphia, PA 19140, USA. † Department of Pathology and Laboratory Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA. 573 Perspective Origins of imprinting TABLE 1. Phylogenetic distribution of parental origin effects Time (Myr) 1000 750 500 250 Organism Parental origin effect Refs Mouse Androgenote and gynogenote death X-inactivation Gene expression DDK syndrome Level of aneuploidy in sperm (Rob translocations) Transgene methylation 3 41 1,6,7 40 29 27 Human X-inactivation Gene expression Transmission ratio distortion DNA methylation CML translocations Recombination 42 1 12,13,37 28 38 31 Sheep Hindquarters development (Callipyge) 39 Kangaroo X-inactivation 43 0 Eutherians Marsupials Opossum Gene expression 44 Birds Chicken (Monoallelic expression of IGF2 ) 44,45 Fish Zebrafish Transgene methylation 46 Drosophila Gene expression Position effect variegation Chromosome breakage 11 10 47 Arthropods Fungi Scale insects Chromosome elimination 48 Sciara Chromosome elimination 2,48 Yeast Mating type 49 Maize Aleurone pigmentation Demethylation and expression of zein genes 50 50 Arabidopsis Genome activation during seed development Maternal control of embryogenesis by MEDEA 50 50 Marsilea Non-random distribution of chromatids 51 Flowering plants Ferns The list of parental origin effects is not intended to be complete but to illustrate the diversity of organisms in which they are observed. Examples fulfil the criteria that the effect is epigenetic, parent-of-origin dependent, linked to the nuclear genome and does not include classical maternal or paternal effects. Divergence times (in millions of years before present; Myr) are indicated on the horizontal axis. Arrows, times at which natural selection as a result of ‘parental conflict’ might have arisen (excluding postnatal parental conflict). The large arrowhead indicates the time at which the selective force discussed in the text may have arisen. The Igf2 locus exhibits imprinted expression in mammals but is ‘monoallelic’ in chickens45. purpose of establishing epigenetic differences between maternal and paternal genomes is the transcriptional control of gene expression. The early identification of several genes that were transcribed from only one parental allele5–7 provided experimental support for this view but it is important not to underestimate the role of the parental conflict hypothesis in its general acceptance. Limitations of the parental conflict hypothesis in explaining parental origin effects The parental conflict hypothesis4 states that natural selection acted upon epigenetic differences between maternal and paternal genomes such that the expression of at least some genes involved in embryonic growth became restricted to only the maternal or only the paternal allele. The most relevant requirements of the hypothesis, with respect to control of embryonic growth, are an unequal investment in parental care and multiple paternity4. If postnatal parental care is excluded, these requirements are valid in only some phylogenetic groups, including mammals. The hypothesis makes the important predictions that imprinted genes that enhance growth will be expressed from the paternal allele, and that imprinted genes that suppress growth will be expressed from the maternal allele, as is observed at the mouse Igf2 and Igf2r 574 TIG December 2000, volume 16, No. 12 loci, respectively5,6 (Ref. 8 provides a detailed discussion of the parental conflict hypothesis and parental-origindependent gene expression). The process appears to guard against the perceived threat of parthenogenesis9, providing additional support for the idea that there is something peculiarly ‘mammalian’ about imprinting. This interplay between embryological and biochemical data, on the one hand, and evolutionary theory, on the other, made it easy for many investigators (including us) to discount or ignore an important but unstated requirement of the parental conflict hypothesis: generation of the substrate upon which natural selection operates (i.e. epigenetic differences between maternal and paternal genomes) must be, like genetic differences that arise between genomes by mutation, a basic property of the system. In other words, natural selection does not create epigenetic differences between maternal and paternal genomes any more than natural selection creates mutations. However, once epigenetic differences have occurred, natural selection can act on those differences and also on any genetic factors that enhance or suppress those differences, just as natural selection can act on mutations and also on genetic factors that increase or decrease the rate of mutation. It is at the level of selection of the genetic factors that modify the establishment of epigenetic differences between Perspective Origins of imprinting maternal and paternal genomes, either in cis or in trans, that the ‘function’ of imprinting is determined. This statement stems from a general tenet of evolutionary biology – but one that is important, in this context, to state explicitly – that is, to define the function of a structure or process, one must identify the selective force that has directed the formation of that structure or process. By this logic, if some aspect of ‘parental conflict’ constitutes a selective force that is unique to mammals and this force favours the silencing of one parental allele at loci involved in embryonic growth, then there could be features of transcriptional silencing that are peculiar to mammals. However, it is important to stress that this phenomenon is predicted to be limited to an unknown, but probably small, fraction of loci in those phylogenetic groups in which this selective force has operated. Imprinting and ‘other’ parental origin effects: do they have anything in common? The observation that parental origin effects occur in a wide variety of organisms (Table 1) cannot be used as an argument that parental origin effects, per se, have been selected to serve some purpose because the generation of epigenetic differences between maternal and paternal genomes might be a consequence of sexual reproduction. However, we can infer that the opportunity for selection to act on these differences has existed for much of evolutionary history (Table 1). If a particular type of epigenetic difference appears consistently, it suggests that the difference has persisted as a result of natural selection. The pertinent questions are what selective forces might act on differences between maternal and paternal genomes and whether any of these forces could result in many or all of the parental origin effects observed. Epigenetic parental origin effects fall into two general classes: first, those that differentially affect the expression of a particular gene or phenotype (violations of Mendel’s first law; see glossary in Box 1), and second, those that differentially affect the transmission of particular alleles (violations of Mendel’s second law). The first class of effects is mediated through transcriptional silencing or activation of only one allele, and the second class might be mediated through postmeiotic selection on the expression or segregation of alleles, or through meiotic selection that results in non-random segregation of chromosomes. In considering selective pressures that might be common to all phylogenetic groups and all epigenetic parental origin effects, it is reasonable to ask first whether these two seemingly disparate types of effects, one a property of somatic cells and the other a property of the germline, need to be related in any way. If the two classes of effects cannot be related in any mechanistic way, then they might be subject to different selective forces, which might operate at completely different levels. However, if the two classes reflect alternative effects of a common structure or pathway, then it is possible that the same selective force might act at both levels, through a common substrate. In insects, both classes of effect are clearly related to the establishment of epigenetic differences in chromatin structure. There are many examples, but the most historically relevant concerns the original use of the term ‘imprinting’ in genetics: Crouse2 demonstrated that preferential segregation in Sciara of the maternal X chromosome to a functional meiotic product, rather than a nonfunctional meiotic product, is associated with a heterochromatic domain on the maternal X chromosome. Epigenetic differences in chromatin structure also influence gene expression in the somatic cells of insects. All of the variegating position effects that are sensitive to parental origin in Drosophila10 are associated with translocations that result in the juxtaposition of heterochromatic regions with euchromatic regions. Parentalorigin-dependent variability in phenotype is observed as variation in mosaic expression of the affected allele and many modifiers of position effect variegation encode proteins that influence chromatin structure. In fact, Lloyd et al.11 have demonstrated a parental-origin-dependent gene expression phenomenon in Drosophila that is indistinguishable from imprinting in mammals except for the lack of detectable DNA methylation differences. These authors propose that imprinting is an ancient and conserved mechanism of gene silencing based on the establishment of differences in chromatin structure. Data implicating epigenetic differences in chromatin structure in both types of parental origin effects in mammals are highly suggestive. Transmission ratio distortion of maternal alleles at X chromosome loci in the human is sensitive to the parental origin of the X chromosome in the mother12, as well as the previous inactivation status of the X chromosome (i.e. a heterochromatic versus a euchromatic state)13. And, of course, maternal and paternal alleles at loci that exhibit transcriptional imprinting are known to exhibit parental-origin-dependent differences in chromatin structure (reviewed in Ref. 14), as assayed through sensitivity to DNase I or trichostatin A, replication timing and allele-specific binding of the chromatin ‘insulator’ protein CTCF (Refs 15, 16). Additional data indicating that differences in chromatin structure, per se, might directly affect meiotic chromosome segregation come from the study of maternal meiotic drive of a variant mouse chromosome 1 containing a large, homogeneously staining region17 and ‘knob’ heterochromatin in maize18; these differences in chromatin structure are not dependent on parental origin, unlike the case in Sciara. A common selective force in meiotic and mitotic cells We assume that parental origin effects that result in both differential expression (a somatic cell phenomenon) and differential transmission (a germline phenomenon) of genes are mediated by differences in the chromatin structure of homologous chromosomes. If these differences in chromatin structure are present in both somatic and germline cells, then any biochemical process that occurs in both the soma and the germline, and for which a distinction between maternal and paternal genomes is important, could exert a selective force. We propose that natural selection caused the establishment and maintenance of epigenetic differences between the maternal and paternal genomes of sexually reproducing organisms for the purpose of homologous pairing of chromosomes at meiosis and the associated processes of DNA repair and recombination during both meiosis and mitosis. In meiotic cells, homologous pairing and repair of DNA double-strand breaks has been selected to take place between maternal and paternal chromosomes (meiotic recombination), rather than sister chromatids19. Unless these processes occur between homologues, segregation of homologous chromosomes is adversely affected20. In TIG December 2000, volume 16, No. 12 575 Perspective Origins of imprinting BOX 1. Glossary Knob heterochromatin: Knobs are cytological features of maize chromosomes that can influence chromosome segregation. They are heterochromatic and consist of thousands to millions of 180- and 350-basepair repeats. Microsatellite instability: A phenomenon in which errors made during the replication of mono- and di-nucleotide repeats are not corrected. The process has been associated with defective DNA mismatch repair. Microsatellite instability is a quantitative character detected as increases or decreases in the length of alleles at some portion of tested loci. Mendel’s 1st law: Although not formally defined by Mendel, the laws of segregation and independent assortment require that the genetic material is stable between generations and functionally equivalent when inherited either maternally or paternally. Historically, new mutations and rare meiotic recombination events within genes have violated this law, and imprinting provides a third exception. Mendel’s 2nd law: Each pair of homologous chromosomes segregate at meiosis in each generation, ensuring maintenance of proper chromosome number in sexually reproducing organisms and resulting in equal probability of transmitting either allele at any locus. Replication asynchrony: Differential timing of the replication of the two alleles at a locus during S phase of mitosis. The phenomenon is commonly observed for alleles at loci on the active versus inactive X chromosome in females but has also been reported for alleles at imprinted loci. Gene conversion: The phenomenon was first described in fungi as a recombination process in which the transfer of information between homologues is non-reciprocal. The process results in tetrads in which the segregation of alleles at a locus is not 1:1. Position effect variegation: Mosaic expression of a phenotype caused by a chromosomal rearrangement in which the new euchromatic–heterochromatic chromosomal boundary influences the expression of adjacent genes. Transmission ratio distortion: A significant departure from the Mendelian inheritance ratio expected, regardless of the origin of the distortion. Uniparental disomy: The abnormal inheritance of both members of a homologous chromosome pair from only one parent in a chromosomally balanced individual. Both uniparental isodisomy (two copies of the same chromosome) and uniparental heterodisomy (both copies of a homologous pair from the same parent) have been observed. mitotic cells, repair of DNA double-strand breaks and other types of DNA damage, and any associated mitotic recombination, has been selected to take place between sister chromatids rather than between maternal and paternal homologous chromosomes19. Potentially large-scale functional hemizygosity as a result of gene conversion or mitotic recombination is thus avoided. The selective pressure to distinguish maternal and paternal homologous chromosomes from each other and from sister chromatids during DNA repair and recombination is universal and occurs in both the soma and the germline of all organisms that reproduce sexually. The selective pressure to maintain this distinction will be least pronounced in organisms such as yeasts that have only a transient diploid stage whose purpose is the creation of the ‘prevalent’, haploid, form. However, the selective pressure to maintain epigenetic differences between maternal and paternal genomes will be strong in organisms in which there are a large number of mitotic divisions between the time of fertilization and 576 TIG December 2000, volume 16, No. 12 the establishment of the germline. In such cases, the identity of maternal and paternal homologous chromosomes must be maintained from the time of fertilization until meiotic recombination takes place. This would explain a number of unexpected observations surrounding the analysis of parental origin effects (discussed below). Observations on imprinting in mammals that are not predicted by natural selection at the level of gene silencing Most studies of imprinted genes in mammals have focused on the description of patterns of gene expression and the identification of factors responsible for parentalorigin-dependent transcription of only one allele1,4–7. Interestingly, when such studies extended beyond the analysis of transcription, several observations were made that are not predicted by models in which the role of imprinting is to control gene expression. These observations provide support for our hypothesis that imprinting was established as a general mechanism for distinguishing homologous chromosomes from each other, from nonhomologous chromosomes and from sister chromatids. The following examples illustrate this point. Somatic cells The loss of epigenetic differences between alleles in somatic cells has been found to affect relationships between alleles and between homolgous chromosomes that were, themselves, unexpected. For example, pairing of homologous chromosomes is not thought to be a common occurrence in the somatic cells of mammals. However, analysis of the position of alleles within interphase nuclei by fluorescence in situ hybridization indicates that homologous chromosomes do associate in the vicinity of the imprinted loci for Prader–Willi and Angelman syndromes on human chromosome 15 and the H19 region of human chromosome 11 (Ref. 21). This association appears to be mediated by differential epigenetic marking of these regions (rather than sequence homology) because the association does not occur in Prader–Willi patients in which both chromosomes 15 are maternally derived. The proximity of maternal and paternal alleles is restricted to late in S phase, when only one allele of the asynchronously replicating pair22 is likely to be undergoing DNA synthesis. The presumed concomitant ‘loss’ of imprinting (or failure to inherit a paternal chromosome, in this case), allelic pairing and replication asynchrony suggests that the maintenance of epigenetic differences is required for this previously unrecognized association between homologues at the time of DNA replication. This is consistent with a role for imprinting in distinguishing homologues during post-replication repair. Most importantly, no hypothesis in which imprinting evolved to control gene expression predicts a physical association between alleles at imprinted loci. However, if imprinting evolved as a mechanism of chromosome recognition and distinction, then such interactions are not unexpected. A more direct indication that there is a relationship between imprinting and DNA repair comes from the association between ‘microsatellite instability’ (see Ref. 23 for review) and ‘loss of imprinting’ in colon tumours24. If loss of imprinting occurs in the precursor cell of a colon tumour (as appears to be often the case24), homologous chromosomes could become indistinguishable from each other and/or from sister chromatids. If the cell then Perspective Origins of imprinting (c) (b) (a) Mat Mat Pat Female germline Recombination — Pat + Male germline Recombination + — Centromeres Telomeres trends in Genetics attempts to correct a substantial replication error (such as the expansion or contraction of a microsatellite array) and chooses the homologous chromosome as a template, rather than the sister chromatid, the DNA repair machinery would probably signal an apoptotic response. This would be caused by an apparently high level of DNA replication errors25 perceived by the DNA repair machinery by comparison of homologous chromosomes rather than sister chromatids. (The estimated DNA sequence diversity (expected heterozygosity across all sites) in the human population is 0.2% (Ref. 26). This difference between homologues is orders-of-magnitude greater than the normal error rate of DNA synthesis.) Thus there will be selection for cells that have inactivated the relevant repair/apoptotic signalling pathways and these cells might also give rise to tumours. These unexpected observations are most simply interpreted if the establishment and maintenance of epigenetic differences between homologous chromosomes in somatic cells reflects a selective pressure that is uncoupled from transcriptional control. Many early observations surrounding parental-origin-dependent methylation of transgene loci in the mouse could also be similarly interpreted: the pattern of differences in methylation between mater- nally and paternally derived transgene arrays is similar in almost all cell types and tissues examined, regardless of whether the transgene was expressed in a specific tissue, in multiple tissues or not at all (reviewed in Ref. 27). Some epigenetic differences between alleles at endogenous loci could also be interpreted this way; the mannose6-phosphate/insulin like growth factor 2 receptor (IGF2R), which is expressed from only the maternal allele in mice, is expressed biallelically in most humans. However, differential methylation of maternal and paternal alleles is maintained in both human and mouse28. Meiotic cells The second type of unexpected observation surrounding imprinting indicates a requirement for the maintenance (rather than the erasure) of differential marking of chromosomes in the germline well beyond the point at which one might expect such differences to have been erased if imprinting functions only to silence genes. In some cases, differences between maternal and paternal chromosomes appear to be maintained until the onset of the first meiotic division. For example, there are significant differences in the frequency of aneuploid sperm found among carrier males when the same robertsonian translocation TIG December 2000, volume 16, No. 12 577 Perspective Origins of imprinting chromosome is inherited maternally as opposed to paternally29. Perhaps the most unexpected meiotic effect reported30 is that methylation differences between maternal and paternal H19 alleles are distinguishable far into meiotic prophase during spermatogenesis. If epigenetic differences between maternal and paternal homologues are required to facilitate homologous pairing (Fig. 1 and discussion below) and DNA repair associated with meiotic recombination, then the epigenetic differences between homologues must survive until at least the zygotene stage of meiosis (when pairing of homologous chromosomes is observed). Consistent with this expectation, Davis et al.30 observed differences in DNA methylation between maternal and paternal H19 alleles at the preleptotene stage (when chromosomes begin to condense) and found that such differences begin to disappear at the pachytene stage (after pairing has occurred and when crossing over begins). Additional support for the hypothesis that parental-origin-specific chromatin structures facilitate meiotic pairing of homologous chromosomes comes from the observation that imprinted regions of human chromosomes display sex-specific recombination frequencies31. Moreover, these sex-specific differences in recombination depend on the parental identity of the imprint in subregions of the imprinted domains. Regions containing genes expressed from the paternal chromosome recombine at higher frequencies through males, whereas regions containing genes expressed from the maternal chromosome show higher recombination rates through females (Fig. 1). It seems improbable that expression of imprinted genes is both parental-origin-specific and sex-specific during the first meiotic prophase. Therefore it is unreasonable to relate these differences in recombination to transcriptional states. Such differences might be expected, however, if these regions are intimately involved in meiotic pairing. Indirect support for the maintenance of epigenetic differences during meiosis is also provided by maternal transmission ratio distortion at loci that are either known to be transcriptionally imprinted32 or show very strong parental origin effects on phenotype33. The asymmetry of female meiosis provides a unique opportunity for the direct selection of epigenetic differences in chromosome structure as a result of preferential segregation of one homologue to the polar body and the other to the ovum (female meiotic drive). Transmission ratio distortion in this instance in the mouse is a consequence of preferential segregation of chromosomes at meiosis33, but this is not proven in humans. Parental origin effects: a unifying view Given the antiquity of epigenetic differences between maternal and paternal genomes (Table 1), it is worth recalling that the raison d’être of the sexual mode of reproduction is the meiotic pairing and recombination of homologous chromosomes. Although meiotic pairing occurs between homologous chromosomes, initiation of pairing is thought not to be mediated directly by homologous DNA sequence but by epigenetic factors34. These factors have not been identified, but a complementary References 1 Tilghman, S.M. (1999) The sins of the fathers and mothers: genomic imprinting in mammalian development. Cell 96, 185–193 2 Crouse, H.V. (1960) The controlling element in sex chromosome 578 code of maternal and paternal imprints has the potential to fulfil this role. A conceptually simple system is possible, in which oppositely imprinted domains are templates by which homologous chromosomes might recognize each other and, equally importantly, discriminate against pairing of non-homologous chromosomes (Fig. 1). This mechanism explains why imprinted loci are non-randomly distributed on chromosomes and why oppositely imprinted genes are found in clusters35; multiple imprinted domains will be required to provide specificity of pairing and pairing will be initiated in specific regions of chromosomes. Once pairing and recombination are complete, the maternal or paternal ‘pairing code’ (imprint) can then be established on both homologues and transmitted to the next generation. The maintenance or additional modification of these codes in somatic cells can lead to variable amounts of allelic silencing36, as well as distinguish homologues from sister chromatids during DNA repair. However, the maintenance of these differences could also engender a tendency for transient pairing of homologues during mitosis, occasionally resulting in mitotic recombination. There are a number of potentially interesting implications of this hypothesis. For example, the observation of parental-origin-dependent transmission ratio distortion during the mapping of complex genetic diseases has generally been interpreted to imply that a transcriptionally imprinted gene is involved in the etiology of the disease37. However, it is also possible that these parental origin effects reflect biases in meiotic chromosome segregation, rather than transcription of an allele. In the same vein, if some non-homologous chromosomes carry complementary codes of sufficient similarity, specific translocations could exhibit a parental origin bias, even though the genes involved in the translocation might not be transcriptionally imprinted38. Another interesting possibility with respect to human disease etiology, is that reactivation of DNA repair pathways in tumours that show microsatellite instability and loss of imprinting24, mighty result in an apoptotic response. The hypothesis presented here also predicts that uniparental disomy (for any chromosome) will lead to alterations in meiotic recombination as well as increased aneuploidy of the uniparentally disomic chromosome. Although we agree that ‘parental conflict’ might have been an important selective force in the evolution of transcriptional control, we believe that the selective force that has maintained most epigenetic differences between maternal and paternal genomes, throughout evolution, has not operated at the level of gene silencing in somatic cells. Consideration of ‘imprinting effects’ from this viewpoint could provide new insights into several phenomena, including mechanisms of chromosome pairing and segregation34, sex determination2 and the unusual genetics of some parental origin effects39,40. Acknowledgements We thank M. Bartolomei, M. Hansen and K. Latham for their comments on an earlier version of this manuscript. We apologize to the authors of many relevant papers that could not be cited because of space limitations. behavior in Sciara. Genetics 45, 1429–1443 3 McGrath, J. and Solter, D. (1984) Completion of mouse embryogenesis requires both the maternal and paternal genomes. 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(1980) Different behaviour of maternal and paternal genomes during embryogenesis in the fern, Marsilea. Eur. J. Cell Biol. 21, 28–36 Hanno Bolz is a clinical genetics counsellor and research assistant in the Faculty of Medicine, University of Hamburg, Germany. TIG December 2000, volume 16, No. 12 579