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Development 1990 Supplement, 141-148 Printed in Great Britain © The Company of Biologists Limited 1990 141 How imprinting is relevant to human disease JUDITH G. HALL Department of Medical Genetics, University of British Columbia, Vancouver, B.C. Canada Summary Genomic imprinting appears to be a ubiquitous process in mammals involving many chromosome segments whose affects are dependent on their parental origin. One of the challenges for clinical geneticists is to determine which disorders are manifesting imprinting effects and which families are affected. Re-evaluation of cases of chromosomal abnormalities and family histories of disease manifestations should give important clues. Examination of the regions of human chromosomes homologous to mouse imprinted chromosomal regions may yield useful information. Cases of discordance in monozygous twins may also provide important insights into imprinted modification of diseases. Introduction uniparental disomy and imprinting, (6) asymmetric expression in monozygotic twins, and finally, (7) the role of chromosome pairing in relationship to parent of origin differences in imprinting recombination and mutation. Evidence has been accumulating from various kinds of research that genomic imprinting is a common occurrence in mammals including humans (Hall, 1990a; Reik, 1989; Searle et al. 1989). The lines of research include: (1) androgenetic and gynogenetic mouse embryos and their human homologs, complete moles and ovarian teratomas; (2) triploid phenotypes in humans which are quite different depending on whether the extra set of chromosomes comes from the father or the mother; (3) chromosome deletions as they relate to: (a) loss of heterozygosity in human cancer tissue, and (b) the phenotypes seen in human chromosomal deletion syndromes; (4) uniparental disomies in both mice and humans; (5) transgene methylation and expression in mice; and (6) single gene expression in both humans and mice. This type of work has only been possible because of the development of molecular genetic techniques that allow identification of the parent of origin for a particular chromosome, chromosome segment or locus, and the ability to trace the region of interest through several generations. This paper will concentrate on the present state of knowledge regarding (1) the human chromosome deletion syndromes and their phenotypes, (2) uniparental disomy in humans, (3) the human chromosomal areas homologous to chromosome regions where imprinting is observed in mice, (4) patterns of inheritance for imprinted traits and diseases in model pedigrees, (5) the nomenclature which is appropriate for designating areas of chromosomes involved in Key words: imprinting, human diseases, uniparental disomy, twinning, chromosome deletion syndromes, human/mouse homologies, nomenclature. Chromosome deletion syndromes The phenotypes of various chromosome deletion syndromes in humans have been described over the last 30 years (Schinzel, 1983). The most common viable ones, involving relatively large visible deletions, were of course described first (eg. 13q-, 18p-, 18q- and 21q-). The fact that chromosomes 13, 18 and 21 are tolerated in trisomy form or with large visible deletions in humans suggests that they may carry less 'important' genetic information and that they may be atypical with regard to other chromosomal behaviour, such as recombination, meiotic pairing and genomic imprinting. Other human chromosome deletion syndromes took longer to define and the phenotypes are often quite variable (Schinzel, 1983). The Prader-Willi syndrome has been recognized for over 30 years (Prader et al. 1956) as a specific syndrome characterized by hypotonia in infancy, obesity with hyperphagia beginning in early childhood, hypogonadotrophic hypogonadism, mental retardation, development of small hands and feet and characteristic facies (Butler, 1990) (Fig. 1). About 10 years ago, a chromosome deletion of 15qll—13 associated with the disease was first noted (Ledbetter et al. 1981). Subsequently, more than half of the affected individuals have been found to have cytogenetically detectable deletions and many others to have submicroscopic 142 J. G. Hall Fig. 1. An individual with typical features of Prader-Willi syndrome including obesity, small hands and feet, narrow forehead, almond shaped eyes. deletions detected by molecular probes (Magenis et al. 1990; Nicholls et al. 1989; Williams et al. 1990). More recently, the deleted chromosome has been shown to be always of paternal origin (Magenis et al. 1990). About 25 years ago, Angelman (Angelman, 1965) described a syndrome in children with a happy disposition, mental retardation, unusual and frequent laughter and bizarre, repetitive, symmetric, ataxic movements, specific facies, which involved a large mouth, protruding tongue, and an unusual type of seizure (Fig. 2). Subsequently, about half of the affected individuals have been found to have a cytogenetically detectable deletion of 15q 11-13 (Imaizumi et al. 1990; Magenis et al. 1987; Magenis et al. 1990). The deletion is not distinguishable cytogenetically from that seen in Prader-Willi patients. However, the deletions in the Angelman syndrome appear to always involve the maternally inherited chromosome 15 (Magenis etal. 1990; Williams et al. 1990). At this time it is not entirely clear whether the deletions of chromosome 15 in the Prader-Willi and Angelman syndromes involve exactly the same areas of the long arm of chromosome 15, but the DNA studies do suggest that Fig. 2. An individual with typical features of Angelman syndrome including happy disposition, large mouth, and repetitive movements. there may be at least a common overlap segment (Magenis et al. 1990). In addition, familial cases of Angelman syndrome have been reported that seem to lack the deletion (Frynse/fl/. 1989; Hall, 19906; Pembreye/o/. 1989). In two of these cases, there has been a chromosome translocation involving the chromosome J5q 1J —13 region which has been inherited from the phenotypically normal mother. It has been suggested (Pembrey et al. 1989; Fryns et al. 1989) that in these families the translocation has deleted a gene and that this deletion has uncovered an abnormal mutation on the other chromosome, eg. the paternally derived chromosome, allowing expression of an autosomal recessive trait. The Prader-Willi and Angelman cases raise the issue of parental origin of chromosome abnormalities in general and have implications for the "classical" observed phenotypes in conditions such as 4p-, 18q-, etc., in terms of whether they are also always deletions of the chromosome derived from the mother or from the father. The concept of imprinting implies that some translocations. inversions, duplications, and other How imprinting is relevant to human disease chromosomal rearrangements will result in phenotypic abnormalities only when they occur in the chromosome transmitted from the mother or from the father. Thus, families with chromosomal rearrangements that come to attention because of a phenotypically abnormal child need to be re-evaluated in relation to the sex of the parent transmitting the rearrangement. In the past, when a phenotypically normal parent had the same chromosomal rearrangement as the abnormal child, the chromosomal abnormality was dismissed as a cause of the phenotypic features. However, if one takes the concept of genomic imprinting seriously, the parent of origin may be critical and the offspring may only survive or only manifest particular features depending on the parental origin of the abnormal chromosome. In our experience, for instance, the deleterious effect of deletion 22q has only been seen when the chromosome 22 has been inherited from the father. Similarly, when two children, particularly of the opposite sex, have a disorder and the parents are phenotypically normal, we have assumed this to represent autosomal recessive inheritance. However, many studies using DNA markers have shown that submicroscopic deletions defined by molecular analysis, may lead to phenotypes similar to those seen with longer cytogenetically visible deletions. If such an area was imprintable, then we would expect non-expression when transmitted from a parent of one sex and manifestations of the deletion when transmitted from the parent of the opposite sex. Uniparental dlsomy Uniparental disomy has been studied systematically in mice for almost all segments of the mouse chromosomes by Cattanach and Kirk (1985), Searle and Beechey (1985), and Lyon and Glenister (1977). Uniparental disomy of specific chromosome segments from the mother or the father are produced in mice by breeding animals with Robertsonian and reciprocal translocations. In this way, the mice have a balanced set of chromosomes but both copies of a particular chromosome or chromosome segment have been derived from one or the other parent. At least seven mouse chromosome segments appear to have major differential effects on growth, behaviour and survival depending on whether inheritance is from the mother or the father. Several other chromosome segments seem to give distorted ratios of expected number of offspring suggesting non-reciprocal lethality. What is known about this kind of process in humans? How often does uniparental disomy occur? There are numerous human cases involving the X chromosome, the most frequent being 47,XXY and 47,XXX. However, there are at this time only two documented situations involving human autosomes (cystic fibrosis and Prader-Willi). Two cases of cystic fibrosis with uniparental disomy have been reported (Spence et al. 1988; Voss et al. 1989). Uniparental disomy was recognized by chance in these cystic fibrosis cases 143 because DNA polymorphisms close to the cystic fibrosis gene were being traced in the families. However, maternal uniparental disomy of chromosome 7 may occur relatively frequently without causing cystic fibrosis (Hall, 1990c). In both the cases of cystic fibrosis with uniparental disomy, the affected children have acquired both of their copies of chromosome 7 (or at least a major part of the chromosome as recognized through DNA studies) from their mothers. Their fathers do not appear from haplotype analysis to be carriers of cystic fibrosis. Non-paternity has been excluded by identification of DNA markers on other chromosomes demonstrating that these children are the biological offspring of the purported father. In each case, the child is homozygous for maternal markers at all loci tested on chromosome 7. Thus, all the evidence supports maternally derived isodisomy of chromosome 7. These appear to be cases of cysticfibrosisin which an autosomal recessive disorder is not 'familial' in the usual sense, since both parents are not carriers. Uniparental disomy has a number of other implications, but for the purpose of considering imprinting, it is worth noting that both of these children, one a male and one a female, had moderate to severe intrauterine and post-natal growth retardation. Normally, children with cystic fibrosis are a normal size at birth. Interestingly, the homologous area of mouse chromosome 6 gives a similar phenotype with uniparental maternal disomy; that is, there is intrauterine growth retardation (Cattanach and Kirk, 1985). There are, of course, a number of other explanations for the intrauterine growth retardation in these two children including the unmasking of another recessive condition by the isodisomy. Intrauterine growth retardation with and without asymmetry of the body is frequently observed in humans. The most common type is often called RussellSilver dwarfism (Donnai et al. 1988; Saal et al. 1985). It tends to be sporadic and as yet has evaded elucidation. With the advent of chromosome markers and polymorphisms, it seems relatively easy to go back and evaluate this type of case to ask if it is caused by uniparental disomy (Hall, 1990c). Many of the affected individuals have asymmetry of their bodies with one side more under grown; thus, one can imagine a situation of mosaicism interacting with uniparental disomy accounting for the asymmetric hypoplasia that is observed. For instance, the hypoplastic part of the body could have uniparental disomy occurring through a mitotic error while the other part of the body does not. If this were the reason for the commonly observed asymmetry seen in these individuals, molecular studies would give a method of comparing the differences between body areas in these individuals and help to define which imprinted chromosomes are involved in these individuals or in such a process. To return to Prader-Willi and Angelman syndromes, recently Nicholls et al. (1989) have observed several cases of Prader-Willi syndrome in which no DNA deletion could be demonstrated but in which both copies of chromosome 15 in the affected individual had 144 J. G. Hall been inherited from the mother. Some of these cases represented uniparental isodisomy, others uniparental heterodisomy. Thus, these cases of Prader-Willi represent a second example of autosomal uniparental disomy in humans. They strongly suggest that it is the lack of a paternal 15 chromosome, or at least the lack of a critical part of the 15q 11-13 region coming from father, which leads to the Prader-Willi phenotype. The converse, that is that cases of Angelman syndrome without cytogenetically detectable lesions represent uniparental disomy, has not been demonstrated. The two cases of Angelman syndrome with translocations inherited from the mother mentioned earlier (Fryns et al. 1989; Pembrey et al. 1989) could represent cases of heterodisomy of chromosome 15. However, thus far, the DNA markers for these cases indicating parent of origin have not been reported. The cases of familial recurrence of Angelman syndrome (Fryns et al. 1989; Pembrey et al. 1989; Williams et al. 1989) in which no deletion is detected by cytogenetic or molecular methods remain a puzzle. Spence et al. (1988) thoroughly discuss the possible mechanisms that might produce human uniparental disomy. They pointed out very clearly that two aneuploid events are necessary. If those events are independent, uniparental disomy should be quite rare (Warburton, 1988). Whether this is so, is not yet clear. The most appealing explanation for the cases of uniparental disomy associated with cystic fibrosis is that a conception occurred with trisomy 7 which then predisposed to the loss of one copy of chromosome 7 since, without such a loss, trisomy 7 would result in intrauterine lethality. If the first aneuploid event producing a gamete with two copies of chromosome 7 was in the first meiotic division, then heterodisomy could occur. If the aneuploid event was in second meiotic division then isodisomy would be expected. Because chiasmata are obligatory, we would not expect complete isodisomy for the whole chromosome in half the cases. From studies of non-disjunction in chromosome 13 and chromosome 21, it appears that 20-30% of nondisjunction is paternal and 70-80% maternal in origin. This discrepancy in the parent of origin of trisomies may explain the relatively more common occurrence of Prader-Willi compared to Angelman syndromes. If we assume that the non-deletion Prader-Willi started as trisomy 15 followed by random loss of the extra chromosome 15 early in development of a trisomy 15 conceptus allowing survival, then the frequency of Prader-Willi as compared with Angelman syndrome is consistent with the observations. Since trisomy 7 and trisomy 15 are non-viable, then a very strong selection for disomic cells is expected if the pregnancy is to survive. However, obviously, if uniparental disomy for a particular chromosome is lethal neither the trisomy nor the uniparental disomic cells could survive and only selection for non-disomy would lead to survival. It appears that uniparental disomy for chromosome 7 and chromosome 15 is viable in the human. The real question is how many other uniparental disomies, either maternally derived or paternally derived, are tolerated in humans (assuming of course that there has not been homozygosity for some other recessive gene produced by the isodisomy which then leads to lethality). Kalousek (1988) has shown that children with intrauterine growth retardation frequently have chromosomal mosaicism of the placenta with no chromosomal abnormalities observed in tissues from the child. Confined chromosomal mosaicism of the placenta is found in 2-5 % of chorionic villus sampling. The question is how many of these cases of confined mosaicism actually represent situations where selection for, and overgrowth of, nonaneuploid tissue has allowed survival and how frequently uniparental disomy is present. One third of cases beginning as a trisomy should end up with uniparental disomy, if no selection against uniparental disomy is present. In mouse studies defining the phenotypes of uniparental disomy, it is important to note that major congenital anomalies are not observed (Cattanach and Kirk, 1985; Lyon and Glenister, 1977; Searle and Beechey, 1985). Rather, variations in growth, behaviour and survival are seen. Thus, if one reflects on common human syndromes that are as yet unexplained, such as Rubinstein-Taybi syndrome, Cornelia de Lange syndrome, Williams syndrome, Russell-Silver syndrome, etc. the possibility that they represent uniparental disomy for other chromosomes must be explored, since they are syndromes in which the major abnormalities consist of disharmonic growth and abnormal behaviour rather than major structural congenital anomalies involving multiple systems. One example of an X-linked disorder associated with uniparental disomy is worth considering in detail. It is the recently reported male-to-male transmission of hemophilia A (Vivaud et al. 1989). This had been thought to be impossible. However, the male child inherited both the X and the Y chromosome from the father. The maternal X was apparently lost either during development or was absent in the fertilized egg. Obviously, in such a case cytogenetic examination of the placenta and other tissues would be very helpful. It seems quite feasible as well that such a case of male-tomale transmission of an X-linked disorder is actually an example of a mosaic Klinefelter syndrome and that during the course of development the maternal X chromosome has been lost in some tissues. Human mouse homologous chromosomal regions The Oxford grid demonstrates the homologous regions of various chromosomes in human and mouse. It can help to suggest possible areas of imprinting in humans (Hall, 1990a; Searle et al. 1989). Thus, genes in and around known imprinted areas in the mouse become of interest and need to be examined in the human. In addition, genes closely linked to genes that are thought to be imprinted in humans deserve particular examination to see if the pedigrees or inheritance patterns also How imprinting is relevant to human disease suggest imprinting (Hall, 1990a). There is some suggestion that malignant hyperthermia, which is very closely mapped to myotonic dystrophy (MacLennan et al. 1990; McCarthy et al. 1990) on chromosome 19, may demonstrate imprinting effects in some families. Patterns of inheritance of imprinted genes Since imprinting appears to be a ubiquitous phenomenon in humans, it is important to re-examine pedigrees in known disorders for possible effects. From the data that is already available, it appears that if an imprinting effect does occur, it may not be present in all families for example, myotonic dystrophy and Huntington disease families. Thus, individual large families should be examined carefully with the idea that there may be differences in phenotypic expression depending on the parent transmitting the gene. As seen in Fig. 3, in an imprinted condition one would expect differences in the phenotypic expression in the offspring dependent on parent of origin. The silencing or turning off of the gene will occur if the offspring has inherited the gene from only one particular parent, mother or father. The imprintable gene would be expected to be transmitted PATERNAL D T* | on ^ (•> D O i-i oonooocro On©!-] *¥TTOOn¥» 00ETO MATERNAL T •"1° s on © DO 145 in a Mendelian manner but expression would be determined by the sex of the parent transmitting the gene. This has been seen in glomus cell tumors (van der Mey et al. 1989), familial Wilms tumor (Huff et al. 1988), and to a lesser extent, in the WiedemannBeckwith syndrome (Lubinsky et al. 1974) and in familial retinoblastoma (Scheffer et al. 1989). In maternal imprinting, the phenotypic expression of a known or an abnormal gene does not occur when transmitted to the mother's offspring of both sexes. The gene is basically 'turned off when inherited from the mother but not when the same gene is transmitted by her father, by her brothers, or by her son. When her sons, who carry but do not manifest the phenotype, transmit the gene, their offspring who inherit the genes will express it and manifest the phenotype but her nonmanifesting daughter's children will not. Just the opposite is seen in paternal imprinting (Hall 1990a). The following should be noted. (1) Equal numbers of affected or non-manifesting males and females are seen in each generation in both maternal and paternal imprinting. (2) Non-manifesting but transmitting ('skipped') individuals are the clue to whether a trait is maternally or paternally imprinted, i.e. in maternal imprinting, a male is the non-manifesting or less manifesting carrier who transmits to manifesting offspring and in paternal imprinting, females are the non-manifesting carriers who transmit the trait. (3) The pedigree of a gene that is imprinted can look like autosomal dominant inheritance, autosomal recessive inheritance, or multifactorial inheritance depending on that part of the family tree is being observed. Thus, conditions that have been considered to be multifactorial need to be re-examined with imprinting in mind. In addition, when there are two genetic forms of a disorder, as defined by linkage (eg. as in Tuberous Sclerosis and Polycystic Kidney Disease) each form needs to be examined with imprinting in mind. (4) Finally, the pedigree observed in imprinting is quite different from that which is seen in mitochondrial or cytoplasmic inheritance. OD0H Fig. 3. Idealized pedigrees for maternal and paternal imprinting. These figures diagram what a pedigree of human disease which has imprinting effects might look like. The term 'imprinting' implies a modification in expression of a gene or allele. An imprintable allele will be transmitted in a Mendelian manner, but expression will be determined by the sex of the transmitting parent. In these idealized pedigrees the term maternal imprinting is used to imply that there will be no phenotypic expression of the abnormal allele when transmitted from the mother and paternal imprinting is used to imply that there will be no phenotypic expression when transmitted from the father. Because there will be a phenotypic affect only when the gene in question or chromosome segment in question is transmitted from one or the other parent, there are a number of non-manifesting offspring. There are an equal number of manifesting males and females or of nonmanifesting male and female carriers for each generation. Nomenclature The nomenclature used to designate uniparental disomy and imprinting must be developed and agreed upon. Most of the appropriate symbols are already available: 'upd' has traditionally been used for uniparental disomy in mice; 'mat' and 'pat' have traditionally been used as a designation for maternal or paternal inheritance; T could be used for isodisomy, and 'h' for heterodisomy. Thus, 46,XY,upd h(7)mat would mean uniparental heterodisomy of a maternally derived chromosome 7; while 46,XX,upd i(15)pat would mean uniparental isodisomy of a paternally derived chromosome 15. If only a segment of chromosome has been shown to be isodisomic it could be designated by 46,XY,upd i(15qll-14)mat. For the sex chromosome disomies there would be four different viable types: 2 146 J. G. Hall heterodisomies and 2 isodisomies. The heterodisomies could be designated h upd (XY)pat, h upd (XX)mat, and the isodisomies i upd (XY)pat and i upd (XX)mat (it should be noted that allodisomy and homodisomy may be needed as more precise molecular definitions of imprinted areas is possible). 'Imp' could be used to designate imprinted or functionally turned off segments of chromosomes. Since imprinting appears to be a dominant function it would be capitalized. Used before a chromosome segment together with parent of origin it would indicate the chromosome or segment was imprinted, eg. 46,XY,Imp(15qll-13)mat would mean that segment qlJ-13 was functionally turned off on the maternally derived chromosome 15. This approach could also be used for single gene designations as well, eg. HD,Imp(4pl6.3)pat would mean that the Huntington Disease gene that was inherited from the father was functionally turned off. These designations are proposed for consideration, but it does seem that with the advent of being able to mark the derivation of a particular chromosome, their use will become more and more important. dant with only one twin having the disorder (Litz et al. 1988; Olney et al. 1988). One concordant pair of monozygous twins with Wiedemann-Beckwith syndrome has been reported. Similarly, when the pedigrees of narcolepsy, which occasionally appears in families manifesting as an autosomal dominant disorder are examined, unusual transmission suggestive of imprinting leading to non-expression is seen. When monozygous affected twins with narcolepsy have been reported (Guillemault et al. 1989), there is discordance with only one of the monozygous twins being affected. This contrasts with other disorders such as diabetes mellitus of the MODY (maturity onset) type where there is a 100% concordance of identical twins. Interestingly, there appears to be discordance in monozygous twins with the Fragile X as well (Laird, personal communication). Thus, there may be something in the process(es) leading to monozygous twinning that is occurring around the same time as genomic imprinting and affects both autosomal and X-chromosome imprinting. These discordant cases may be a clue to understanding the mechanism of imprinting and to identifying human disorders in which genomic imprinting is occurring. Asymmetric expression in monozygotic twins Role of chromosome pairing As discussed in other parts of this symposium, X-inactivation may be a special form of a common process of genomic imprinting that may apply to autosomes. Monozygotic twinning in humans is a poorly understood phenomenon. It is thought to occur during the second week of embryonic development around the same time as X-inactivation is occurring. In recent years several unusual cases of X-linked diseases manifesting in only one of monozygous twin girls have been reported. Careful studies in the last two years show marked asymmetry of X-inactivation (Richards et al. 1990) in several disorders. This asymmetry could be by chance alone, but in the case of Duchenne Muscular Dystrophy, there are few cases, if any, of monozygotic twinning without asymmetry. This suggests that there is something about the process of monozygous twinning that may. in some cases, interact with X-inactivation (Zneimer et al. 1990). If X-inactivation is a form of genomic imprinting, this unusual asymmetric expression of diseases in monozygous twins could, potentially, be relevant to understanding the process of genomic imprinting of autosomes. Two diseases in which imprinting can be strongly suspected from the pedigrees are Wiedemann-Beckwith (Lubinsky et al. 1974; Niikawa et al. L986) and narcolepsy (Guilleminault et al. 1989). Both have already been noted to have asymmetric expression in monozygous twins. Wiedemann-Beckwith is suspected of being paternally imprinted because mothers who display no symptoms frequently transmit the disease to their children of both sexes. The gene in familial cases has been mapped to distal lip (Koufos et al,, 1989). Of eight reported cases of monozygous twins with Wiedemann-Beckwith syndrome, all are female and discor- It is an understatement to say that the actual mechanism(s) of imprinting is (are) not understood at this time. It is strongly suspected that at least some part of the process leading to parent of origin differential phenotypic expression must occur during the pachytene (chromosome pairing) stage of first meiosis (Hulten and Hall, 1990). There are many other things going on at this stage including homologous pairing, crossing over and condensation. It seems very likely that these four processes (and possible parent of origin differences in mutation rates) are somehow interrelated or can affect each other. It appears that crossing over usually occurs at least once in each arm of a chromosome during meiosis. It is hard to believe that such a regular occurrence would happen in a totally random manner. Some areas of chromosomes have higher rates of recombination in males, others have higher rates in females, just as some areas of the chromosomes appear to be markedly different with regard to imprinting. Further, some mutations of both single gene (Jadayel et al. 1990) and of chromosomes (Magenis et al. 1990) have marked parent of origin differences. It makes sense that imprinting sites, recombination sites and initiation of replication sites have specific structural properties. Mismatching, malalignment, or failure to have normal pairing during meiosis, could lead to an increased mutation rate, failure of normal recombination, failure of condensation, or aberrant imprinting. Imprinting must involve some form of 'tagging' of the chromatin that will survive mitosis, but not meiosis. It would appear that the mechanism of imprinting can be divided into: (1) erasure or wiping off the previous How imprinting is relevant to human disease 147 imprinting; (2) preparation of the chromatin or DNA for new modification; (3) new modification of the chromatin in a parental-specific way; and (4) tissuespecific phenotypic expression of parentally derived imprinting in the offspring (Hulten and Hall, 1990). Careful re-evaluation of the pedigrees of human disorders will almost surely help to predict which disorders are likely to be imprinted. It seems likely that this non-traditional form of inheritance is very important in human biology and may explain a number of hitherto confusing observations in human diseases. For very helpful discussions and suggestions, thanks to Maj Hulten, Dagmar Kalousek, John Edwards, Rob Nicholls, Uta Francke and Art Alysworth. I also thank Diane McPherson and Minette Manson for their secretarial help. References ANGELMAN, H. (1965). 'Puppet' children: A report on three cases. Dev Med. Child Nenrol. 7, 681-683. BUTLER, M. G. (1990). Prader-Willi syndrome: Current understanding of cause and diagnosis. Am. J. med. Genet. 35, 319-332. CATTANACH, B. M. AND KIRK, M. (1985). Differential activity of maternally and paternally derived chromosome regions in mice. Nature 315, 496-498. DONNAI, D., THOMPSON, E., ALLANSON, J. AND BARAITSER, M. (1988). Severe Silver-Russell syndrome. J. med. Genet. 26, 447-451. FRYNS, J. P., KLECZKOWSKA, A., DECOCK, P. AND VAN DEN BERC.HE, H. (1989). 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