Human Molecular Genetics 2004 13(Review Issue 2):R225-R233; doi:10.1093/hmg/ddh254
Human Molecular Genetics, Vol. 13, Review Issue 2 © Oxford University Press 2004; all rights reserved
Mechanisms of non-Mendelian inheritance in genetic disease
Veronica van Heyningen* and
Patricia L. Yeyati
MRC Human Genetics Unit, Western General Hospital, Edinburgh EH4 2XU, UK
Received July 23, 2004; Accepted July 26, 2004
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ABSTRACT
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Single gene disorders with Mendelian inheritance patterns have
contributed greatly to the identification of genes and pathways
implicated in genetic disease. In these cases, molecular analysis
predicts disease status relatively directly. However, there
are many abnormalities which show familial recurrence and have
a clear genetic component, but do not show regular Mendelian
segregation patterns. Defining the causative gene for non-Mendelian
diseases is more difficult, and even when the underlying gene
is known, there is uncertainty for prenatal prediction. However,
detailed examination of the different mechanisms that underlie
non-Mendelian segregation provides insight into the types of
interaction that regulate more complex disease genetics.
Mendelian inheritance patterns are well-established, and readily recognizable as ‘textbook’ examples, for many single gene diseases (1), and a few digenic cases (2–4). However, in most clinical genetics settings many cases are seen where the disease diagnosed is well known to have a strong genetic component, and show some familial recurrence, but no clear Mendelian inheritance. Such cases clearly pose additional problems in counselling and the estimation of recurrence risk. Here, we review some of the different molecular mechanisms that lead to such irregular inheritance patterns, focussing mostly on diseases where at least one implicated gene and some underlying mutations have been identified. It is useful to attempt to categorize the different ways in which the observed inheritance patterns are generated (Table 1) and then to consider in more detail some examples in each category.
Some detailed molecular mechanisms underlying non-Mendelian
inheritance patterns will be unfolded below, but first some
general concepts need to be clarified. Incomplete penetrance
(
5), where not all mutation carriers present with the expected
phenotype, is commonly observed in human family studies. This
forms a continuum with variable expressivity, which can be so
extreme that subtle manifestations of carrier status are sometimes
only identified with hindsight (
6). Even some of the most classical
Mendelian traits, like cystic fibrosis (CF), show complex variation
(
7,
8). A significant proportion of variability can be ascribed
to allelic differences (
9,
10), some of which will be cryptic
regulatory variation, influencing gene expression levels (
11,
12).
The existence of widespread variation is not surprising, as
gene products fulfil their function through finely tuned interactions
with other cellular components, often showing some degree of
threshold requirement (
7). Each component is subject to regulation,
and variation, at every stage: transcription, splicing, translation
(
13), protein folding, oligomerization, translocation and compartmentalization
within the cell or export from it (
14). Subsequently, there
is controlled turnover, through well-policed pathways of destruction
(
15,
16). When focussing on gene products, we mostly think of
proteins, but should increasingly remember that many cellular
processes are regulated by RNA molecules, or at the RNA level
(
17). The complexity of the proteome is strongly affected by
controlled alternative splicing, a mechanism often altered or
damaged through sequence variation or mutation. Protein folding,
association and sub-cellular localization, also require some
helper systems, such as molecular chaperones, which often double
as stress response proteins (
18), and these are very likely
implicated in extreme phenotypic variability, and hence segregation
pattern variability (
19,
20).
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SPORADIC OCCURRENCE OF GENETICALLY LETHAL SINGLE GENE ANOMALIES
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An apparently sporadic pattern of disease incidence is observed
if virtually all cases arise as a result of new mutation. No
parent to child inheritance of the phenotype is seen, generally
because the affected individuals are consistently unable to
reproduce through infertility or for physical or social reasons.
Occasionally sibling recurrence is seen in such cases, if the
parent in whom the new mutation arose has gonadal mosaicism,
which is sometimes accompanied by somatic mosaicism. Such recurrent
new mutations are seen in Apert syndrome, with craniosynostosis
and severe syndactyly caused by gain-of-function paternal mutations
(
21) at specific sites in the
FGFR2 gene (
22). A significant
proportion of severe bilateral anophthalmias is caused by
de novo loss-of-function mutations in the early neural and eye
development gene
SOX2 (
23). Predicted loss of function mutations
were recently identified in another developmental anomaly with
no vertical transmission, Cornelia de Lange syndrome, in the
human orthologue,
NIPBL, of the Drososphila Nipped-B protein,
with homology to sister chromatid cohesion protein SCC2 and
a possible role in promoter-enhancer interactions (
24,
25). Most
early onset severe cases of congenital central hypoventilation
syndrome (CCHS) are associated with polyalanine expansion mutations
in the paired-like homeobox gene
PHOX2B (
26). Frameshift changes
in
PHOX2B were also found in CCHS, including a single nucleotide
deletion inherited from an asymptomatic mother (
27). Some CCHS
patients had additional manifestations of autonomic nervous
system disease, such as Hirschsprung disease (HSCR) (
26,
27),
and in two cases coincident
RET and
GDNF missense changes were
seen (
26), which may act as modifiers of the CCHS phenotype.
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OLIGOGENIC DISEASE WITH INCOMPLETE PENETRANCE, PHENOTYPIC VARIABILITY AND LOCUS HETEROGENEITY
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Oligogenic inheritance patterns are increasingly recognized,
as the techniques of population studies are adapted, or even
developed using these simpler, more clearly familial disease
models. HSCR is phenotypically variable aganglionosis (failure
of sympathetic innervation) of the colon. Long-segment L-HSCR,
sometimes syndromic, is caused by coding sequence mutations
at one of several loci including
RET,
GDNF,
SOX10,
EDN3 and
EDNRB (
28,
29). Short segment S-HSCR (80% of cases) reveals complex
segregation patterns involving contributions from at least three
loci, one of which is unequivocally the
RET gene on chromosome
10q11; multiplicative interaction with other loci at 3p21 and
19q12, encompassing currently unidentified genes, has been proposed
(
29). Distinct
RET mutations in the extracellular domain are
preferentially associated with S-HSCR, and it is clear that
mutations outside the coding region are missed (
29).
Holoprosencephaly is characterized by incomplete separation of the forebrain into distinct halves, and is usually associated with craniofacial features (30). Many cases are apparently sporadic, but some show familial recurrence. Severity of phenotypes is extremely variable, even within families, from prenatal lethality with cyclopia, to hypertelorism, or the presence of a single central incisor; 36% of obligate carriers have no clinical phenotype (31). A number of causative genes have been identified, with SHH, ZIC2, SIX3 and TGIF most frequently involved, but only 
20% of HPE cases have revealed mutations in any of the eight identified genes (31–33). SHH mutations are most frequently associated with familial disease, and some cases have mutations in two of the known genes (31,33), suggesting gene interaction. It should be noted that generally only coding region mutations are sought, but for SHH at least, complex cis-regulatory regions are known (34,35), and these may harbour disease-causing mutations with unknown phenotypic spectrum or penetrance. As SHH protein is cholesteroylated, related mutations, dietary cholesterol and drugs which interfere with its metabolism may influence the incidence of HPE (36–38).
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LOW-PENETRANCE DISEASE PREDISPOSITION WITH IDENTIFIED GENETIC MODIFIER EFFECT
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Hereditary haemochromatosis (HH) is tissue damage resulting
from excessive iron storage, mostly involving homozygosity for
mutations at different loci (
39). Rare juvenile forms exist
with severe mutations in
HJV, a protein of unknown function
(
40,
41), and recently homozygous mutations in the antibacterial
inflammatory peptide hepcidin (
HAMP) (
42,
43) were identified.
The more common, late onset, forms of HH are most frequently
found in individuals homozygous or compound heterozygous for
two common variants (C282Y and H63D) of the MHC-linked protein
HFE. However, the penetrance of these mutations is low, particularly
in premenopausal women. It was recently found that double heterozygosity
for
HFE and
HAMP mutations leads to much higher frequency and
sometimes earlier and more severe symptoms (
39,
44). Interactions
with other loci are also expected, making HH another unpredictable
oligogenic disease. Considerable controversy surrounds proposals
for population screening for these common potentially detrimental
alleles.
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PHENOTYPE MODIFICATION BY THE WILD-TYPE ALLELE VARIANT PRESENT IN TRANS WITH THE MUTANT ALLELE
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Variation in expression of the ‘normal’ allele opposite
to a mutant one can influence the penetrance of a mutant phenotype.
Examples of this include incomplete penetrance at RP11, one
of the dominant retinitis pigmentosa loci, where mutations in
the ubiquitously expressed splicing factor
PRPF31 were shown
to cause disease, but only in individuals carrying a high expressing
‘wild-type’ allele (
45). The mechanism underlying
variable expression at the normal allele is not clear, but regulatory
polymorphisms are likely (
12). A similar situation has also
been identified in erythropoietic protoporphyria (EPP) where
mutations in the ferrochelatase gene (
FECH) fail to lead to
a deficiency phenotype, when the allele
in trans carries a single
nucleotide variant in intron 3, that strengthens a cryptic splice
site, the more frequent utilization of which leads to reduced
levels of normally spliced mRNA (
46). Although it has not been
discussed in this mechanistic category, the observation of some
cases of congenital absence of the vas deferens (CAVD) associated
with
CFTR mutations also fit this model. Most individuals with
this phenotype have no overt CF phenotype, though occasionally
they have one of the signs of CF (bronchiectasis, or nasal polyps),
and some have a partial conductive chloride transport defect
(
9,
47,
48). A few cases have two
CFTR mutations, one of which
is generally a known mild allele, but others are heterozygous
for one severe (or sometimes mild) allele. In some cases the
mild allele is a variant wild-type allele with a stretch of
only five thymidines (T5) instead of seven (T7) or nine (T9).
The T5 allele produces a proportion of transcripts with an in-frame
deletion of exon 9. It is the most frequent second allele in
CAVD, often found
in trans to
F508, the most common severe allele,
but which generally does not manifest a heterozygote phenotype.
CAVD is, of course, doubly abnormal in its inheritance pattern,
as vertical transmission is unlikely with an infertility phenotype,
at least until the recent advent of assisted reproductive technologies,
such as intracytoplasmic sperm injection.
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REDUCED PENETRANCE ALLELES AT TUMOUR SUPPRESSOR LOCI
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Germ line mutations at tumour suppressor loci predispose to
familial cancer, although in accordance with the two-hit hypothesis
there is a requirement to lose the normal allele of the gene
in tumour tissue (
49). Searching the literature on the best
known of the tumour suppressor loci suggests, however, that
in most cases the second hit is not rate limiting, so that once
a predisposing mutation is present the inheritance pattern for
the relevant malignancy is essentially dominant Mendelian. There
are, however, specific alleles at some well known tumour suppressor
loci that give rise to highly incomplete penetrance, sometimes
accompanied by unusual phenotypes. In Brazil, where the incidence
of paediatric adrenocortical carcinoma (ACC) is 10–15-fold
higher than elsewhere, a
TP53 allele, with a recurrently arising
R337H missense change, has been associated with non-Mendelian
familial aggregations of ACC, but no other cancer types (
50).
A pH-dependent molecular mechanism has been proposed for the
tissue-specific function of this relatively mild mutation (
51).
Other distinct, specifically ACC-associated, incompletely penetrant
TP53 mutations have also been identified (
52). These families
do not manifest the multiple cancer types generally associated
with the broader
TP53-associated Li-Fraumeni syndrome, where
most common mutations lie in the DNA-binding domain (
53). Splice
donor site mutations in
RB1, leading to an in-frame deletion
of exon 13, have been described in two families with low-penetrance
presentation of mainly unilateral retinoblastoma, which in one
family was associated with later onset lipomas (
54). A number
of other reduced penetrance
RB1 mutations have been reported
(
55,
56).
Hereditary non-polyposis colon cancers (HNPCC) associated with DNA repair enzyme mutations in MLH1 and MLH2 are quite highly penetrant in males (80%), but less so in females (40%) (57), where oestrogen is thought to play a protective role. Some specific low-penetrance alleles of MLH1 have been reported, including the D132H missense variant which is found at fairly high frequency in Jewish populations (58). This allele is associated with late onset tumours (average age 70 years), and it is thought to act through a dominant negative mechanism, with no loss of heterozygosity and no microsatellite instability (58). MSH6 mutations with reduced (58%) penetrance have been identified in a cohort of HNPCC-spectrum cases which were not initially selected for familial occurrence (59).
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KNOWN OR UNDEFINED ENVIRONMENTAL TRIGGER REQUIRED FOR EMERGENCE OF THE PHENOTYPE
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Infection-dependent inflammatory triggers have long been suggested
to be required in a number of diseases where a significant genetic
component has been demonstrated, for example through twin studies,
and familial recurrence is clearly observed, but non-Mendelian.
In Type 1 juvenile-onset insulin dependent diabetes mellitus
(IDDM), heterozygosity for HLA class 2 alleles
DR3/DR4 (old
nomenclature) was established as the strongest risk factor many
years ago. Although the molecular and biological mechanisms
are not understood, aberrant antigen presentation in viral infection
has been suggested. The genotype at a VNTR site closely linked
to the insulin gene, has additional modifier effect on the probability
of developing anti-islet antibodies by the age of 4 years (
60,
61).
Recent work on inflammatory bowel disease, which again shows
familial clustering but no clear inheritance pattern, has successfully
identified a gene initially named
NOD2, now
CARD15, which carries
fairly common variants (predominantly two missense changes and
a frame shift) that are strongly associated with the development
of Crohn's disease and ulcerative colitis. The relative risk
of developing these phenotypes is only 2-fold for heterozygotes
but 30–40-fold for compound heterozygotes or homozygotes
(
62). The cytoplasmic CARD15 protein is an intracellular sensor
of bacterial peptidoglycan and plays a role in the response
to bacterial antigens (
63). Recently, using linkage studies
with large numbers of affected sib pairs, two further IBD-associated
loci were identified, one encoding adjacent cation transporters,
SLC22A4 and
SLC22A5, which interact with CARD15 (
64), the other
an intracellular scaffold protein,
DLG5, implicated in maintaining
cell shape and polarity (
65). Immune responsiveness to bacterial
antigens is also implicated in several spondyloarthropathies,
like ankylosing spondylitis, which are strongly associated with
the presence of the
HLAB27 genotype at the major histocompatibility
locus of affected individuals (
66). Acute intermittent porphyria
is a low-penetrance disease, with variants in the haeme biosynthetic
enzyme hydroxymethylbilane synthase (
HMBS), with several different
predisposing alleles, some arising repeatedly. The 10–20%
of individuals with reduced enzyme activity develop intermittent
attacks of sometimes fatal neurovisceral dysfunction, precipitated
by drugs, alcohol, starvation and stress (
67).
Several ion-channel genes are implicated in the aetiology of Long QT (LQT) syndrome, involving cardiac pacemaking anomalies, associated with episodes of bradycardia, tachycardia, fainting attacks (syncope) and sudden death (68). Many mutation carriers are asymptomatic, sometimes with a phenotype detectable only by electrocardiogram (69–71). Identifying carriers by molecular analysis can save lives through appropriate drug treatment or provision of a cardiac pacemaker. Psychological and physical stress are among the triggers for the most severe symptoms, and different implicated genes may be associated with predominantly different episodic triggers (72). Hypertrophic cardiomyopathy mutations, also frequently associated with sudden death, are similarly quite often present in asymptomatic, but at risk carriers (73,74). Other channelopathies with incomplete penetrance include some epilepsies (75,76).
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SYNDROMES WITH SOME INCOMPLETELY PENETRANT COMPONENTS
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Some mutations lead to complex phenotypes with multiple components
some of which are fully penetrant, for example deafness associated
with
GATA3 loss-of-function mutations, whereas other aspects
such as overt parathyroid disease is observed only in some mutation
carriers, although measurable hypocalcaemia is often present,
and cryptic renal abnormalities may also be found (
77). As many
different deafness genes are known, it is only when the rare
phenotypic component is observed in a family the correct causative
gene will be considered. Another recently reported example describes
the identification of an X-linked synapsin (
SYN1) mutation in
a family with epilepsy where some of the affected males have
normal intelligence, whereas others have various combinations
of epilepsy, learning difficulty, macrocephaly and aggressive
behaviour (
78). The authors originally debated whether a single
gene disorder could account for the phenotypic spectrum in this
family.
In some extreme cases, the phenotypic disease signs can be so mild and variable that diagnosis of affected status is sometimes only made following careful examination of defined mutation carriers, if at all. Such situations have been reported for holoprosencephaly (33), and tuberous sclerosis, where TSC1 mutations may lead to very mild phenotypes in some cases, whereas TSC2 is generally more severe (6). A specific SHH mutation, associated in several families solely with a single central incisor, has been identified (79). Incomplete penetrance is seen in families with capillary malformation, where RASA1 mutations have been identified, and each family has at least one individual with ateriovenous malformation, ateriovenous fistula or Parkes Weber syndrome, although some obligate carriers show only mild, commonly observed cutaneous anomalies (80).
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IMPRINTING DISEASES
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Imprinting anomalies, such as Beckwith–Wiedemann syndrome
(BWS) and Prader Willi/Angelman syndrome (PW/AS) generally arise
sporadically. However, where familial recurrence is seen, the
inheritance pattern is not Mendelian. Any heritable mutations
will reveal effects only when inherited from the appropriate
parent. Duplications including the
IGF2 gene, for example, only
lead to overgrowth and other BWS-related anomalies, when inherited
paternally. Loss of imprinting is generally sporadic, although
there are suggestions from animal models that the parental imprints
may be incompletely erased in the germ line (
81) and epigenetic
changes can be heritable (
82), but patterns of inheritance will
not be fully Mendelian. Biallelic
IGF2 and
H19 expression is
frequently seen in some human tissues, without phenotypic abnormality,
and it has been recently proposed that imprinting status may
be modulated by environmental and nutritional factors (
83).
The relative frequency of the different types of BWS ‘mutations’
is described by Weksberg
et al. (
84). A novel genetic mechanism
for BWS is also presented showing the occurrence of excess discordant
female monozygotic twins, in whom the body tissues, but not
the shared haemopoietic system, of the affected twin shows altered
methylation of the maternal
KvDMR1, in the upstream CpG island
region of
KCNQ1OT1, and biallelic expression of the gene itself.
For PW/AS, both heritable deletions and epigenetic alterations
were also revealed in an analysis of 136 cases (
85). Diseases
associated with other imprinted regions, such as transient neonatal
diabetes on chromosome 6q24, also reveal different genetic origins:
paternal uniparental disomy, paternally inherited duplications
and methylation defects in a CpG island imprinting region (
86),
none of which show Mendelian inheritance as imprinting and epigenetic
modifications are involved.
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PARADOXICAL INHERITANCE PATTERNS
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Interesting rare cases of unusual segregation patterns are seen
in some specific diseases: for example in one large consanguineous
kindred in eastern Quebec, cases of glaucoma involving the K423E
allele of
TIGR (trabecular meshwork-inducible glucocorticoid
response) gene, are only found in heterozygotes (
87). Presumably
the homozygotes are able to form functional dimers, leaving
them unaffected. A slightly similar situation was recently reported
when the underlying defect in craniofrontonasal syndrome was
reported (
88,
89). This X-linked phenotype was shown to be caused
by mutations in ephrin B1 (
EFNB1), a transmembrane ligand for
the ephrin receptor tyrosine kinases. Heterozygous females are
more severely affected than hemizygous mutant males. It is suggested
that this ligand–receptor system plays a role in establishing
tissue-boundaries, and the abnormalities are more severe in
females with random X-inactivation where mutant and wild-type
ligand-bearing tissues abut each other. The mouse
Efnb1 knock-out
model recapitulates the greater female severity (
89).
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SEGREGATION DISTORTION
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Repeated finding of an excess of affected offspring, significantly
over the expected 50%, from an autosomal dominant disease phenotype
is the rare, but interesting finding in the case of chromosome
10q24-linked split-hand/split-foot malformation (
SHFM3) (
90).
There is an excess of affected sons from affected fathers, but
the number of affected daughters from these fathers is also
increased. An implicated gene has been tentatively identified
through repeated disruption/partial duplication of the dactylin
gene in seven independent families (
91). The molecular mechanism
of the mutation is not clear, but together with similar physical
gene disruptions identified in mouse models (
92), the suggestion
of long-range control disruption should be considered.
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ANTICIPATION DISTORTS SEGREGATION PATTERN
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Classically, anticipation through sudden trinucleotide repeat
expansion can increase the severity, and therefore the apparent
penetrance, of a disease in a family. The archetypal examples
of intergenerational instability that give rise to unusual patterns
of inheritance, are fragile X syndrome, affecting the
FMRP gene
and myotonic dystrophy (DM). The underlying pathological mechanisms
are still debated but are probably distinct, although both may
ultimately function through RNA-level control (
93,
94). Recently,
an untranslated CTG expansion was shown to be involved in spinocerebellar
ataxia 8 (
SCA8), which is a neurodegenerative disease generally
with very low penetrance, although a more completely penetrant
family was also described (
95), and the molecular mechanism
has not been clarified. Anticipation is also reported in dyskeratosis
congenita where the underlying mutation is in the RNA component
of telomerase (
TERC), and the increasing disease severity through
the generations is imposed through the co-inheritance of the
TERC mutation with the progressively shortened telomere length
(
96).
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OTHER MECHANISMS
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Non-Mendelian segregation of polymorphic microsatellite markers
for the telomeric regions of multiple chromosomes, can be used
to flag up possible cryptic telomeric rearrangements, associated
with idiopathic mental retardation (
97). The major original
non-Mendelian segregation patterns were produced by mitochondrially
inherited disease mechanisms. These, extensively reviewed diseases
affecting many high energy-consuming tissues, such as retina,
heart, kidney and muscle, show maternal inheritance, as classically
only oocytes contain mitochondria (
98–
100).
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CONCLUDING REMARKS
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We have touched upon several distinct mechanisms implicated
in non-Mendelian inheritance patterns in human disease. Each
case covered has at least one identified gene aetiologically
implicated, allowing discussion of at least some aspects of
the underlying molecular mechanism. Many more examples are known
with no underlying gene or pathway defined. The cases discussed
are summarized in Table
1. Some general themes to pull together
these apparently diverse mechanisms are presented in Figure
1. Oligogenic diseases with no regular recognizable segregation
patterns are emerging increasingly, where phenotypes owing to
specific mutations at one or a few loci are modified through
a number of cellular and environmental mechanisms. Distinct
processes participating in general cellular metabolism play
key roles: cell cycle and proliferation control (
101), transcriptional
machinery (
102) and splicing control (
103) are emerging as major
modifying mechanisms, translational regulation (
104) and the
machinery of energy management through oxidative control are
also important players (
105). In addition, surveillance mechanisms
have been imposed throughout evolution, so that mutant proteins
and aberrant RNAs are dealt with through defined pathways: prematurely
truncated proteins are subject to nonsense-mediated decay if
produced from a multi-exonic gene (
106); protein turnover is
regulated by the components of the proteasome pathway and ubiquitinylation
(
107); aberrantly folded proteins are carefully chaperoned by
the stress-response system (
108); a major new area is our growing
insight into the many different levels of RNA-mediated regulation
of gene expression (
17); and pathways controlling the damaging
effects of oxidative stress and the generation of free radicals
are emerging as key mechanisms in aging and decay (
109). Naturally,
all these systems are plastic and subject to genetic and environmental
variation. It is becoming clear that there are many allelic
variants throughout the genome, and these are not just coding
variants, but differences in transcriptional control through
promoter and enhancer differences are increasingly emerging
(
12,
110). Some
cis-regulatory elements act at great genomic
distance and can be pinpointed through evolutionary sequence
conservation across mammals or broader vertebrate classes (
111,
112).
This approach may ultimately be useful for understanding mechanisms
of regulatory variation. Gene expression is clearly subject
to complex epigenetic control (
113), and we are just beginning
to understand the rules involved in the modulation of chromatin
structure (
114). Finally, environmental variation plays a major
role in modulating all aspects of gene expression (
115), but
individual responses to environmental factors are under partial
genetic control. Each mutation seen in any individual is unique
in its physiological, genomic and environmental and spatiotemporal
context, so that ultimately pure Mendelian inheritance does
not exist. There is a continuum between ‘single gene’
disorders and oligo- and multigenic regulation, with the constant
superimposition of environmental factors, whose effect may be
modulated through stress response pathways (
116,
117). The study
of molecular mechanisms in non-Mendelian genetic disease, with
some insight into the pathways affected, provides a useful bridge
from single gene anomalies to complex disease.
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Figure 1. Factors which can influence the phenotypic outcome of a particular mutation. Genetic, epigenetic and environmental components can play a role in modifying the outcome of specific mutants at a defined locus. Variation in normal regulated cellular processes, and in the surveillance systems, contribute to the end phenotype.
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ACKNOWLEDGEMENTS
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The authors thank Dian Donnai and Andrew Wilkie for helpful
advice and discussion on some of the examples used.
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FOOTNOTES
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* To whom correspondence should be addressed. Tel: +44 1314678405; Fax: +44 1314678456; Email:
v.vanheyningen{at}hgu.mrc.ac.uk
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