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Development 1990 Supplement, 141-148
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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
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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.
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