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Genetic control of intra-uterine growth
European Journal of Obstetrics & Gynecology and Reproductive Biology 92 (2000) 29±34
Genetic control of intra-uterine growth Koen Devriendt* Center for Human Genetics, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium
Abstract The expression of a few genes in the human genome depends on whether they are located on the maternal or on the paternal chromosome. This phenomenon is called genomic imprinting. Several of these genes have a role in normal embryonic and fetal growth, as indicated by an abnormal development associated with disturbed genomic imprinting. This has lead to the suggestion that the genomic imprinting has evolved as a mechanism to regulate embryonic and fetal growth. # 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Imprinting; Uniparental disomy; Syndrome; Intrauterine growth restriction
1. Introduction It has been known for a long time that both maternal and paternal gametes are required for a normal mammalian development and growth, indicating a functional difference between the maternal and paternal genome. Recent progress in genetics has revealed that for speci®c genes, only one of the two alleles is active, depending on the parental origin. For certain genes, only the gene on the chromosome inherited from the mother is active and the paternal allele is silenced, for others, only the gene on the paternal chromosome is active, whereas the maternally inherited gene is silenced. This is called genomic imprinting. This genetic mechanism explains the occurrence or inheritance of certain genetic disorders, such as the Beckwith±Wiedemann or Angelman syndromes, that could not be understood by traditional Mendelian genetics. Moreover, from a more fundamental point of view, genomic imprinting sheds new light on some of the underlying mechanisms of intrauterine growth. 2. A complementary role for the maternal and paternal genome in development Nuclear transfer experiments in mice have made possible the creation of embryos carrying solely maternal chromosomes `gynogenetic embryos' by replacement of the paternal by a maternal pronucleus (reviewed in Solter [1]). This effect is similar as in parthenogenetic embryos. Such * Corresponding author. Tel.: 32-16-345906; fax: 32-16-346051. E-mail address: [email protected] (K. Devriendt).
embryos do not develop well and die in a few days after implantation, due to failure of development of the extraembryonic components [2,3]. In contrast `androgenetic embryos', which contain only paternal chromosomes, develop well initially reaching the blastocyst stage. However, at implantation, only the extraembryonic components develop [4]. In the human, similar observations have been made, respectively in teratoma and in the complete hydatiform mole. Teratomata may arise from parthenogenetically activated oocytes with duplication of the maternal genome, and thus, contain only maternal chromosomes. This leads to a tumor consisting of different tissues from all three germ layers, but without extraembryonic components, indicating that maternal genes are necessary for the development of the embryo itself. In contrast, in the complete hydatiform mole, no embryo is formed. There is an abundance of placental tissue, with villi that have a swollen vesicular aspect but absence of fetal circulation. The most frequent mechanism leading to a complete mole is the fertilization of an oocyte that lacks a maternal pronucleus, followed by a duplication of the paternal chromosomes. In a complete mole, all chromosomes are of paternal origin [5], indicating that placental development depends on the expression of speci®c genes on the paternal chromosomes. Thus, the overall impression is that genes on the paternal genome are required for development of the placenta, whereas certain maternal genes are essential for the development of the embryo itself. To understand better why androgenetic or gynogenetic embryos fail to develop normally, mouse chimeras, consisting of cells from two different sources, have been constructed. Chimeric embryos can be made where only part of the cells are either androgenetic or gynogenetic through the
0301-2115/00/$ ± see front matter # 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 3 0 1 - 2 1 1 5 ( 0 0 ) 0 0 4 2 2 - X
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K. Devriendt / European Journal of Obstetrics & Gynecology and Reproductive Biology 92 (2000) 29±34
fusion of cells from a androgenetic or gynogenetic embryo with a normal embryo. These embryos survive allowing a proper analysis of the phenotype. It was found that androgenetic and gynogenetic cells contribute to different parts of the developing embryo and fetus [6]. Gynogenetic chimera cells are speci®cally found in ectodermal derivatives, e.g. the central nervous system (mainly the cortex and striatum) but are absent from the placenta and the yolk sac. Such embryos are growth restricted, but often display an enhanced growth of the brain. In contrast, androgenetic chimera cells are preferentially located in trophoblastic tissue, primitive endoderm lineages (the yolk sac), mesodermal derivatives (muscles and heart) and in speci®c parts of the brain (e.g. the hypothalamus). Such fetuses display an overall overgrowth, often with a reduced brain development. These phenotypes are highly reminiscent of the triploidic condition in the human, where cells contain 69, instead of 46 chromosomes. The phenotypes of triploid embryos differ and depend on the parental origin of the extra set of chromosomes [7,8]. When there are two sets of maternal chromosomes, fetal growth is severely restricted with relative macrocephaly and a very small placenta. Such pregnancies can evolve until far into the second trimester. In contrast, in triploidy with an extra set of paternal chromosomes, the fetus has a relatively normal growth, with either a normal head size or microcephaly. Such pregnancies usually miscarry early during pregnancy whereas the placenta has the typical features of a partial mole. The interpretation of these observations in both mice and humans is that there must be speci®c genes that are important in normal embryonic and fetal development, with an expression that is restricted to only one of the two alleles. Monoallelic expression is also found for most genes on the X-chromosome in females, as a result of the random inactivation of one of the two chromosomes in somatic cells. Genomic imprinting, however, is not random, but depends on the parental origin of the chromosome: for certain genes only the maternal allele is active, (paternal imprinting), whereas for others the paternal allele is active (maternal allele is silenced or imprinted). The next question is to identify the imprinted genes, to localize them to speci®c chromosomal fragments and ®nally to isolate them. 3. Chromosome localization of imprinted genes in mice: uniparental disomy Using mice carrying well-de®ned chromosomal translocations, it has been possible to breed mice where speci®c chromosomal fragments were derived from a single parent, either the mother or the father [9]. Thus, instead of all chromosomes (as in the nuclear transfer experiments or chimeras), only part of a chromosome was derived from a single parent. This is called uniparental disomy (UPD). For several chromosomal fragments the resulting phenotype was normal, and it could then be concluded that these chromo-
somal regions do not carry imprinted genes. For other chromosomal fragments, an abnormal phenotype was observed, indicating the location of an imprinted gene. This has allowed to construct a chromosomal map for imprinted genes in mice [9]. For instance, fetuses with a maternal UPD (UPDmat) of distal chromosome 7 are growth restricted, and die around day 16 of gestation [10]. Paternal UPD (UPDpat) for the same chromosomal region results in an even earlier death, so that no speci®c phenotype could be described. More insight was obtained using chimeric mice that carry UPDpat in only part of the cells. Interestingly, such embryos show the opposite phenotype, i.e. enhanced embryonic growth. This chromosomal region harbours the gene for insulin-like growth factor II, a major embryonic and fetal growth factor [10]. This gene is maternally imprinted, expressed only from the paternal allele whereas the maternal allele is always silenced [10]. This explains why in embryos with two maternal IGFII-genes, IGFII expression is very low, resulting in an impaired growth. In contrast, in mice with two paternal alleles IGFII production is increased and growth is therefore enhanced. The observations in IGFII-knock-out mice support this concept. Disruption of the IGFII-gene does not result in an abnormal phenotype when the mutation is inherited from the mother, but mice are growth de®cient when the disrupted IGFII gene is inherited from the father [11]. 4. Uniparental disomy in humans related to growth disturbances As indicated before, examples from human fetal pathology show the existence of genomic imprinting in humans. During evolution, the chromosomes are being reshuf¯ed continuously, but using the maps of conserved genes, it has been possible to delineate the human chromosomes homologous to the mouse chromosomal fragments carrying imprinted genes. In many instances, these human chromosomes also carry imprinted genes [12]. For example, the distal part of human chromosome 11p is homologous to distal mouse chromosome 7. The Beckwith± Wiedemann syndrome (BWS) is an overgrowth syndrome, characterized by high birth weight, macroglossia, omphalocoele, neonatal hypoglycemia, visceromegaly and hemihypertrophy. Adrenal carcinoma, nephroblastoma, hepatoblastoma, and rhabdomyosarcoma occur with increased frequency [13]. Several genetic defects have been described in BWS, all involving one or more genes on chromosome 11p15 (reviewed by Li et al. [14]). In some patients, trisomy for the distal part of chromosome 11p is detected, with in all instances, two paternally derived chromosome 11p fragments. In a subset of BWS patients, uniparental disomy for chromosome 11p is found. This is present in a mosaic state, i.e. only in a proportion of somatic cells and only for part of chromosome 11 [15,16].
K. Devriendt / European Journal of Obstetrics & Gynecology and Reproductive Biology 92 (2000) 29±34 Table 1 Overview of known clinical manifestations of UPDs for specific chromosomesa Chromosome
Maternal UPD
Paternal UPD
2 6 7 11 14
(IUGR) [45] ± Silver±Russel ± IUGR, pubertas praecox [48] Prader±Willi (IUGR) IUGR [50]
± Neonatal diabetes [46] ± Beckwith±Wiedemann [47] Short limbed dwarfism [49]
15 16 20
Angelman syndrome ± ±
a
( ) Indicate that it is not yet certain whether the phenotype is related to the UPD or to an associated CPM. References are shown between [ ].
The common region of UPD is chromosome 11p15, where the imprinted genes map, including human IGFII. The mechanism leading to partial and mosaic UPD11 is a postzygotic error in chromosome segregation, with somatic mitotic recombination [15,16]. A postzygotic error also explains why monozygotic twins can be discordant for this genetic condition since the error occurs after division of the embryo in two separate twin embryos. When UPD11pat is present in all somatic cells the embryo formed is unviable [16]. In humans, UPD has been observed for most chromosomes [17,18]. In most instances, there is no associated phenotype, indicating that these chromosomes do not carry imprinted genes, whereas UPD of other chromosomes causes a distinct phenotype (Table 1). It is of interest that many of these UPDs are associated with disturbed intrauterine growth, mostly growth restriction. Enhanced growth has only been observed in the Beckwith±Wiedemann syndrome. With the exception of the BWS, the Prader±Willi syndrome and the Angelman syndrome, the imprinted genes responsible for the phenotype are not known. The Silver±Russel syndrome (SRS) is a prototype of a disorder characterized by pre- and post-natal growth restriction [19]. Additional features include triangular face and a relatively large head, clinodactyly of the ®fth ®ngers and hypospadias. It is clear that this clinical de®nition is rather loose, and that this condition is etiologically heterogeneous. In some children with the SRS, body asymmetry is found, and this may re¯ect somatic mosaicism for a genetic mutation. In approximately 10% of cases, maternal uniparental disomy for chromosome 7 is found [20±22]. Two imprinted genes have been mapped to chromosome 7, the PEG1/Mest gene and the [g]2-COP gene, but so far, no mutations affecting these genes have been found in patients with the SRS without UPD7mat [23,24]. Interestingly, a patient with a de novo duplication of the maternal chromosome 7p11.2p13 has been reported [25]. This suggests that the IUGR seen in UPD7mat may result from an increased dose of a paternally imprinted gene on chromosome 7, rather than the absence of a growth promoting gene.
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Uniparental disomy for chromosome 15 is the most frequent UPD, and associated with the Prader±Willi syndrome (PWS) when the UPD is maternal, and Angelman syndromes in UPD15pat. The study of these two disorders has been particularly helpful in de®ning the mechanisms underlying genomic imprinting. The PWS is characterized by severe neonatal hypotonia with major feeding dif®culties and failure to thrive, distinct facial features, developmental delay, short stature and hypogonadotrophic hypogonadism. Interestingly, around the age of 2±3 years, these children develop an uncontrolled appetite, which leads to an severe obesity when feeding is not controlled [26]. In approximately 25% of patients, UPD is found. The remaining patients have either a deletion in chromosome 15q11±13 (70%) or an imprinting mutation (< 5%) [27]. Several imprinted genes, expressed from the paternal chromosome only have been identi®ed in this region, and probably, the disorder results from the reduced expression of several of these genes. The phenotype of the Angelman syndrome is entirely different, and characterized by severe mental retardation, epilepsy, ataxia and characteristic facial features. Typically, these children do not develop speech. The disorder is a single gene disorder, and caused by the absence of the UBE3A gene, which is found nearby the genes responsible for the PWS on chromosome 15q11±13, but shows an opposite imprinting pattern. The UBE3A gene is only active on the maternal chromosome 15, and interestingly, only so in the brain, since in other tissues, both alleles are expressed [28]. The Angelman syndrome can thus be caused by a number of different mechanisms, all leading to a de®ciency of the UBE3A gene: a deletion of maternal chromosome 15q11±13(70%),mutationsinthematernalUBE3Agene(25%) and, more rarely, by a paternal uniparental disomy for chromosome 15 (2%) or an imprinting mutation (< 5%) [27]. 5. Mechanisms leading to uniparental disomy There are several mechanisms causing UPD. With the exception of the partial UPD as observed for chromosome 11p, UPD involves the entire chromosome, and is caused by at least two errors in chromosome segregation, either during meiosis or during mitosis. UPD15mat has been studied most extensively, since it is the most common UPD. The most frequent mechanism for maternal UPD15 is as follows [29](Fig. 1). During meiosis I, a non-disjunction of the two chromosomes 15 occurs, leading to an oocyt with two chromosomes 15. After fertilization, this results in a trisomy 15. This is unviable, unless a correction or a `trisomy rescue' occurs. The loss of one of the maternal chromosomes 15 leads to a normal embryo, whereas the loss of the paternal chromosome 15 leads to maternal UPD15. The initial error therefore is a non-disjunction, and, as for trisomy 21, the risk for non-disjunction is related to advanced maternal age. It is therefore not surprising to observe an advanced mean maternal age in children with
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K. Devriendt / European Journal of Obstetrics & Gynecology and Reproductive Biology 92 (2000) 29±34
Fig. 1. Most common mechanism leading to maternal uniparental disomy for chromosome 15. Maternal non-disjunction leads to an oocyte with two chromosomes 15. After fertilisation, trisomy 15 is present. Trisomy rescue will lead to a loss of one of the chromosmes 15, either (A) the paternal one resulting in UPD15mat or Prader±Willi syndrome, or (B) one of the maternal chromosomes 15 resulting in a normal situation.
Prader±Willi syndrome caused by a maternal UPD15 [30]. In Angelman syndrome UPD15pat is and caused by a different mechanism. Here, fertilization of an oocyt lacking a chromosome 15 by a normal sperm cell leads to a zygote with monosomy 15. In a subsequent mitosis, non-disjunction of the chromatids 15 restores the normal chromosome complement, but with the presence of two paternal chromosomes 15 [29]. 6. Confined placental mosaicism Con®ned placental mosaicism (CPM) means the presence of a chromosomal aberration (usually a trisomy) present in the placenta, but not in the fetus [31]. This is not exceptional, and found in approximately 1±2% of chorionic villus biopsies. CPM has important clinical consequences, since it may cause intra-uterine growth restriction. One possible mechanism is a postzygotic error, occurring in the placental cell lineage. In this instance, the mosaicism is usually found in either the trophoblast cells (type I CPM; detected after direct culture of the chorionic villi) or in the chorionic extra-embryonic mesenchym (type II CPM; detected after long term culture of the chorionic villi) [32]. An alternative mechanism is trisomy rescue. Depending on the timing of the trisomy rescue, a proportion of either somatic or placental cells will present with for example a trisomy15. This can result in either a somatic mosaicism for trisomy 15, which is exceptional and usually lethal [33] or in a CPM. In certain instances, the rescue occurs for only part of the chromosome leading to an associated trisomy for part of chromosome 15 [34]. In CPM caused by trisomy rescue, the trisomic cells are usually found in both the trophoblast and chorionic extra-embryonic mesenchym (type III CPM)[32]. It is of interest that different chromosomes are associated with speci®c types of CPM [31].
In type III CPM, the CPM can be associated with UPD for the chromosome involved. Hence, when during prenatal diagnosis a con®ned placental mosaicism is found for one of the chromosomes known to carry imprinted genes, one should search for the presence of the uniparental disomy in the fetus. Also, it is not always clear whether the observed IUGR is actually caused by the CPM or the associated UPD. For instance, UPD16mat is almost always associated with con®ned placental mosaicism for trisomy 16, and patients have been described with similar features with CPM trisomy 16 but without UPD16 [35,36]. In addition, a patient with normal birthweight with a low level of CPM16 and with UPD16 was reported [37]. In a systematic study of 35 cases with unexplained IUGR, Moore et al. [38] found two cases with UPD16, and both were associated with CPM 16. Van Opstal et al. [39] found 1 UPD16mat with CPM out of 23 cases with IUGR. In cases of unexplained IUGR, examination of the placenta for CPM can be valuable. However, at the present time, this is technically demanding, time consuming and therefore not yet routinely available. 7. What is the evolutionary role of genomic imprinting? Several theories have been suggested to explain the occurrence of genomic imprinting. One of the most attractive hypothesis is the so called con¯ict theory, also known as `the battle of sexes' [40±42]. According to this theory, it is the interest to both the mother and the father to have a maximum number of viable offspring in order to maintain their genes in the population. When mating is polygamous, it is of the interest for the father to ensure maximal growth of his offspring, and thus, recruit as many resources from the mother as possible. In contrast, mothers wants to limit embryonic and fetal growth, to be able to reproduce again, with another male. This necessitates dividing her resources over different pregnancies. The fact that several imprinting disorders are associated with IUGR or, in one instance also overgrowth, supports this theory. Also in accordance with this theory is that paternal genes are important for placenta development, necessary to transfer resources from the mother to the developing fetus. It is of interest that in birds, imprinting is not observed. In these species, once the egg is laid, resources are ®xed and consequently cannot be altered anymore by paternal genes. Interestingly, genomic imprinting also has a role in postnatal feeding behavior. One of the hallmark features of the PWS is severe neonatal hypotonia, with major feeding dif®culties [26]. More interesting is the mouse Mest or peg1-gene, which is only active on the paternal chromosome (peg stands for paternally expressed gene 1). Peg1-knock-out mice are normal when they inherit the disrupted gene from their father. When they inherit the knock-out gene from their mother, newborn peg1-de®cient mice are growth restricted, and show a high neonatal mortality. However, as adults, they are physically normal.
K. Devriendt / European Journal of Obstetrics & Gynecology and Reproductive Biology 92 (2000) 29±34
Interestingly, adult female knock-out mice neglect their young, indicating that this gene has a role in postnatal nursing behavior of mothers [43]. Besides the con¯ict theory, a more `cooperative' theory suggests that genomic imprinting makes sex necessary, since both the maternal and paternal genomes are complementary. As a result of sex, genetic variation increases, which is advantageous for the species. Another theory states that, thanks to genomic imprinting, parthenogenesis in the ovarium will only lead to a teratoma, and not to highly invasive trofoblast tumors [44]. 8. Conclusion Intrauterine growth is a complex process, which is in part genetically determined. Recent insights have revealed that there are speci®c human genes that are active only on one of the two chromosomes, depending on whether they are located on the paternal or maternal chromosome. Disruption of these genes will lead to abnormal development, and of interest, this is frequently associated with an disturbed growth of the embryo and the fetus. In most cases, IUGR is observed, whereas enhanced growth is only seen in the Beckwith±Wiedemann syndrome. This indicates that genomic imprinting has a fundamental role in regulating antenatal growth. However, the precise mechanisms through which these genes control intrauterine growth are unknown, and this awaits their identi®cation and further characterization. References [1] Solter D. Differential imprinting and expression of maternal and paternal genomes. Annu Rev Genet 1988;22:127±46. [2] Surani MA, Barton SC, Norris ML. Development of reconstituted mouse eggs suggests imprinting of the genome during gametogenesis. Nature 1984;308:548±50. [3] Surani MA, Reik W, Norris ML, Barton SC. Influence of germline modifications of homologous chromosomes on mouse development. J Embryol Exp Morphol 1986;97(Suppl.):123±36. [4] McGrath J, Solter D. Completion of mouse embryogenesis requires both the maternal and paternal genomes. Cell 1984;37:179±83. [5] Lindor NM, Ney JA, Gaffey TA, Jenkins RB, Thibodeau SN, Dewald GW. A genetic review of complete and partial hydatidiform moles and nonmolar triploidy. Mayo Clin Proc 1992;67:791±9. [6] Surani MA, Barton SC, Howlett SK, Norris ML. Influence of chromosomal determinants on development of androgenetic and parthenogenetic cells. Development 1988;103:171±8. [7] McFadden DE, Kalousek DK. Two different phenotypes of fetuses with chromosomal triploidy: correlation with parental origin of the extra haploid set. Am J Med Genet 1991;38:535±8. [8] McFadden DE, Kwong LC, Yam IY, Langlois S. Parental origin of triploidy in human fetuses: evidence for genomic imprinting. Hum Genet 1993;92:465±9. [9] Cattanach BM, Kirk M. Differential activity of maternally and paternally derived chromosome regions in mice. Nature 1985;315:496±8. [10] Ferguson-Smith AC, Cattanach BM, Barton SC, Beechey CV, Surani MA. Embryological and molecular investigations of parental imprinting on mouse chromosome 7. Nature 1991;351:667±70.
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Genetic control of intra-uterine growth Koen Devriendt* Center for Human Genetics, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium
Abstract The expression of a few genes in the human genome depends on whether they are located on the maternal or on the paternal chromosome. This phenomenon is called genomic imprinting. Several of these genes have a role in normal embryonic and fetal growth, as indicated by an abnormal development associated with disturbed genomic imprinting. This has lead to the suggestion that the genomic imprinting has evolved as a mechanism to regulate embryonic and fetal growth. # 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Imprinting; Uniparental disomy; Syndrome; Intrauterine growth restriction
1. Introduction It has been known for a long time that both maternal and paternal gametes are required for a normal mammalian development and growth, indicating a functional difference between the maternal and paternal genome. Recent progress in genetics has revealed that for speci®c genes, only one of the two alleles is active, depending on the parental origin. For certain genes, only the gene on the chromosome inherited from the mother is active and the paternal allele is silenced, for others, only the gene on the paternal chromosome is active, whereas the maternally inherited gene is silenced. This is called genomic imprinting. This genetic mechanism explains the occurrence or inheritance of certain genetic disorders, such as the Beckwith±Wiedemann or Angelman syndromes, that could not be understood by traditional Mendelian genetics. Moreover, from a more fundamental point of view, genomic imprinting sheds new light on some of the underlying mechanisms of intrauterine growth. 2. A complementary role for the maternal and paternal genome in development Nuclear transfer experiments in mice have made possible the creation of embryos carrying solely maternal chromosomes `gynogenetic embryos' by replacement of the paternal by a maternal pronucleus (reviewed in Solter [1]). This effect is similar as in parthenogenetic embryos. Such * Corresponding author. Tel.: 32-16-345906; fax: 32-16-346051. E-mail address: [email protected] (K. Devriendt).
embryos do not develop well and die in a few days after implantation, due to failure of development of the extraembryonic components [2,3]. In contrast `androgenetic embryos', which contain only paternal chromosomes, develop well initially reaching the blastocyst stage. However, at implantation, only the extraembryonic components develop [4]. In the human, similar observations have been made, respectively in teratoma and in the complete hydatiform mole. Teratomata may arise from parthenogenetically activated oocytes with duplication of the maternal genome, and thus, contain only maternal chromosomes. This leads to a tumor consisting of different tissues from all three germ layers, but without extraembryonic components, indicating that maternal genes are necessary for the development of the embryo itself. In contrast, in the complete hydatiform mole, no embryo is formed. There is an abundance of placental tissue, with villi that have a swollen vesicular aspect but absence of fetal circulation. The most frequent mechanism leading to a complete mole is the fertilization of an oocyte that lacks a maternal pronucleus, followed by a duplication of the paternal chromosomes. In a complete mole, all chromosomes are of paternal origin [5], indicating that placental development depends on the expression of speci®c genes on the paternal chromosomes. Thus, the overall impression is that genes on the paternal genome are required for development of the placenta, whereas certain maternal genes are essential for the development of the embryo itself. To understand better why androgenetic or gynogenetic embryos fail to develop normally, mouse chimeras, consisting of cells from two different sources, have been constructed. Chimeric embryos can be made where only part of the cells are either androgenetic or gynogenetic through the
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K. Devriendt / European Journal of Obstetrics & Gynecology and Reproductive Biology 92 (2000) 29±34
fusion of cells from a androgenetic or gynogenetic embryo with a normal embryo. These embryos survive allowing a proper analysis of the phenotype. It was found that androgenetic and gynogenetic cells contribute to different parts of the developing embryo and fetus [6]. Gynogenetic chimera cells are speci®cally found in ectodermal derivatives, e.g. the central nervous system (mainly the cortex and striatum) but are absent from the placenta and the yolk sac. Such embryos are growth restricted, but often display an enhanced growth of the brain. In contrast, androgenetic chimera cells are preferentially located in trophoblastic tissue, primitive endoderm lineages (the yolk sac), mesodermal derivatives (muscles and heart) and in speci®c parts of the brain (e.g. the hypothalamus). Such fetuses display an overall overgrowth, often with a reduced brain development. These phenotypes are highly reminiscent of the triploidic condition in the human, where cells contain 69, instead of 46 chromosomes. The phenotypes of triploid embryos differ and depend on the parental origin of the extra set of chromosomes [7,8]. When there are two sets of maternal chromosomes, fetal growth is severely restricted with relative macrocephaly and a very small placenta. Such pregnancies can evolve until far into the second trimester. In contrast, in triploidy with an extra set of paternal chromosomes, the fetus has a relatively normal growth, with either a normal head size or microcephaly. Such pregnancies usually miscarry early during pregnancy whereas the placenta has the typical features of a partial mole. The interpretation of these observations in both mice and humans is that there must be speci®c genes that are important in normal embryonic and fetal development, with an expression that is restricted to only one of the two alleles. Monoallelic expression is also found for most genes on the X-chromosome in females, as a result of the random inactivation of one of the two chromosomes in somatic cells. Genomic imprinting, however, is not random, but depends on the parental origin of the chromosome: for certain genes only the maternal allele is active, (paternal imprinting), whereas for others the paternal allele is active (maternal allele is silenced or imprinted). The next question is to identify the imprinted genes, to localize them to speci®c chromosomal fragments and ®nally to isolate them. 3. Chromosome localization of imprinted genes in mice: uniparental disomy Using mice carrying well-de®ned chromosomal translocations, it has been possible to breed mice where speci®c chromosomal fragments were derived from a single parent, either the mother or the father [9]. Thus, instead of all chromosomes (as in the nuclear transfer experiments or chimeras), only part of a chromosome was derived from a single parent. This is called uniparental disomy (UPD). For several chromosomal fragments the resulting phenotype was normal, and it could then be concluded that these chromo-
somal regions do not carry imprinted genes. For other chromosomal fragments, an abnormal phenotype was observed, indicating the location of an imprinted gene. This has allowed to construct a chromosomal map for imprinted genes in mice [9]. For instance, fetuses with a maternal UPD (UPDmat) of distal chromosome 7 are growth restricted, and die around day 16 of gestation [10]. Paternal UPD (UPDpat) for the same chromosomal region results in an even earlier death, so that no speci®c phenotype could be described. More insight was obtained using chimeric mice that carry UPDpat in only part of the cells. Interestingly, such embryos show the opposite phenotype, i.e. enhanced embryonic growth. This chromosomal region harbours the gene for insulin-like growth factor II, a major embryonic and fetal growth factor [10]. This gene is maternally imprinted, expressed only from the paternal allele whereas the maternal allele is always silenced [10]. This explains why in embryos with two maternal IGFII-genes, IGFII expression is very low, resulting in an impaired growth. In contrast, in mice with two paternal alleles IGFII production is increased and growth is therefore enhanced. The observations in IGFII-knock-out mice support this concept. Disruption of the IGFII-gene does not result in an abnormal phenotype when the mutation is inherited from the mother, but mice are growth de®cient when the disrupted IGFII gene is inherited from the father [11]. 4. Uniparental disomy in humans related to growth disturbances As indicated before, examples from human fetal pathology show the existence of genomic imprinting in humans. During evolution, the chromosomes are being reshuf¯ed continuously, but using the maps of conserved genes, it has been possible to delineate the human chromosomes homologous to the mouse chromosomal fragments carrying imprinted genes. In many instances, these human chromosomes also carry imprinted genes [12]. For example, the distal part of human chromosome 11p is homologous to distal mouse chromosome 7. The Beckwith± Wiedemann syndrome (BWS) is an overgrowth syndrome, characterized by high birth weight, macroglossia, omphalocoele, neonatal hypoglycemia, visceromegaly and hemihypertrophy. Adrenal carcinoma, nephroblastoma, hepatoblastoma, and rhabdomyosarcoma occur with increased frequency [13]. Several genetic defects have been described in BWS, all involving one or more genes on chromosome 11p15 (reviewed by Li et al. [14]). In some patients, trisomy for the distal part of chromosome 11p is detected, with in all instances, two paternally derived chromosome 11p fragments. In a subset of BWS patients, uniparental disomy for chromosome 11p is found. This is present in a mosaic state, i.e. only in a proportion of somatic cells and only for part of chromosome 11 [15,16].
K. Devriendt / European Journal of Obstetrics & Gynecology and Reproductive Biology 92 (2000) 29±34 Table 1 Overview of known clinical manifestations of UPDs for specific chromosomesa Chromosome
Maternal UPD
Paternal UPD
2 6 7 11 14
(IUGR) [45] ± Silver±Russel ± IUGR, pubertas praecox [48] Prader±Willi (IUGR) IUGR [50]
± Neonatal diabetes [46] ± Beckwith±Wiedemann [47] Short limbed dwarfism [49]
15 16 20
Angelman syndrome ± ±
a
( ) Indicate that it is not yet certain whether the phenotype is related to the UPD or to an associated CPM. References are shown between [ ].
The common region of UPD is chromosome 11p15, where the imprinted genes map, including human IGFII. The mechanism leading to partial and mosaic UPD11 is a postzygotic error in chromosome segregation, with somatic mitotic recombination [15,16]. A postzygotic error also explains why monozygotic twins can be discordant for this genetic condition since the error occurs after division of the embryo in two separate twin embryos. When UPD11pat is present in all somatic cells the embryo formed is unviable [16]. In humans, UPD has been observed for most chromosomes [17,18]. In most instances, there is no associated phenotype, indicating that these chromosomes do not carry imprinted genes, whereas UPD of other chromosomes causes a distinct phenotype (Table 1). It is of interest that many of these UPDs are associated with disturbed intrauterine growth, mostly growth restriction. Enhanced growth has only been observed in the Beckwith±Wiedemann syndrome. With the exception of the BWS, the Prader±Willi syndrome and the Angelman syndrome, the imprinted genes responsible for the phenotype are not known. The Silver±Russel syndrome (SRS) is a prototype of a disorder characterized by pre- and post-natal growth restriction [19]. Additional features include triangular face and a relatively large head, clinodactyly of the ®fth ®ngers and hypospadias. It is clear that this clinical de®nition is rather loose, and that this condition is etiologically heterogeneous. In some children with the SRS, body asymmetry is found, and this may re¯ect somatic mosaicism for a genetic mutation. In approximately 10% of cases, maternal uniparental disomy for chromosome 7 is found [20±22]. Two imprinted genes have been mapped to chromosome 7, the PEG1/Mest gene and the [g]2-COP gene, but so far, no mutations affecting these genes have been found in patients with the SRS without UPD7mat [23,24]. Interestingly, a patient with a de novo duplication of the maternal chromosome 7p11.2p13 has been reported [25]. This suggests that the IUGR seen in UPD7mat may result from an increased dose of a paternally imprinted gene on chromosome 7, rather than the absence of a growth promoting gene.
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Uniparental disomy for chromosome 15 is the most frequent UPD, and associated with the Prader±Willi syndrome (PWS) when the UPD is maternal, and Angelman syndromes in UPD15pat. The study of these two disorders has been particularly helpful in de®ning the mechanisms underlying genomic imprinting. The PWS is characterized by severe neonatal hypotonia with major feeding dif®culties and failure to thrive, distinct facial features, developmental delay, short stature and hypogonadotrophic hypogonadism. Interestingly, around the age of 2±3 years, these children develop an uncontrolled appetite, which leads to an severe obesity when feeding is not controlled [26]. In approximately 25% of patients, UPD is found. The remaining patients have either a deletion in chromosome 15q11±13 (70%) or an imprinting mutation (< 5%) [27]. Several imprinted genes, expressed from the paternal chromosome only have been identi®ed in this region, and probably, the disorder results from the reduced expression of several of these genes. The phenotype of the Angelman syndrome is entirely different, and characterized by severe mental retardation, epilepsy, ataxia and characteristic facial features. Typically, these children do not develop speech. The disorder is a single gene disorder, and caused by the absence of the UBE3A gene, which is found nearby the genes responsible for the PWS on chromosome 15q11±13, but shows an opposite imprinting pattern. The UBE3A gene is only active on the maternal chromosome 15, and interestingly, only so in the brain, since in other tissues, both alleles are expressed [28]. The Angelman syndrome can thus be caused by a number of different mechanisms, all leading to a de®ciency of the UBE3A gene: a deletion of maternal chromosome 15q11±13(70%),mutationsinthematernalUBE3Agene(25%) and, more rarely, by a paternal uniparental disomy for chromosome 15 (2%) or an imprinting mutation (< 5%) [27]. 5. Mechanisms leading to uniparental disomy There are several mechanisms causing UPD. With the exception of the partial UPD as observed for chromosome 11p, UPD involves the entire chromosome, and is caused by at least two errors in chromosome segregation, either during meiosis or during mitosis. UPD15mat has been studied most extensively, since it is the most common UPD. The most frequent mechanism for maternal UPD15 is as follows [29](Fig. 1). During meiosis I, a non-disjunction of the two chromosomes 15 occurs, leading to an oocyt with two chromosomes 15. After fertilization, this results in a trisomy 15. This is unviable, unless a correction or a `trisomy rescue' occurs. The loss of one of the maternal chromosomes 15 leads to a normal embryo, whereas the loss of the paternal chromosome 15 leads to maternal UPD15. The initial error therefore is a non-disjunction, and, as for trisomy 21, the risk for non-disjunction is related to advanced maternal age. It is therefore not surprising to observe an advanced mean maternal age in children with
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Fig. 1. Most common mechanism leading to maternal uniparental disomy for chromosome 15. Maternal non-disjunction leads to an oocyte with two chromosomes 15. After fertilisation, trisomy 15 is present. Trisomy rescue will lead to a loss of one of the chromosmes 15, either (A) the paternal one resulting in UPD15mat or Prader±Willi syndrome, or (B) one of the maternal chromosomes 15 resulting in a normal situation.
Prader±Willi syndrome caused by a maternal UPD15 [30]. In Angelman syndrome UPD15pat is and caused by a different mechanism. Here, fertilization of an oocyt lacking a chromosome 15 by a normal sperm cell leads to a zygote with monosomy 15. In a subsequent mitosis, non-disjunction of the chromatids 15 restores the normal chromosome complement, but with the presence of two paternal chromosomes 15 [29]. 6. Confined placental mosaicism Con®ned placental mosaicism (CPM) means the presence of a chromosomal aberration (usually a trisomy) present in the placenta, but not in the fetus [31]. This is not exceptional, and found in approximately 1±2% of chorionic villus biopsies. CPM has important clinical consequences, since it may cause intra-uterine growth restriction. One possible mechanism is a postzygotic error, occurring in the placental cell lineage. In this instance, the mosaicism is usually found in either the trophoblast cells (type I CPM; detected after direct culture of the chorionic villi) or in the chorionic extra-embryonic mesenchym (type II CPM; detected after long term culture of the chorionic villi) [32]. An alternative mechanism is trisomy rescue. Depending on the timing of the trisomy rescue, a proportion of either somatic or placental cells will present with for example a trisomy15. This can result in either a somatic mosaicism for trisomy 15, which is exceptional and usually lethal [33] or in a CPM. In certain instances, the rescue occurs for only part of the chromosome leading to an associated trisomy for part of chromosome 15 [34]. In CPM caused by trisomy rescue, the trisomic cells are usually found in both the trophoblast and chorionic extra-embryonic mesenchym (type III CPM)[32]. It is of interest that different chromosomes are associated with speci®c types of CPM [31].
In type III CPM, the CPM can be associated with UPD for the chromosome involved. Hence, when during prenatal diagnosis a con®ned placental mosaicism is found for one of the chromosomes known to carry imprinted genes, one should search for the presence of the uniparental disomy in the fetus. Also, it is not always clear whether the observed IUGR is actually caused by the CPM or the associated UPD. For instance, UPD16mat is almost always associated with con®ned placental mosaicism for trisomy 16, and patients have been described with similar features with CPM trisomy 16 but without UPD16 [35,36]. In addition, a patient with normal birthweight with a low level of CPM16 and with UPD16 was reported [37]. In a systematic study of 35 cases with unexplained IUGR, Moore et al. [38] found two cases with UPD16, and both were associated with CPM 16. Van Opstal et al. [39] found 1 UPD16mat with CPM out of 23 cases with IUGR. In cases of unexplained IUGR, examination of the placenta for CPM can be valuable. However, at the present time, this is technically demanding, time consuming and therefore not yet routinely available. 7. What is the evolutionary role of genomic imprinting? Several theories have been suggested to explain the occurrence of genomic imprinting. One of the most attractive hypothesis is the so called con¯ict theory, also known as `the battle of sexes' [40±42]. According to this theory, it is the interest to both the mother and the father to have a maximum number of viable offspring in order to maintain their genes in the population. When mating is polygamous, it is of the interest for the father to ensure maximal growth of his offspring, and thus, recruit as many resources from the mother as possible. In contrast, mothers wants to limit embryonic and fetal growth, to be able to reproduce again, with another male. This necessitates dividing her resources over different pregnancies. The fact that several imprinting disorders are associated with IUGR or, in one instance also overgrowth, supports this theory. Also in accordance with this theory is that paternal genes are important for placenta development, necessary to transfer resources from the mother to the developing fetus. It is of interest that in birds, imprinting is not observed. In these species, once the egg is laid, resources are ®xed and consequently cannot be altered anymore by paternal genes. Interestingly, genomic imprinting also has a role in postnatal feeding behavior. One of the hallmark features of the PWS is severe neonatal hypotonia, with major feeding dif®culties [26]. More interesting is the mouse Mest or peg1-gene, which is only active on the paternal chromosome (peg stands for paternally expressed gene 1). Peg1-knock-out mice are normal when they inherit the disrupted gene from their father. When they inherit the knock-out gene from their mother, newborn peg1-de®cient mice are growth restricted, and show a high neonatal mortality. However, as adults, they are physically normal.
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Interestingly, adult female knock-out mice neglect their young, indicating that this gene has a role in postnatal nursing behavior of mothers [43]. Besides the con¯ict theory, a more `cooperative' theory suggests that genomic imprinting makes sex necessary, since both the maternal and paternal genomes are complementary. As a result of sex, genetic variation increases, which is advantageous for the species. Another theory states that, thanks to genomic imprinting, parthenogenesis in the ovarium will only lead to a teratoma, and not to highly invasive trofoblast tumors [44]. 8. Conclusion Intrauterine growth is a complex process, which is in part genetically determined. Recent insights have revealed that there are speci®c human genes that are active only on one of the two chromosomes, depending on whether they are located on the paternal or maternal chromosome. Disruption of these genes will lead to abnormal development, and of interest, this is frequently associated with an disturbed growth of the embryo and the fetus. In most cases, IUGR is observed, whereas enhanced growth is only seen in the Beckwith±Wiedemann syndrome. This indicates that genomic imprinting has a fundamental role in regulating antenatal growth. However, the precise mechanisms through which these genes control intrauterine growth are unknown, and this awaits their identi®cation and further characterization. References [1] Solter D. Differential imprinting and expression of maternal and paternal genomes. Annu Rev Genet 1988;22:127±46. [2] Surani MA, Barton SC, Norris ML. Development of reconstituted mouse eggs suggests imprinting of the genome during gametogenesis. Nature 1984;308:548±50. [3] Surani MA, Reik W, Norris ML, Barton SC. Influence of germline modifications of homologous chromosomes on mouse development. J Embryol Exp Morphol 1986;97(Suppl.):123±36. [4] McGrath J, Solter D. Completion of mouse embryogenesis requires both the maternal and paternal genomes. Cell 1984;37:179±83. [5] Lindor NM, Ney JA, Gaffey TA, Jenkins RB, Thibodeau SN, Dewald GW. A genetic review of complete and partial hydatidiform moles and nonmolar triploidy. Mayo Clin Proc 1992;67:791±9. [6] Surani MA, Barton SC, Howlett SK, Norris ML. Influence of chromosomal determinants on development of androgenetic and parthenogenetic cells. Development 1988;103:171±8. [7] McFadden DE, Kalousek DK. Two different phenotypes of fetuses with chromosomal triploidy: correlation with parental origin of the extra haploid set. Am J Med Genet 1991;38:535±8. [8] McFadden DE, Kwong LC, Yam IY, Langlois S. Parental origin of triploidy in human fetuses: evidence for genomic imprinting. Hum Genet 1993;92:465±9. [9] Cattanach BM, Kirk M. Differential activity of maternally and paternally derived chromosome regions in mice. Nature 1985;315:496±8. [10] Ferguson-Smith AC, Cattanach BM, Barton SC, Beechey CV, Surani MA. Embryological and molecular investigations of parental imprinting on mouse chromosome 7. Nature 1991;351:667±70.
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