Uncertainty, Heterogeneity, and Variable Expression of Mendelian Phenotypes 129

I Figure 5.9 A pedigree illustrating matrilineal

inheritance for a mitochondrial DNA
disorder. Mitochondrial DNA disorders are
transmitted by females only (because mtDNA
II originating from the sperm is quickly degraded
in the early embryo). However, an affected
female can pass on the condition to both sons
and daughters. A common feature of mtDNA
III
disorders is incomplete penetrance, as shown here
by the absence of clinical phenotypes in several
individuals who must be gene carriers, including
three clear carrier females in generation IV, each
IV 6
of whom were born to an affected mother and
went on to produce affected children of their own
(the females in generations I and II might also
have been expected to be carriers of the mutant
V 6
mtDNA). One cause of this intrafamilial variability
is variable heteroplasmy. The mutation here was
Genetics in Medicine | A0509 shown to be a nucleotide substitution in the
every mtDNA
Tom Strachan | molecule carries the causative mutation (homoplasmy), but
© garland science design by blink studio ltd mitochondrial 12S rRNA gene that was associated
affected individuals frequently have cells with a mixed population of nor-
with variable hearing loss. (From Prezant TR et al.
mal and mutant mtDNAs (heteroplasmy). The clinical features depend [1993] Nat Genet 4:289–294; PMID 7689389. With
mostly on the proportion of mutant to normal mtDNA molecules in the permission from Macmillan Publishers Ltd.)
cells of tissues with high energy requirements.
Although a human egg cell is haploid for nuclear DNA, it contains more
than 100,000 mtDNA molecules. A heteroplasmic mother can give rise
to children who differ widely from her and from each other in the ratio
of mutant to normal mtDNA molecules in their tissues (variable het-
eroplasmy). As a result, there can be very significant clinical variability
between affected members of the same family.
To explain rapid shifts in heteroplasmy that occur over only one gen-
eration, the mitochondrial genetic bottleneck hypothesis envisages that,
during early development, germ-line cells pass through a bottleneck stage
in which they contain very few mtDNA molecules. By chance, germ-line
cells at this stage may have a much higher or much lower proportion of
mutant mtDNA molecules than the somatic cells. As a result, a hetero-
plasmic mother could give rise ultimately to eggs with a much higher or
much lower proportion of mutant mtDNA molecules than are present in
her affected tissues.
Another contributor to variable heteroplasmy is the rapid evolution of a
mtDNA variant within an individual. Mutant mtDNAs that have a large
deletion or a large duplication can evolve rapidly, so that different tissues
or even the same tissue at different times may show different distribu-
tions of the mtDNA variant.

5.3 Uncertainty, Heterogeneity, and Variable

Expression of Mendelian Phenotypes
Section 5.2 dealt with the different modes of inheritance for phenotypes
that are determined principally by single genes. Some complications
were covered, including the effects of X-inactivation in females and
hemizygosity in males, occasional differences between homozygotes and
heterozygotes for autosomal dominant disorders, the occasional expres-
sion of disease symptoms in carriers of an autosomal recessive disorder,
the mimicking of autosomal inheritance by genes in the pseudoauto-
somal regions of the X and Y chromosomes, and the unique features of
mitochondrial DNA inheritance.
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 130 Chapter 5 Single-Gene Disorders: Inheritance Patterns, Phenotype Variability, and Allele Frequencies

In this section we discuss broader complications that relate to uncer-

tainty of mode of inheritance, and difficulties posed by heterogeneity in
the links between DNA variation and phenotypes. In addition, we con-
sider how affected individuals within a single family can show variable
phenotypes for Mendelian disorders.

Difficulties in defining the mode of inheritance in small

pedigrees
Many families are small and may have only a single affected person. If the
disorder is rare and we do not know the underlying disease gene, how
can we work out the mode of inheritance? Knowing the mode of inherit-
ance is important in genetic counseling because it is on that basis that we
calculate the risk of having a subsequent affected child. Until a disease
gene has been identified and screened for mutations, however, the mode
of inheritance inferred from examining the pedigree should be regarded
simply as a working hypothesis.
Having a single affected child in a family with no previous history of a
presumed genetic disorder might suggest the possibility of a recessive
disorder, with a 1 in 4 risk that each subsequent child would be affected.
Alternatively, it could be a dominant disorder and the affected individual
could be a heterozygote. In that case, one parent carries the disease gene
but does not display the phenotype, or the disorder is due to a de novo
mutation (see below).
One possible way to work out the mode of inheritance is to study multiple
families with the same disorder and calculate the overall proportion of
affected children, (called the segregation ratio). But there are many dif-
ficulties with this approach. First, the disorder may be heterogeneous and
be due to different genes in different families. Secondly, the total num-
bers of children who can be studied are often too small to get reliable
estimates.
There are also problems in how the families are ascertained (that is, in
finding the people and families who will be studied). Imagine trying to
establish that a disorder is autosomal recessive. We could collect a set of
families and try to show a segregation ratio of 1 in 4. However, there will
be ascertainment bias: if there is no independent way of recognizing carri-
ers, the families will be identified only through an affected child (families
with two carrier parents and only unaffected children seems perfectly
normal and not be included). By focusing on families who already have
at least one affected child, the segregation ratio will inevitably be high.
Ascertainment bias is most obvious for recessive conditions, but more
subtle biases can distort the estimated ratios in any condition.
Happily, we are rapidly moving into an era in which underlying disease
genes can quickly be found even for rare single-gene disorders. Rapid
next-generation DNA sequencing is now being widely used to screen
exomes (in practice, all exons of protein-coding genes) of affected indi-
viduals with the same condition. As described in later chapters, genes
underlying some rare single-gene disorders have been successfully iden-
tified after sequencing exomes from only a very few unrelated individuals
with the disorder.

New mutations and mosaicism

For a single-gene disorder, the observed incidence of mutant alleles in a
defined population can be quite stable over time. A proportion of mutant
alleles are transmitted from one generation to the next, and a propor-
tion are lost because some individuals possessing mutant alleles do not
transmit them. To keep the frequency of mutant alleles constant, new
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 Uncertainty, Heterogeneity, and Variable Expression of Mendelian Phenotypes 131

mutations make up for the loss of mutant alleles that are not transmitted
to the next generation.
Persons who have a severe disorder usually do not reproduce or have
a much reduced reproductive capacity (unless the disorder is not mani-
fested until later in life). In severe autosomal recessive conditions,
however, for each affected individual there are very many asymptomatic
carriers who can transmit mutant alleles to the next generation. Because
only a very small proportion of mutant alleles go untransmitted, the inci-
dence of new mutation is low.
For severe dominant disorders, the mutant alleles are concentrated in
affected individuals. If most individuals who carry the disease allele do
not reproduce (because the disorder is congenital, say), the incidence of
new mutation will be very high. If, however, there is a relatively late age
at onset of symptoms, as with Huntington disease, individuals with the
mutant allele may reproduce effectively, and the rate of new mutation
may be very low.
For severe X-linked recessive disorders, the incidence of new mutation
will also be quite high to balance the loss of mutant alleles when affected
males do not reproduce. However, female carriers will usually be able to
transmit mutant alleles to the next generation.
As a result of a new mutation, an affected person may be born in a family
with no previous history of the disorder and would present as an iso-
lated (sporadic) case. In rare disorders that have not been well studied,
a sporadic case poses difficulty for calculating the risk that subsequent
children could also be affected. The affected individual could be a hetero-
zygote (as a result of de novo mutation, or the failure of the disorder to be
expressed in one parent), but alternatively could be a homozygote born
to carrier parents, or a hemizygous boy whose mother is a carrier of an
X-linked recessive condition.

Post-zygotic mutations and mosaicism

Most mutations arise as a result of endogenous errors in DNA replica-
tion and repair. Mutations can occur during gametogenesis and produce
sperm and eggs with a new mutant allele. In addition, de novo pathogenic
mutations can also occur at any time in post-zygotic life. As a result of
post-zygotic mutations, each individual person is a genetic mosaic with
genetically distinct populations of cells that have different mutational
spectra.
Post-zygotic mutations may result in somatic mosaicism that will have
consequences only for that individual (Box 5.3). But certain post-zygotic
mutations, often occurring comparatively early in development, may also
result in germ-line mosaicism. A person who has a substantial propor-
tion of mutant germ-line cells (a germ-line mosaic or gonadal mosaic)
may not show any symptoms but will produce some normal gametes and
some mutant gametes. The risks of having a subsequently affected child
are much higher than if an affected child carries a mutation that origi-
nated in a meiotic division.

Heterogeneity in the correspondence between phenotypes

and the underlying genes and mutations
There is no one-to-one correspondence between phenotypes and genes.
Three levels of heterogeneity are listed below. As we will see below and
in later chapters, both nongenetic factors (environmental and epige-
netic) and additional genetic factors can also influence the phenotypes of
single-gene disorders.
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 132 Chapter 5 Single-Gene Disorders: Inheritance Patterns, Phenotype Variability, and Allele Frequencies

Box 5.3 Post-Zygotic (Somatic) Mutations and Why We Are All Genetic Mosaics.

A pathogenic new mutation can be imagined to occur
during gamete formation in an entirely normal per-
son. Most mutations arise as a result of endogenous
errors in DNA replication and repair, and although
mutations do occur during gametogenesis and pro-
duce sperm and eggs with a new mutant allele, they
can also occur at any time in post-zygotic life. As
a result of post-zygotic mutations, each individual
person is a genetic mosaic with genetically distinct
populations of cells that have different mutational
spectra.
Human mutation rates are around 10–6 per gene per
generation, and so a person with a wild-type allele
at conception has a roughly one in a million chance
of transmitting it to a child as a mutant allele. In this
case we are considering the chance of a mutation
occurring in a lineage of germ-line cells from zygote
to gamete, involving a series of about 30 cell divi-
sions in females and several hundred divisions in
males (about 400 by age 30 and increasing by about
23 per year because spermatogenesis continues
through adult life).
Now consider post-zygotic mutations in somatic cell
lineages. The journey from single-celled zygote to
an adult human being involves a total of about 1014
mitotic cell divisions. With so many cell divisions,
post-zygotic mutation is unavoidable—we must all
be mosaics for many, many mutations. Having so
many potentially harmful somatic mutations is usu-
ally not a concern because the number of cells that
will fail to function correctly is normally very small.
A cell will usually function normally after sustaining
a harmful mutation in a gene that is not normally
expressed in that cell type, and even if the cell does
function abnormally as a result of mutation it might
not give rise to many mutant descendants.
A person may be at risk of disease, however, if a
mutated cell is able to give rise to substantial num-
bers of descendant cells that act abnormally (Figure 1).
The biggest disease risk posed by somatic mutations
is that they set off or accelerate a process that leads
to cancer. As we describe in Chapter 10, cancers are
unusual in that although they can be inherited, the
biggest contribution to disease comes from somatic
mutations.

fertilization genetic
change

Figure 1 Genetic mosaicism. As illustrated here, post-zygotic mosaicism may often have consequences just for
the individual who possesses the mutant cells; that is, the mutation affects somatic cells only. Sometimes, however,
post-zygotic mutations can occur in germ-cell precursors (germ-line mosaicism), and that has important implications
concerning the possibility of transmitting a disorder.
mosaic

Genetics in Medicine | AB503-01

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Locus heterogeneity
The same clinical phenotype can often be produced by mutations in genes
at two or more loci. The different genes often make related products that
work together as a complex or in a common pathway; sometimes one
gene is the primary regulator of another gene.
Locus heterogeneity explains how parents who are both affected with the
same common recessive disorder produce multiple unaffected children.
Recessively inherited deafness is the classic example (sensorineural

GiM_ch05_4thpp_15Apr14.indd 132 6/2/14 1:36 PM

 Uncertainty, Heterogeneity, and Variable Expression of Mendelian Phenotypes 133

hearing impairment mostly shows autosomal recessive inheritance, and DEAF1: D/D DEAF1: N/N
deaf persons often choose to have children with another deaf person). If DEAF2: N/N DEAF2: D/D
two deaf parents are homozygous for mutations at the same gene locus,
one would expect that all their children would also have impaired hear-
ing. If, instead, the parents are homozygous for mutations at two different
recessive deafness loci, all their children would be expected to be double
heterozygotes and have normal hearing (Figure 5.10).
As the underlying genes for single-gene disorders become known, it has
become clear that very many conditions show locus heterogeneity. One DEAF1: D/N
might anticipate that many different genes contribute at different steps to DEAF2: N/D
broad general pathways (responsible for hearing or vision, for example).
It is therefore unsurprising that autosomal recessive deafness or retini- Genetics in Medicine | A0510
Figure
Tom 5.10
Strachan | Locus heterogeneity explains
tis pigmentosa (hereditary retinal diseases with degeneration of rod and garland
why
© twoscience by blink
designwith
parents studio ltd recessive
autosomal
cone photoreceptors) can result from mutations in different genes. deafness can consistently produce
More specific phenotypes can also be caused by mutations at any one unaffected children. Imagine that the two
of many different gene loci. Usher syndrome, for example, involves pro- parents are deaf because they have two mutant
found sensorineural hearing loss, vestibular dysfunction, and retinitis alleles at different autosomal recessive deafness
loci, which we represent here as DEAF1 and
pigmentosa; autosomal recessive forms can be caused by mutations at
DEAF2. We represent normal alleles as N and
any one of at least 11 different gene loci.
deafness-associated alleles as D. In this case, sperm
Bardet–Biedl syndrome (PMID 20301537) provides another illustrative produced by the father would carry the DEAF1*D
example. It is a pleiotropic disorder (many different body systems and allele and the DEAF2*N allele, and eggs produced
functions are impaired) and the primary features are: degeneration of by the mother would carry the DEAF1*N allele and
light-sensitive cells in the outer regions of the retina (causing night blind- the DEAF2*D allele. All children would therefore be
ness, tunnel vision, reduced visual acuity), learning disabilities, kidney unaffected because they would be heterozygous
disease, extra toes and/or fingers, obesity, and abnormalities of the at both loci. The normal phenotypes of each child
gonads. Autosomal recessive inheritance is the typical inheritance pat- result from complementation between normal
tern, and the disorder is caused by mutations in any of at least 15 genes, alleles at the two loci. If, instead, both parents had
all involved in regulating how cilia function (Figure 5.11). autosomal recessive deafness caused by different
mutations in the same gene, all their children
would be expected to be deaf as a result of
Allelic and phenotypic heterogeneity
inheriting two mutant alleles at that locus.
Many different mutations in one gene can have the same effect and
produce similar phenotypes. For example, β-thalassemia results from a
deficiency of β-globin and can arise by any number of different mutations
in the hemoglobin β chain (HBB) gene. Different mutations in a single
gene can also often result in different phenotypes. That can arise in two
ways: either different types of mutation somehow have different effects
on how the underlying gene works—which we consider here—or some
factors outside the disease locus have varying effects on the phenotype
(described below).
Phenotype variation due to different mutations at a single gene locus
may differ in degree (severe or mild versions of the same basic pheno-
type) or be extensive and result in rather different disorders. For example,

other BBS1, 11q13

Figure 5.11 Extraordinary locus
23.8% heterogeneity for Bardet–Biedl syndrome.
20.8%
Where shown, percentages indicate the proportion
of mutant alleles that are attributable to indicated
CEP290, 12q121
genes (whose subchromosomal locations are given
MKS1, 17q22 4.5%
8.1% BBS2, 16q21 below or adjacent to the gene symbol). Seven of
BBS12, 4q27 5.0% the genes (BBS1, BBS2, MKKS, PTHB1, BBS10, BBS12,
ARL6, 3q11
and MKS1) account for almost three-quarters of the
TRIM32, 9q33 BBS4, 15q22
5.8% BBS5, 2q31 identified pathogenic mutations in Bardet–Biedl
20.0%
syndrome. (Adapted from Zaghloul NA & Katsanis
6.0% MKKS, 20p12 N [2009] J Clin Invest 119:428–437; PMID 19252258.
BBS7, 4q27 With permission from the American Society for
TTC8, 14q31
Clinical Investigation.)
BBS10, 12q21 PTHB1, 7p14

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 134 Chapter 5 Single-Gene Disorders: Inheritance Patterns, Phenotype Variability, and Allele Frequencies

Table 5.1 Remarkable heterogeneity of CLASS OF DISORDER DISORDER INHERITANCE OMIM NO.
clinical phenotypes resulting from mutation PATTERNa
in the lamin A (LMNA) gene. aAR, autosomal Lipodystrophy lipodystrophy, familial partial AD 151660
recessive; AD, autosomal dominant. mandibulosacral dysplasia type A with AR 248370
lipodystrophy
Muscle/heart disease limb girdle muscular dystrophy type IB AD 159001
Emery–Dreifuss muscular dystrophy type 2 AD 181350
Emery–Dreifuss muscular dystrophy type 3 AR 181350
congenital muscular dystrophy AD 613205
cardiomyopathy, dilated type IA AD 150330
Malouf syndrome (cardiomyopathy, dilated, AR 212112
with hypertrophic hypogonadism)
heart–hand syndrome, Slovenian type AD 610140
Neuropathy Charcot–Marie–Tooth disease, type 2B1 AR 605588
Progeria Hutchinson–Gilford progeria syndrome AD 176670
atypical Werner syndrome
atypical progeroid syndrome

Duchenne and Becker muscular dystrophies (OMIM 310200 and 300376,

respectively) represent severe and mild forms of the same type of mus-
cular dystrophy and are both examples of dystrophinopathies (PMID
20301298). More extreme phenotype heterogeneity can result from muta-
tions at some genes (see the example of the lamin A/C gene in Table 5.1).
Clinical phenotypes can also vary between affected members of the same
family even although they have identical mutations. As we saw in Section
5.2, heteroplasmy can explain divergent phenotypes in family members
affected by a mitochondrial DNA disorder. But single-gene disorders can
also show intrafamilial variation in phenotype that may be due to genetic
and nongenetic factors as described below.

Non-penetrance and age-related penetrance

The penetrance of a single-gene disorder is the probability that a person
who has a mutant allele will express the disease phenotype. Dominantly
inherited disorders, by definition, are manifested in heterozygotes and
might be expected to show 100% penetrance. That might be true for cer-
tain dominant disorders. For many others, however, penetrance is more
variable and the disorder can sometimes appear to skip a generation so
that a person who must have inherited the disease allele is unaffected
(non-penetrance—Figure 5.12).
Non-penetrance should not be viewed as surprising. Even in single-gene
disorders—in which, by definition, the phenotype is largely dictated by
the genotype at just one locus—other genes can play a part, as can epige-
netic and environmental factors.

Variable age at onset in late-onset disorders

A disease phenotype may take time to manifest itself. If a disorder is
present at birth, it is said to be congenital. In some disorders, however,
there is a late age at onset so that the penetrance is initially very low but
then increases with age. Age-related penetrance means a late onset of
symptoms, and quite often the disease first manifests in adults.
The slow development of disease in adult-onset disorders may occur in
different ways. Harmful products may be produced slowly but build up
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 Uncertainty, Heterogeneity, and Variable Expression of Mendelian Phenotypes 135

II

III

IV

Figure in
Genetics 5.12 Non-penetrance
Medicine | A0512 in an autosomal dominant disorder. have inherited a mutant allele from their father (in each case the unaffected
Tom Strachan with
Individuals | a red asterisk are asymptomatic disease gene carriers: they individuals with a red asterisk inherited a mutant allele from their mother).
© garland science design by blink studio ltd
have inherited a mutant allele ultimately from the affected great-great- As described in the text, an epigenetic mechanism known as imprinting can
grandmother in generation I, but none of them expresses the disease result in this type of parent-of-origin effect on the phenotype.
phenotype. In this example, the disorder is evident only in individuals who

over time, for example. If pathogenesis involves a gradual process of cell

death, it may take some time before the number of surviving cells drops
to critically low levels that produce clinical symptoms. In hereditary can-
cers, a mutation is inherited at a tumor-suppressing gene locus and a
second, somatic mutation is required to initiate tumor formation. The
second mutation occurs randomly, but the probability of a second muta-
tion increases with time and therefore with age.
Huntington disease (PMID 20301482) is a classic example of a late-onset
single-gene disorder. In this case, mutant alleles produce an abnormal
1.0
protein that is harmful to cells and especially toxic to neurons. The loss
of neurons is gradual but eventually results in a devastating neurodegen-
erative condition. Huntington disease is highly penetrant. The onset of
0.8
symptoms typically occurs in middle to late adult life, but juvenile forms
are also known (Figure 5.13).
Age-at-onset curves for late-onset disorders are used in genetic coun- 0.6
seling to calculate the chance that an asymptomatic person at risk of
probability

developing the disease carries the mutation. In Huntington disease an

unaffected person who has an affected parent will have a 50% a priori risk 0.4
that decreases with age (see Figure 5.13); if one is still free of symptoms
by age 60, for example, the chance of developing the disease falls to less
than 20%. 0.2

Variable expression of Mendelian phenotypes within families

Phenotypes resulting from mutation in mitochondrial DNA are highly 0
0 10 20 30 40 50 60 70
variable because of the special mitochondrial property of heteroplasmy age (years)
(see Section 5.2). Some types of Mendelian disorders, notably dominant
phenotypes, are also prone to variable expression, and different family Genetics
Figurein5.13
Medicine | A0513
Age-related onset of Huntington
Tom Strachan |
members show different features of disease (sometimes called variable ©disease.
garland The
science curve
design shows
by blink the probability
studio ltd that an
expressivity—see Figure 5.14 for an example pedigree). But, like non-pen- individual carrying a Huntington disease allele will
etrance, variable phenotype expression is occasionally seen in recessive have developed symptoms by a given age.
pedigrees. (From Harper PS [2010] Practical Genetic
Counselling, 7th ed. With permission from
Non-penetrance can be regarded as an extreme endpoint of vari- Taylor & Francis Group LLC.)
able expression, and the factors that produce variable expression of
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 136 Chapter 5 Single-Gene Disorders: Inheritance Patterns, Phenotype Variability, and Allele Frequencies

I epilepsy (onset facial

in childhood) angiofibromas

learning and
behavior renal
II difficulties angiomyolipomata

infantile spasms cardiac

and severe rhabdomyomata
learning disability
III

Genetics in Medicine | A0514

Tom Strachan |
© garland5.14
scienceVariable
design by blink studio ltd in a
Figure phenotypes
tuberous sclerosis family. Tuberous sclerosis
is an autosomal dominant disorder caused
by mutations in either the TSC1 or TSC2 gene.
These two genes make two subunits of a tumor
suppressor protein complex that works in a
signaling pathway to regulate cell growth and
proliferation. The disorder affects multiple body
systems with characteristic tumor-like lesions
in the brain, skin, and other organs, and is often
associated with seizures and learning difficulties.
However, as is evident in this family from the
northeast of England, there can be considerable
differences in expressivity of the disorder. (Pedigree
information provided by Dr Miranda Splitt,
Northern Region Genetics Service UK and Institute
of Genetic Medicine, Newcastle University.)
Figure 5.15 Main explanations for
phenotype variation in Mendelian disorders.
(A) Interfamilial variation in phenotype. Unrelated
individuals with the same Mendelian disorder may
often have different mutations (red symbols) at the
disease gene locus with different consequences
for gene expression and disease. (B) Intrafamilial
variation in phenotype. Affected members of a
single family can be expected to have the same
mutation at the disease gene locus but can
nevertheless show differences in phenotype
because of genetic or nongenetic factors. In the
former case, the affected individuals may have
different alleles at one or more modifier gene loci.
Modifier genes make products that interact with
the primary gene locus so as to modulate the
phenotype, and different alleles of a modifier gene
can have different effects. Alternatively, nongenetic
factors can explain phenotype variation; an
example is epigenetic regulation, in which the
phenotypes within families are the same as those that result in non-
penetrance. They include nongenetic factors—epigenetic regulation and
environmental factors (Figure 5.15B) and stochastic factors. Additional
genetic factors are also involved, notably modifier genes that regulate or
interact with a Mendelian locus, affecting how it is expressed. Different
alleles at a modifier gene locus may have rather different influences on
the expression of the Mendelian locus (Figure 5.15B).
Imprinting
Certain phenotypes show autosomal dominant inheritance with parent-
of-origin effects. Both sexes are affected, and the mutant allele can be
transmitted by either sex but is expressed only when inherited from a
parent of one particular sex. For some conditions, a mutant allele must
be inherited from the father for the disease to be expressed (see Figure
5.12 for a possible pedigree). For other conditions, such as Beckwith–
Wiedemann syndrome, the disease phenotype is expressed only if the
disease allele is inherited from the mother (Figure 5.16).
The parent-of-origin effects are due to an epigenetic mechanism known
as imprinting, which we describe in detail in Chapter 6. The mutant
allele that is not expressed is often described as the imprinted allele.
Beckwith–Wiedemann syndrome is said to be paternally imprinted,
because paternally inherited alleles are not expressed.
Anticipation
Some disorders show consistent generational differences in phenotype.
Disorders such as fragile X mental retardation syndrome, myotonic dys-
trophy, and Huntington disease are caused by unstable mutations (often
called dynamic mutations) whose characteristics can change after they
undergo DNA replication. As a result, the phenotype can vary between
affected individuals in families but in a directional way; that is, it can be
(A) interfamilial (B) intrafamilial variation in phenotype
variation
Ma
Mb EF

disease allele can be silenced by an altered

chromatin conformation (green hatched box) or
by variable exposure to an environmental factor Mc
(green circle) such as a specific virus or chemical
during development in utero. different mutant effect of different alleles at epigenetic environmental
alleles at gene locus a modifier gene locus (M) regulation factors (EF)

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 Allele Frequencies in Populations 137

I Figure 5.16 Parent-of-origin

1 2 3 effect on the expression of
an inherited disorder. This
pedigree shows autosomal
II dominant Beckwith–Wiedemann
1 2 3 4 5 6 7 8 9 10 11 12 syndrome (PMID 20301568),
which manifests only when
the underlying mutant allele is
III 5 2 2 3 2 maternally inherited. The affected
individuals in generation III must
have inherited the mutant allele
from their common grandfather
IV
I-2 but none of his 10 children in
generation II have symptoms of
Genetics in Medicine | A0516 disease, including two daughters,
expressed
Tom Strachan | at an earlier age
and become increasingly severe with each
new
© generation
garland science design by of
blinkaffected
individuals. This phenomenon is known as
studio ltd II-2 and II-8, who have gone on to
anticipation (Figure 5.17). We consider the molecular mechanisms in have multiple affected children.
detail in Chapter 7. (From Viljoen D & Ramesar R
[1992] J Med Genet 29:221–225;
PMID 1583639. With permission
from BMJ Publishing Group Ltd.)
5.4 Allele Frequencies in Populations
Genetic disorders that are comparatively common and serious have
somehow avoided being eliminated by natural selection. This raises two
questions: Are high mutation rates enough to explain why harmful dis-
ease alleles persist? And if so, why should some single-gene disorders be
comparatively common but others very rare? In this section we are con-
cerned primarily with allele frequencies and the factors that affect them.
The frequency of a single-gene disorder in a population relates to the
frequency in the population of pathogenic alleles at the relevant disease
locus (or loci). A high disease allele frequency might result if a gene were
to be particularly susceptible to mutation. Genes that are very large, such
as the dystrophin gene, or that contain many repetitive sequences that
confer structural instability, might be expected to be especially prone to
mutation.
Some of the most common single-gene disorders, such as sickle-cell ane-
mia and the thalassemias, result from mutation in tiny genes—as we will
see below, autosomal recessive disorders do not require high mutation
rates to be common. Even in some autosomal dominant disorders, a high
incidence of the disorder may not necessarily mean that the underlying
gene loci have high mutation rates, as described below.
Some disorders may be caused by a selfish mutation. Achondroplasia
(PMID 20301331) is a common single-gene disorder but is caused exclu-
sively by mutation at just a single nucleotide, producing a highly specific
Figure 5.17
Genetics in A three-generation
Medicine | A0517 family
change (glycine-to-arginine substitution at residue 380) in the FGFR3 Tom Strachan |
affected with myotonic dystrophy. The
(fibroblast growth factor receptor type 3) protein. The nucleotide that is © garland science design by blink studio ltd
degree of severity increases in each generation.
altered is not thought to be highly mutable. Instead, the mutation may The grandmother (right) is only slightly affected,
promote its own transmission: male germ-line cells that contain it may but the mother (left) has a characteristic narrow
have a proliferative advantage and make a disproportionate contribution face and somewhat limited facial expression.
to sperm (so that there is a high allele frequency even although the muta- The baby is more severely affected and has the
tion rate is not so exceptional). We consider selfish mutations in detail in facial features of children with neonatal-onset
Section 7.2. myotonic dystrophy, including an open, triangular
We also need to explain why some single-gene disorders are common mouth. The infant has more than 1000 copies of
in some human populations but very rare in others. Cystic fibrosis is par- the trinucleotide repeat, whereas the mother and
grandmother each have about 100 repeats. (From
ticularly common in northern European populations, for example, and
Jorde LB, Carey JC & Bamshad MJ [2009] Medical
sickle-cell anemia is especially frequent in tropical Africa but virtually
Genetics, 4th ed. With permission from Elsevier.)
absent from many other human populations.
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