Development 1990 Supplement, 141-148Printed 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 processin mammals involving many chromosome segmentswhose affects are dependent on their parental origin.One of the challenges for clinical geneticists is todetermine which disorders are manifesting imprintingeffects and which families are affected. Re-evaluation ofcases of chromosomal abnormalities and family historiesof disease manifestations should give important clues.Examination of the regions of human chromosomes

homologous to mouse imprinted chromosomal regionsmay yield useful information. Cases of discordance inmonozygous twins may also provide important insightsinto imprinted modification of diseases.

Key words: imprinting, human diseases, uniparentaldisomy, twinning, chromosome deletion syndromes,human/mouse homologies, nomenclature.

Introduction

Evidence has been accumulating from various kinds ofresearch that genomic imprinting is a common occur-rence in mammals including humans (Hall, 1990a;Reik, 1989; Searle et al. 1989). The lines of researchinclude:(1) androgenetic and gynogenetic mouse embryos andtheir human homologs, complete moles and ovarianteratomas;(2) triploid phenotypes in humans which are quitedifferent depending on whether the extra set ofchromosomes 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 ofthe development of molecular genetic techniques thatallow identification of the parent of origin for aparticular chromosome, chromosome segment or locus,and the ability to trace the region of interest throughseveral generations.

This paper will concentrate on the present state ofknowledge regarding (1) the human chromosomedeletion syndromes and their phenotypes, (2) uniparen-tal disomy in humans, (3) the human chromosomalareas homologous to chromosome regions whereimprinting is observed in mice, (4) patterns ofinheritance for imprinted traits and diseases in modelpedigrees, (5) the nomenclature which is appropriatefor designating areas of chromosomes involved in

uniparental disomy and imprinting, (6) asymmetricexpression in monozygotic twins, and finally, (7) therole of chromosome pairing in relationship to parent oforigin differences in imprinting recombination andmutation.

Chromosome deletion syndromes

The phenotypes of various chromosome deletionsyndromes in humans have been described over the last30 years (Schinzel, 1983). The most common viableones, involving relatively large visible deletions, wereof course described first (eg. 13q-, 18p-, 18q- and 21q-).The fact that chromosomes 13, 18 and 21 are toleratedin trisomy form or with large visible deletions in humanssuggests that they may carry less 'important' geneticinformation and that they may be atypical with regardto other chromosomal behaviour, such as recombi-nation, meiotic pairing and genomic imprinting. Otherhuman chromosome deletion syndromes took longer todefine and the phenotypes are often quite variable(Schinzel, 1983).

The Prader-Willi syndrome has been recognized forover 30 years (Prader et al. 1956) as a specific syndromecharacterized by hypotonia in infancy, obesity withhyperphagia beginning in early childhood, hypo-gonadotrophic hypogonadism, mental retardation, de-velopment of small hands and feet and characteristicfacies (Butler, 1990) (Fig. 1). About 10 years ago, achromosome deletion of 15qll—13 associated with thedisease was first noted (Ledbetter et al. 1981).Subsequently, more than half of the affected individualshave been found to have cytogenetically detectabledeletions and many others to have submicroscopic

142 J. G. Hall

Fig. 1. An individual with typical features of Prader-Willisyndrome including obesity, small hands and feet, narrowforehead, almond shaped eyes.

deletions detected by molecular probes (Magenis et al.1990; Nicholls et al. 1989; Williams et al. 1990). Morerecently, the deleted chromosome has been shown to bealways of paternal origin (Magenis et al. 1990).

About 25 years ago, Angelman (Angelman, 1965)described a syndrome in children with a happydisposition, mental retardation, unusual and frequentlaughter and bizarre, repetitive, symmetric, ataxicmovements, specific facies, which involved a largemouth, protruding tongue, and an unusual type ofseizure (Fig. 2). Subsequently, about half of theaffected individuals have been found to have acytogenetically detectable deletion of 15q 11-13(Imaizumi et al. 1990; Magenis et al. 1987; Magenis et al.1990). The deletion is not distinguishable cytogeneti-cally from that seen in Prader-Willi patients. However,the deletions in the Angelman syndrome appear toalways involve the maternally inherited chromosome 15(Magenis etal. 1990; Williams et al. 1990). At this time itis not entirely clear whether the deletions of chromo-some 15 in the Prader-Willi and Angelman syndromesinvolve exactly the same areas of the long arm ofchromosome 15, but the DNA studies do suggest that

Fig. 2. An individual with typical features of Angelmansyndrome including happy disposition, large mouth, andrepetitive movements.

there may be at least a common overlap segment(Magenis et al. 1990).

In addition, familial cases of Angelman syndromehave been reported that seem to lack the deletion(Frynse/fl/. 1989; Hall, 19906; Pembreye/o/. 1989). Intwo of these cases, there has been a chromosometranslocation involving the chromosome J5q 1J —13region which has been inherited from the phenotypi-cally normal mother. It has been suggested (Pembrey etal. 1989; Fryns et al. 1989) that in these families thetranslocation has deleted a gene and that this deletionhas uncovered an abnormal mutation on the otherchromosome, eg. the paternally derived chromosome,allowing expression of an autosomal recessive trait.

The Prader-Willi and Angelman cases raise the issueof parental origin of chromosome abnormalities ingeneral and have implications for the "classical" ob-served phenotypes in conditions such as 4p-, 18q-, etc.,in terms of whether they are also always deletions of thechromosome derived from the mother or from thefather. The concept of imprinting implies that sometranslocations. inversions, duplications, and other

How imprinting is relevant to human disease 143

chromosomal rearrangements will result in phenotypicabnormalities only when they occur in the chromosometransmitted from the mother or from the father. Thus,families with chromosomal rearrangements that cometo attention because of a phenotypically abnormal childneed to be re-evaluated in relation to the sex of theparent transmitting the rearrangement. In the past,when a phenotypically normal parent had the samechromosomal rearrangement as the abnormal child, thechromosomal abnormality was dismissed as a cause ofthe phenotypic features. However, if one takes theconcept of genomic imprinting seriously, the parent oforigin may be critical and the offspring may only surviveor only manifest particular features depending on theparental origin of the abnormal chromosome. In ourexperience, for instance, the deleterious effect ofdeletion 22q has only been seen when the chromosome22 has been inherited from the father.

Similarly, when two children, particularly of theopposite sex, have a disorder and the parents arephenotypically normal, we have assumed this torepresent autosomal recessive inheritance. However,many studies using DNA markers have shown thatsubmicroscopic deletions defined by molecular analysis,may lead to phenotypes similar to those seen withlonger cytogenetically visible deletions. If such an areawas imprintable, then we would expect non-expressionwhen transmitted from a parent of one sex andmanifestations of the deletion when transmitted fromthe parent of the opposite sex.

Uniparental dlsomy

Uniparental disomy has been studied systematically inmice for almost all segments of the mouse chromo-somes by Cattanach and Kirk (1985), Searle andBeechey (1985), and Lyon and Glenister (1977).Uniparental disomy of specific chromosome segmentsfrom the mother or the father are produced in mice bybreeding animals with Robertsonian and reciprocaltranslocations. In this way, the mice have a balanced setof chromosomes but both copies of a particularchromosome or chromosome segment have beenderived from one or the other parent. At least sevenmouse chromosome segments appear to have majordifferential effects on growth, behaviour and survivaldepending on whether inheritance is from the motheror the father. Several other chromosome segmentsseem to give distorted ratios of expected number ofoffspring suggesting non-reciprocal lethality.

What is known about this kind of process in humans?How often does uniparental disomy occur? There arenumerous human cases involving the X chromosome,the most frequent being 47,XXY and 47,XXX. How-ever, there are at this time only two documentedsituations involving human autosomes (cystic fibrosisand Prader-Willi). Two cases of cystic fibrosis withuniparental disomy have been reported (Spence et al.1988; Voss et al. 1989). Uniparental disomy wasrecognized by chance in these cystic fibrosis cases

because DNA polymorphisms close to the cystic fibrosisgene were being traced in the families. However,maternal uniparental disomy of chromosome 7 mayoccur relatively frequently without causing cysticfibrosis (Hall, 1990c). In both the cases of cystic fibrosiswith uniparental disomy, the affected children haveacquired both of their copies of chromosome 7 (or atleast a major part of the chromosome as recognizedthrough DNA studies) from their mothers. Theirfathers do not appear from haplotype analysis to becarriers of cystic fibrosis. Non-paternity has beenexcluded by identification of DNA markers on otherchromosomes demonstrating that these children are thebiological offspring of the purported father. In eachcase, the child is homozygous for maternal markers atall loci tested on chromosome 7. Thus, all the evidencesupports maternally derived isodisomy of chromosome7. These appear to be cases of cystic fibrosis in which anautosomal recessive disorder is not 'familial' in theusual sense, since both parents are not carriers.

Uniparental disomy has a number of other impli-cations, but for the purpose of considering imprinting,it is worth noting that both of these children, one a maleand one a female, had moderate to severe intrauterineand post-natal growth retardation. Normally, childrenwith cystic fibrosis are a normal size at birth.Interestingly, the homologous area of mouse chromo-some 6 gives a similar phenotype with uniparentalmaternal disomy; that is, there is intrauterine growthretardation (Cattanach and Kirk, 1985). There are, ofcourse, a number of other explanations for theintrauterine growth retardation in these two childrenincluding the unmasking of another recessive conditionby the isodisomy.

Intrauterine growth retardation with and withoutasymmetry of the body is frequently observed inhumans. The most common type is often called Russell-Silver dwarfism (Donnai et al. 1988; Saal et al. 1985). Ittends to be sporadic and as yet has evaded elucidation.With the advent of chromosome markers and polymor-phisms, it seems relatively easy to go back and evaluatethis type of case to ask if it is caused by uniparentaldisomy (Hall, 1990c). Many of the affected individualshave asymmetry of their bodies with one side moreunder grown; thus, one can imagine a situation ofmosaicism interacting with uniparental disomy account-ing for the asymmetric hypoplasia that is observed. Forinstance, the hypoplastic part of the body could haveuniparental disomy occurring through a mitotic errorwhile the other part of the body does not. If this werethe reason for the commonly observed asymmetry seenin these individuals, molecular studies would give amethod of comparing the differences between bodyareas in these individuals and help to define whichimprinted chromosomes are involved in these indi-viduals or in such a process.

To return to Prader-Willi and Angelman syndromes,recently Nicholls et al. (1989) have observed severalcases of Prader-Willi syndrome in which no DNAdeletion could be demonstrated but in which bothcopies of chromosome 15 in the affected individual had

144 J. G. Hall

been inherited from the mother. Some of these casesrepresented uniparental isodisomy, others uniparentalheterodisomy. Thus, these cases of Prader-Willi rep-resent a second example of autosomal uniparentaldisomy in humans. They strongly suggest that it is thelack of a paternal 15 chromosome, or at least the lack ofa critical part of the 15q 11-13 region coming fromfather, which leads to the Prader-Willi phenotype. Theconverse, that is that cases of Angelman syndromewithout cytogenetically detectable lesions representuniparental disomy, has not been demonstrated. Thetwo cases of Angelman syndrome with translocationsinherited from the mother mentioned earlier (Fryns etal. 1989; Pembrey et al. 1989) could represent cases ofheterodisomy of chromosome 15. However, thus far,the DNA markers for these cases indicating parent oforigin have not been reported. The cases of familialrecurrence of Angelman syndrome (Fryns et al. 1989;Pembrey et al. 1989; Williams et al. 1989) in which nodeletion is detected by cytogenetic or molecularmethods remain a puzzle.

Spence et al. (1988) thoroughly discuss the possiblemechanisms that might produce human uniparentaldisomy. They pointed out very clearly that twoaneuploid events are necessary. If those events areindependent, uniparental disomy should be quite rare(Warburton, 1988). Whether this is so, is not yet clear.The most appealing explanation for the cases ofuniparental disomy associated with cystic fibrosis is thata conception occurred with trisomy 7 which thenpredisposed to the loss of one copy of chromosome 7since, without such a loss, trisomy 7 would result inintrauterine lethality. If the first aneuploid eventproducing a gamete with two copies of chromosome 7was in the first meiotic division, then heterodisomycould occur. If the aneuploid event was in secondmeiotic division then isodisomy would be expected.Because chiasmata are obligatory, we would not expectcomplete isodisomy for the whole chromosome in halfthe cases.

From studies of non-disjunction in chromosome 13and chromosome 21, it appears that 20-30% of non-disjunction is paternal and 70-80% maternal in origin.This discrepancy in the parent of origin of trisomies mayexplain the relatively more common occurrence ofPrader-Willi compared to Angelman syndromes. If weassume that the non-deletion Prader-Willi started astrisomy 15 followed by random loss of the extrachromosome 15 early in development of a trisomy 15conceptus allowing survival, then the frequency ofPrader-Willi as compared with Angelman syndrome isconsistent with the observations.

Since trisomy 7 and trisomy 15 are non-viable, then avery strong selection for disomic cells is expected if thepregnancy is to survive. However, obviously, ifuniparental disomy for a particular chromosome islethal neither the trisomy nor the uniparental disomiccells could survive and only selection for non-disomywould lead to survival. It appears that uniparentaldisomy for chromosome 7 and chromosome 15 is viablein the human. The real question is how many other

uniparental disomies, either maternally derived orpaternally derived, are tolerated in humans (assumingof course that there has not been homozygosity forsome other recessive gene produced by the isodisomywhich then leads to lethality). Kalousek (1988) hasshown that children with intrauterine growth retar-dation frequently have chromosomal mosaicism of theplacenta with no chromosomal abnormalities observedin tissues from the child. Confined chromosomalmosaicism of the placenta is found in 2-5 % ofchorionic villus sampling. The question is how many ofthese cases of confined mosaicism actually representsituations where selection for, and overgrowth of, non-aneuploid tissue has allowed survival and how fre-quently uniparental disomy is present. One third ofcases beginning as a trisomy should end up withuniparental disomy, if no selection against uniparentaldisomy is present.

In mouse studies defining the phenotypes of unipar-ental disomy, it is important to note that majorcongenital anomalies are not observed (Cattanach andKirk, 1985; Lyon and Glenister, 1977; Searle andBeechey, 1985). Rather, variations in growth, behav-iour and survival are seen. Thus, if one reflects oncommon human syndromes that are as yet unexplained,such as Rubinstein-Taybi syndrome, Cornelia de Langesyndrome, Williams syndrome, Russell-Silver syn-drome, etc. the possibility that they represent uniparen-tal disomy for other chromosomes must be explored,since they are syndromes in which the major abnormali-ties consist of disharmonic growth and abnormalbehaviour rather than major structural congenitalanomalies involving multiple systems.

One example of an X-linked disorder associated withuniparental disomy is worth considering in detail. It isthe recently reported male-to-male transmission ofhemophilia A (Vivaud et al. 1989). This had beenthought to be impossible. However, the male childinherited both the X and the Y chromosome from thefather. The maternal X was apparently lost eitherduring development or was absent in the fertilized egg.Obviously, in such a case cytogenetic examination ofthe placenta and other tissues would be very helpful. Itseems quite feasible as well that such a case of male-to-male transmission of an X-linked disorder is actually anexample of a mosaic Klinefelter syndrome and thatduring the course of development the maternal Xchromosome has been lost in some tissues.

Human mouse homologous chromosomalregions

The Oxford grid demonstrates the homologous regionsof various chromosomes in human and mouse. It canhelp to suggest possible areas of imprinting in humans(Hall, 1990a; Searle et al. 1989). Thus, genes in andaround known imprinted areas in the mouse become ofinterest and need to be examined in the human. Inaddition, genes closely linked to genes that are thoughtto be imprinted in humans deserve particular examin-ation to see if the pedigrees or inheritance patterns also

How imprinting is relevant to human disease 145

suggest imprinting (Hall, 1990a). There is somesuggestion that malignant hyperthermia, which is veryclosely mapped to myotonic dystrophy (MacLennan etal. 1990; McCarthy et al. 1990) on chromosome 19, maydemonstrate imprinting effects in some families.

Patterns of inheritance of imprinted genes

Since imprinting appears to be a ubiquitous phenom-enon in humans, it is important to re-examine pedigreesin known disorders for possible effects. From the datathat is already available, it appears that if an imprintingeffect does occur, it may not be present in all families -for example, myotonic dystrophy and Huntingtondisease families. Thus, individual large families shouldbe examined carefully with the idea that there may bedifferences in phenotypic expression depending on theparent transmitting the gene. As seen in Fig. 3, in animprinted condition one would expect differences in thephenotypic expression in the offspring dependent onparent of origin. The silencing or turning off of the genewill occur if the offspring has inherited the gene fromonly one particular parent, mother or father. Theimprintable gene would be expected to be transmitted

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Fig. 3. Idealized pedigrees for maternal and paternalimprinting. These figures diagram what a pedigree ofhuman disease which has imprinting effects might looklike. The term 'imprinting' implies a modification inexpression of a gene or allele. An imprintable allele will betransmitted in a Mendelian manner, but expression will bedetermined by the sex of the transmitting parent. In theseidealized pedigrees the term maternal imprinting is used toimply that there will be no phenotypic expression of theabnormal allele when transmitted from the mother andpaternal imprinting is used to imply that there will be nophenotypic expression when transmitted from the father.Because there will be a phenotypic affect only when thegene in question or chromosome segment in question istransmitted from one or the other parent, there are anumber of non-manifesting offspring. There are an equalnumber of manifesting males and females or of non-manifesting male and female carriers for each generation.

in a Mendelian manner but expression would bedetermined by the sex of the parent transmitting thegene. This has been seen in glomus cell tumors (van derMey et al. 1989), familial Wilms tumor (Huff et al.1988), and to a lesser extent, in the Wiedemann-Beckwith syndrome (Lubinsky et al. 1974) and infamilial retinoblastoma (Scheffer et al. 1989).

In maternal imprinting, the phenotypic expression ofa known or an abnormal gene does not occur whentransmitted to the mother's offspring of both sexes. Thegene is basically 'turned off when inherited from themother but not when the same gene is transmitted byher father, by her brothers, or by her son. When hersons, who carry but do not manifest the phenotype,transmit the gene, their offspring who inherit the geneswill express it and manifest the phenotype but her non-manifesting daughter's children will not. Just theopposite is seen in paternal imprinting (Hall 1990a).The following should be noted.

(1) Equal numbers of affected or non-manifestingmales and females are seen in each generation in bothmaternal and paternal imprinting.

(2) Non-manifesting but transmitting ('skipped')individuals are the clue to whether a trait is maternallyor paternally imprinted, i.e. in maternal imprinting, amale is the non-manifesting or less manifesting carrierwho transmits to manifesting offspring and in paternalimprinting, females are the non-manifesting carrierswho transmit the trait.

(3) The pedigree of a gene that is imprinted can looklike autosomal dominant inheritance, autosomal recess-ive inheritance, or multifactorial inheritance dependingon that part of the family tree is being observed. Thus,conditions that have been considered to be multifac-torial need to be re-examined with imprinting in mind.In addition, when there are two genetic forms of adisorder, as defined by linkage (eg. as in TuberousSclerosis and Polycystic Kidney Disease) each formneeds to be examined with imprinting in mind.

(4) Finally, the pedigree observed in imprinting isquite different from that which is seen in mitochondrialor cytoplasmic inheritance.

Nomenclature

The nomenclature used to designate uniparental dis-omy and imprinting must be developed and agreedupon. Most of the appropriate symbols are alreadyavailable: 'upd' has traditionally been used for unipar-ental disomy in mice; 'mat' and 'pat' have traditionallybeen used as a designation for maternal or paternalinheritance; T could be used for isodisomy, and 'h' forheterodisomy. Thus, 46,XY,upd h(7)mat would meanuniparental heterodisomy of a maternally derivedchromosome 7; while 46,XX,upd i(15)pat would meanuniparental isodisomy of a paternally derived chromo-some 15. If only a segment of chromosome has beenshown to be isodisomic it could be designated by46,XY,upd i(15qll-14)mat. For the sex chromosomedisomies there would be four different viable types: 2

146 J. G. Hall

heterodisomies and 2 isodisomies. The heterodisomiescould 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 homodisomymay be needed as more precise molecular definitions ofimprinted areas is possible).

'Imp' could be used to designate imprinted orfunctionally turned off segments of chromosomes.Since imprinting appears to be a dominant function itwould be capitalized. Used before a chromosomesegment together with parent of origin it would indicatethe chromosome or segment was imprinted, eg.46,XY,Imp(15qll-13)mat would mean that segmentqlJ-13 was functionally turned off on the maternallyderived chromosome 15. This approach could also beused for single gene designations as well, eg.HD,Imp(4pl6.3)pat would mean that the HuntingtonDisease gene that was inherited from the father wasfunctionally turned off.

These designations are proposed for consideration,but it does seem that with the advent of being able tomark the derivation of a particular chromosome, theiruse will become more and more important.

Asymmetric expression in monozygotic twins

As discussed in other parts of this symposium,X-inactivation may be a special form of a commonprocess of genomic imprinting that may apply toautosomes. Monozygotic twinning in humans is a poorlyunderstood phenomenon. It is thought to occur duringthe second week of embryonic development around thesame time as X-inactivation is occurring. In recent yearsseveral unusual cases of X-linked diseases manifestingin only one of monozygous twin girls have beenreported. Careful studies in the last two years showmarked asymmetry of X-inactivation (Richards et al.1990) in several disorders. This asymmetry could be bychance alone, but in the case of Duchenne MuscularDystrophy, there are few cases, if any, of monozygotictwinning without asymmetry. This suggests that there issomething about the process of monozygous twinningthat may. in some cases, interact with X-inactivation(Zneimer et al. 1990). If X-inactivation is a form ofgenomic imprinting, this unusual asymmetric ex-pression of diseases in monozygous twins could,potentially, be relevant to understanding the process ofgenomic imprinting of autosomes.

Two diseases in which imprinting can be stronglysuspected from the pedigrees are Wiedemann-Beck-with (Lubinsky et al. 1974; Niikawa et al. L986) andnarcolepsy (Guilleminault et al. 1989). Both havealready been noted to have asymmetric expression inmonozygous twins. Wiedemann-Beckwith is suspectedof being paternally imprinted because mothers whodisplay no symptoms frequently transmit the disease totheir children of both sexes. The gene in familial caseshas been mapped to distal lip (Koufos et al,, 1989). Ofeight reported cases of monozygous twins with Wiede-mann-Beckwith syndrome, all are female and discor-

dant with only one twin having the disorder (Litz et al.1988; Olney et al. 1988). One concordant pair ofmonozygous twins with Wiedemann-Beckwith syn-drome has been reported. Similarly, when the pedi-grees of narcolepsy, which occasionally appears infamilies manifesting as an autosomal dominant disorderare examined, unusual transmission suggestive ofimprinting leading to non-expression is seen. Whenmonozygous affected twins with narcolepsy have beenreported (Guillemault et al. 1989), there is discordancewith only one of the monozygous twins being affected.This contrasts with other disorders such as diabetesmellitus of the MODY (maturity onset) type wherethere is a 100% concordance of identical twins.Interestingly, there appears to be discordance inmonozygous 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 occurringaround the same time as genomic imprinting and affectsboth autosomal and X-chromosome imprinting. Thesediscordant cases may be a clue to understanding themechanism of imprinting and to identifying humandisorders in which genomic imprinting is occurring.

Role of chromosome pairing

It is an understatement to say that the actualmechanism(s) of imprinting is (are) not understood atthis time. It is strongly suspected that at least some partof the process leading to parent of origin differentialphenotypic expression must occur during the pachytene(chromosome pairing) stage of first meiosis (Hulten andHall, 1990). There are many other things going on atthis stage including homologous pairing, crossing overand condensation. It seems very likely that these fourprocesses (and possible parent of origin differences inmutation rates) are somehow interrelated or can affecteach other.

It appears that crossing over usually occurs at leastonce in each arm of a chromosome during meiosis. It ishard to believe that such a regular occurrence wouldhappen in a totally random manner. Some areas ofchromosomes have higher rates of recombination inmales, others have higher rates in females, just as someareas of the chromosomes appear to be markedlydifferent with regard to imprinting. Further, somemutations of both single gene (Jadayel et al. 1990) andof chromosomes (Magenis et al. 1990) have markedparent of origin differences. It makes sense thatimprinting sites, recombination sites and initiation ofreplication sites have specific structural properties.Mismatching, malalignment, or failure to have normalpairing during meiosis, could lead to an increasedmutation rate, failure of normal recombination, failureof condensation, or aberrant imprinting.

Imprinting must involve some form of 'tagging' of thechromatin that will survive mitosis, but not meiosis. Itwould appear that the mechanism of imprinting can bedivided into: (1) erasure or wiping off the previous

How imprinting is relevant to human disease 147

imprinting; (2) preparation of the chromatin or DNAfor new modification; (3) new modification of thechromatin in a parental-specific way; and (4) tissue-specific phenotypic expression of parentally derivedimprinting in the offspring (Hulten and Hall, 1990).

Careful re-evaluation of the pedigrees of humandisorders will almost surely help to predict whichdisorders are likely to be imprinted. It seems likely thatthis non-traditional form of inheritance is very import-ant in human biology and may explain a number ofhitherto confusing observations in human diseases.

For very helpful discussions and suggestions, thanks to MajHulten, Dagmar Kalousek, John Edwards, Rob Nicholls, UtaFrancke and Art Alysworth. I also thank Diane McPhersonand Minette Manson for their secretarial help.

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