Chapter 5

Sex-Linked and Nontraditional

Modes of Inheritance

Dr. Cui Yan

Email: cuiyanbio45@163.com
 Outline
 X Inactivation
 Sex-Linked Inheritance
 X-Linked Recessive Inheritance
 X-Linked Dominant Inheritance
 Y-Linked Inheritance
 Sex-Limited and Sex Influenced Traits
 Mitochondrial Inheritance
 Genomic Imprinting
 Anticipation and Repeat Expansion

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 Cells

We have 2 types of cells

1. Somatic Cells (2n) – body cells

2. Sex Cells (n) – sperm and egg

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 Chromosomes

 Mendel’s findings were not widely accepted at first

 During the 1900’s, parallels discovered between genes
and chromosomes
 Chromosome Theory of Inheritance:
— Genes located on chromosomes
— accounts for inheritance patterns

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 Chromosomes
 Diploid individuals have 2
sets of homologous
chromosomes
 One from mom, one from
dad
 Gene locus:
— Alleles of a gene reside at same
location

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 Chromosomes

We have 2 types of Chromosomes:

1. Autosomal chromosomes – pairs 1 through
22 in humans (non-sex chromosomes)
2. Sex chromosomes – xx or xy

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 Sex-Linked Genes
 What 2 sex chromosomes make up a male? Female?
— Male = XY, Female = XX

 Which chromosome is physically larger?

— The X. It can hold a lot more genetic info

 Sex linked gene:

— Any gene on a sex chromosome

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 Why boys are at a disadvantage!
 Boys have a higher chance of getting——
 Red-green color blindness
 Hemophilia
 Night blindness
 And Duchenne Muscular Dystrophy, et al
 because of sex-linked inheritance
 The trait is carried on the X chromosome ！

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X vs. Y

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 X Inactivation
 Lyon hypothesis
 One X chromosome in each cell is randomly inactivated
early in the embryonic development of females

 Result: dosage compensation

 An equalization of the amount of X-linked gene products
in males and females

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Mosaics

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XX-distribution of active X
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 Barr Bodies

A highly condensed X chromosome

1 less than the number of X chromosomes
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 X Inactivation

 It happens within 7 to 10 days after fertilization

 X inactivation center: a single 1-Mb region on the
long arm
 Randomly, but Permanent!!
 Except for female’s germline

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 X Inactivation is Incomplete

 ~15% of the genes on the X chromosome escape

inactivation
 Thus, having extra (or missing) copies of active
portions of the X chromosome may have a disease
phenotype

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 XIST

 A gene locates in the X inactivation center

 Transcribed only on the inactive X chromosome
 It’s mRNA coats the inactive X chromosome
 Methylation and histone deacetylation

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 Sex-Linked Inheritance

 Sex-linked genes: genes located on either X or Y

chromosome
 X-Linked Recessive Inheritance
 X-Linked Dominant Inheritance
 Y-Linked Inheritance

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 X-Linked Recessive Inheritance

 Hemophilia A
 Duchenne Muscular Dystrophy
 Red-green color blindness

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 Why boys are at a disadvantage!
 Boys have a higher chance of getting——
 Red-green color blindness
 Hemophilia
 Night blindness
 And Duchenne Muscular Dystrophy, et al
 because of sex-linked inheritance
 The trait is carried on the X chromosome ！

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 Hemophilia A
 1 in 5,000 or 10,000 males
 Caused by deficient or defective factor VIII, a key
component of the clotting cascade
 Prolonged and often severe bleeding from wounds and
hemorrhages in the joints and muscles
 Platelet activity is normal

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Extensive bruising of right outer thigh
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Duchenne Muscular Dystrophy, DMD

 1 in 3500 males
 A progressive weakness and loss of muscle
 Die of respiratory or cardiac failure, ＜ 25y
 The DMD gene is the largest gene known by far,
with high mutation rate

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A patient with late-
stage Duchenne
muscular dystrophy,
showing severe
muscle loss

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Transverse section of gastrocnemius muscle from (A) a normal
boy and (B) a boy with Duchenne muscular dystrophy. Normal
muscle fiber is replaced with fat and connective tissue

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 Red-green color blindness

 Three primary colors—red, green, and blue

 Normal color vision is said to be trichromatic
 8% of European males, 4% to 5% of Asian males

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A, Image perceived by a person with normal color vision. B, The predicted
perception by a person with protanopia, a form of red-green colorblindness.

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People with red-green
color blindness see either
a three or nothing at all

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 Why boys are at a higher risk?

 Male: XAY, or XaY—definitely be sick!!

 Female: XAXA, XAXa, or XaXa
 X inactivation: XAXa—half XA, and half Xa
 Thus, for XAXa, ~50% gene product, is usually
sufficient for normal phenotype

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 Why boys are at a higher risk?

 If the frequency of a gene for X-linked recessive

disease is q
 The fraction for males is q
 The fraction for females is q2 (XaXa)
 Hemophilia A: boys, 1/10,000; girls, 1/100,000,000

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 X-Linked Recessive Diseases
 Character No. 1:
1 are much more common
among males than among females!!

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 X-Linked Recessive Inheritance
Male: XY

his mom his dad

XAXa ， phenotypically normal

Skipped generations

An affected father → All his daughters (carriers) →

~half of their sons affected

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 X-Linked Recessive Diseases
 Character No. 2:
2 absence of father-to-son
transmission, skipped generations.

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(carrier)

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(normal)

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Probabilities:
0% boys affected
100% daughters carriers

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(carrier)

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Probabilities:
50% boys affected
50% daughters affected,
and 50% daughters carriers

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 X-Linked Recessive Diseases
 Character No. 3:
3 recurrence risks are more
complex than for autosomal disorders.

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 About Female
 Some XAXa females can be affected
 ……..Because of random X inactivation!!
 They are called: manifesting heterozygotes
 Yet they are mildly affected because of the small fraction
of active normal X chromosomes
 Females with only one X chromosome may manifest the
diseases

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 X-Linked Recessive Diseases
 Character No. 4:
4 some XAXa females can be
mildly affected because of random X inactivation.

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 X-Linked Recessive Diseases
 Are much more common among males
 Absence of father-to-son transmission, skipped
generations
 Recurrence risks are more complex than for autosomal
disorders
 Some XAXa females can be mildly affected because of
random X inactivation

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 X-Linked Dominant Inheritance

 A lot less common than X-linked recessive diseases

 Hypophosphatemic rickets
 Incontinentia pigmenti type I
 Rett syndrome

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 Hypophosphatemic Rickets

 The kidneys are impaired to reabsorb phosphate

 Results in abnormal ossification, with bending and
distortion of the bones (rickets)

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 Incontinentia Pigmenti Type I

 Character:
Character abnormal skin pigmentation, conical or
missing teeth, and ocular and, in some cases,
neurological abnormalities
 Only seen in females!!
 ……Because males are so severely affected that
they do not survive to term

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 Rett Syndrome
 A neurodevelopmental disorder
 1 in 10, 000 females and a lot less males because most of
them do not survive to term
 Character:
Character autistic behavior, mental retardation, seizures,
and gait ataxia
 The severity varies substantially because of random X
inactivation

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 Rett Syndrome
 Most are caused by mutations in MECP2 gene
 And most of the mutations are de novo events coming
from the paternal germline
 MECP2 protein binds to other genes and repress the
transcription
 Loss-of-function mutations result in the inappropriate
expression of genes involved in brain development

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 X-Linked Dominant Diseases

 Only need 1 disease gene to manifest the disease

 Females: XX; males: XY
 ……..So females are twice as commonly affected
as males unless the disease is lethal in males

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X1, chromosome with normal allele;
X2, chromosome with disease allele.
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 X-Linked Dominant Inheritance
 A lot less common than X-linked recessive diseases
 Much more severe in males
 Twice as common in females as in males
 Skipped generations are uncommon
 Father-to-son transmission is not seen

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Attribute X-Linked Dominant
Recurrence risk for 50% of sons affected; 50%
heterozygous female × of daughters affected
normal male mating
Recurrence risk for 0% of sons affected; 100%
affected male × normal of daughters affected
female mating
Transmission pattern Vertical; disease phenotype
seen in generation after
generation
Sex ratio Twice as many affected
females as affected males
(unless disease is lethal in
males)
Other Male-to-male transmission
is not seen; expression is
less severe in female
heterozygotes than in
affected males
X-Linked Recessive
50% of sons affected;
50% of daughters
heterozygous carriers
0% of sons affected;
100% of daughters
heterozygous carriers
Skipped generations may
be seen, representing
transmission through
carrier females
Much greater prevalence
of affected males;
affected homozygous
females are rare
Male-to-male
transmission not seen;
manifesting
heterozygotes may be
seen in females
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 Y-Linked Inheritance

 Y chromosome contains few genes, mainly are

holandric genes
 All the housekeeping genes on the Y chromosome
have inactivation-escaping homologs on the X
chromosome
 Transmission is strictly from father to son

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Sex-Limited and Sex-Influenced Traits

 Sex-limited traits: occur only in one sex

 E.g.: inherited testicular defects
 Sex-influenced traits: not strictly sex chromosome
linked
 E.g.: male-pattern baldness, with the help of
autosomal genes

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 Mitochondrial DNA (mtDNA)

 Mitochondria:
Mitochondria can produce adenosine triphosphate
(ATP) as essential energy source
 Have their own DNA molecules, which are called
mtDNA
 Each cell contain several hundred or more
mitochondria in the cytoplasm

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 mtDNA
 mtDNA contains no introns
 Encodes 2 ribosomal RNAs (rRNAs), 22 transfer
RNAs (tRNAs) and 13 polypeptides involved in
oxidative phosphorylation
 The transcription happens in the mitochondrion,
which is located in the cytoplasm

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The circular mitochondrial
DNA genome. Locations of
protein encoding genes are
shown, as are the locations
of the 2 ribosomal RNA
genes and 22 transfer RNA
genes. The replication
origins of the heavy (OH)
and light (OL) chains and
the noncoding D loop are
shown.

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 Mitochondrial Inheritance

 Inherited exclusively through the maternal line

 Males do not transit mtDNA to their offspring
 The mutation rate of mtDNA is 10 times higher than
nuclear DNA because of the lack of DNA repair
mechanisms and the damage from the free oxygen
radicals

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Only females can transmit the disease mutation to their offspring.
Complete penetrance of the mutation is shown in this pedigree.

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 Mitochondrial Inheritance
 A single cell may have some molecules having an
mtDNA mutation and others do not
 This is called heteroplasmy
 The larger the percentage of mutant mtDNA, the
more severe the expression of the disease
 The percentage changes through chance variation
or selective advantage during cell division

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 Mitochondrial Inheritance

 Each tissue type has a threshold level for ATP,

below which cells begin to degenerate or die
 So the central nerve system is often affected by
mtDNA mutation because it consumes 20% of the
body’s ATP production

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 Mitochondrial Disorders

 Missense mutations in protein-coding mtDNA genes

 Single-base mutations in a tRNA gene
 Duplications and deletions
 Associated with some common human diseases

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 Missense Mutations
in Protein-Coding mtDNA Genes
 Leber hereditary optic neuropathy (LHON)
 1 in 10, 000 persons
 Rapid loss of vision in the central visual field because of
optic nerve death, begins in their thirties
 Heteroplasmy is minimal, so expression is uniform

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 Single-base mutations
in a tRNA gene
 Myoclonic epilepsy with ragged-red fiber syndrome
(MERRF)
 Mitochondrial encephalomyopathy and stroke-like
episodes (MELAS)
 mtDNA is heteroplasmic so is highly variable in its
expression

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 Duplications and Deletions

 Kearns–Sayre disease
 Pearson syndrome
 Chronic progressive external ophthalmoplegia
(CPEO)

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 Associated with some
common human diseases
 Late-onset deafness
 Alzheimer disease
 Contribute to the aging process

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 Mitochondrial Inheritance

 Mitochondria can produce ATP and have their own

DNA (mtDNA)
 mtDNA is maternally inherited and has a high
mutation rate
 Mitochondral inheritance has its heteroplasmy

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 Genomic Imprinting

 Mendel’s theory: the phenotype is the same whether

the allele is inherited from mom or dad
 Yet it is not always right
 For some human genes, 1 allele is transcriptionally
inactive, depending on the parent from whom it was
received

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 Genomic Imprinting

 Normal individual would have only 1 active allele

 The process of gene silencing is called imprinting
 The transcriptionally silenced genes are said to be
imprinted
 Imprinted alleles are heavily methylated, which is similar
to X-inactivation

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 Prader–Willi
and Angelman Syndromes
 Both are caused by the same deletion of about 4Mb of the
long arm of chromosome 15
 Both are seen in about 1 of 15, 000 persons
 Prader-Willi sydrome (PWS) if the deletion is inherited from
the father
 Angelman syndrome if it is inherited from mother

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 PWS and Angelman Syndrome

 PWS: short stature, hypotonia (poor muscle tone),

small hands and feet, obesity, mild to moderate
mental retardation, and hypogonadism
 Angelman Syndrome: severe mental retardation,
seizures, and an ataxic gait

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Illustration of the effect
of imprinting on
chromosome 15
deletion. A, Inheritance
of the deletion from the
father produces
Prader-Willi syndrome
(PWS) (note the
inverted V-shaped
upper lip, small hands,
and truncal obesity. B,
Inheritance of the
deletion from the
mother produces
Angelman syndrome
(note the characteristic
posture)
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 PWS and Angelman Syndrome
 Are caused by the same deletion
 Why different?
 Because of genomic imprinting:
 The 4-Mb deletion contains several genes that are imprinted on the
chromosome 15 from the mother, while others are imprinted from the
father
 Thus several genes are active on only 1 chromosome
 So the same deletions from mother or father lose different active
genes, resulting in different diseases

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Illustration of the effect of imprinting on chromosome 15 deletion. C,
Pedigrees illustrating the inheritance pattern of this deletion and the
activation status of genes in the critical region (the 4-Mb deletion)

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 PWS and Angelman Syndrome
 Other mechanisms:

1. Uniparental disomy: the person inherits 2 chromosome

from 1 parent and none from the other

– If 2 are both from mather, PWS happens

– If 2 are both from father, Angelman syndrome happens

2. Point mutations: can result in Angelman syndrome

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 Beckwith-Wiedemann Syndrome
 An overgrowth condition accompanied by an
increased predisposition to cancer
 Large size for gestational age, neonatal hypoglycemia, a
large tongue, creases on the ear lobe, and omphalocele
(an abdominal wall defect)
 Having an increased risk for Wilms tumor (a kidney
cancer) and hepatoblastoma (a liver cancer)

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 Beckwith-Wiedemann Syndrome

 20%~30% are caused by the inheritance of 2 copies

of chromosome 11 both from the father
 IGF2 (insulin-like growth factor 2) gene is inactive
on the maternally transmitted chromosome and
active on the paternal one
 So the active IGF2 gene is in double dose

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 Beckwith-Wiedemann Syndrome

 50%~60% are caused by the imprint of CDKN1C

gene in DMR2 (differentially methylated region)
 CDKN1C gene is a growth-suppressing gene
 Resulting in silencing of growth inhibitors and
overgrowth

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Schematic of the organization of several imprinted genes on chromosome
11p15.5 that are involved in the pathogenesis of Bechwith-Wiedemann
syndrome. It can arise from loss of imprinting of the growth promoting
gene, IGF2, on the maternally transmitted chromosome, 2 copies of
paternal allele with an active IGF2 as a consequence of uniparental
disomy, or imprinting of the growth-suppressing gene, CDKN1C, on the
maternally transmitted chromosome
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 Russell-Silver Syndrome

 Growth retardation, proportionate short stature, leg

length discrepancy, and a small, triangular-shaped face
 A third are caused by imprinting abnormalities of
chromosome 11p15.5 that lead to down-regulation of
IGF2
 10% are caused by maternal uniparental disomy

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Imprinting defects that lead to down-regulation of IGF2 on the paternal
allele cause some cases of Russel-Silver syndrome. Red: genes that
are not methylated and therefore expressed; green: genes that are
methylated and therefore silenced.

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 Genomic Imprinting

 Some disease genes may be expressed differently when

inherited from one sex versus the other
 Typically associated with methylation of DNA and
chromatin condensation, which limit the action of
transcription factors and decrease gene expression

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 Anticipation and Repeat Expansion

 Anticipation:
Anticipation some genetic diseases display an
earlier age of onset and/or more severe expression
in the more recent generations

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 Anticipation
 Myotonic dystrophy:
dystrophy an autosomal dominant
disease involving progressive muscle deterioration
and myotonia
 1 in 8000 persons
 Caused by mutations in DMPK, a protein kinase
located on chromosome 19

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A three-generation family affected
with myotonic dystrophy. The
degree of severity increases in
each generation. The grandmother
(right) is only slightly affected, but
the mother (left) has a
characteristic narrow face and
somewhat limited facial
expression. The baby is more
severely affected and has the facial
features of children with neonatal-
onset myotonic dystrophy,
including an open, triangle-shaped
mouth. The infant has more than
1000 copies of the trinucleotide
repeat, whereas the mother and
grandmother each have
approximately 100 repeats.
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 Repeat Expansion
 The disease-causing mutation is an expanded CTG
trinucleotide repeat lying in the 3’UTR of the gene
 The number of these repeats is strongly correlated with
severity of the disease
 Normal persons: 5 to 37 copies
 mildly affected ones: 50 to 100 copies
 Those with full-blown myotonic dystrophy: have anywhere
from 100 to several thousand copies

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 Repeat Expansion
 The number of repeats often increases with
succeeding generations
 As the number increases, the age of onset
decreases and severity often increases
 So the expansion of this trinucleotide repeat is the
cause of anticipation in myotonic dystrophy

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A, Myotonic dystrophy pedigree illustrating anticipation. In this
case, the age of onset for family members affected with an
autosomal dominant disease is lower in more recent
generations.

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B, An autoradiogram from a
Southern blot analysis of the
myotonic dystrophy gene in
three individuals. Individual a
is homozygous for a 4- to 5-
repeat allele and is normal.
Individual b has one normal
allele and one disease allele of
175 repeats; this individual has
myotonic dystrophy. Individual
c is also affected with myotonic
dystrophy and has one normal
allele and a disease-causing
allele of approximately 900
repeats.
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 Repeat Expansion
 The expanded repeat produces an mRNA product that
remains in the nucleus of the cell
 The abnormal mRNA interacts with proteins that normally
bind other RNA products to regulate their splicing.
 As a result, several proteins are abnormally formed,
giving rise to some of the pleiotropic features of the
disease phenotype

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 Repeat Expansion

 A 4-bp (CCTG) expanded repeat on a gene on

chromosome 3 was discovered recently to cause
myotonic dystrophy
 Also, this mutation produces a toxic mRNA that
interferes with the normal function of RNA-binding
proteins

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 Repeat Expansion
 Have been identified as the cause of more than 20
genetic diseases
 3 categories:
 1st: neurological diseases. The mutations often have a gain-of-
function effect
 2nd: phenotypically more diverse diseases
 3rd: the repeat expansions are much larger than 1st and 2nd

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 Summary for Anticipation

 Refers to progressively earlier or more severe expression of a

disease in more recent generations
 Expansion of DNA repeats has been shown to cause
anticipation in some genetic diseases
 The diseases can be divided into 3 major categories

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 The Fragile X Story
 There is a 25% excess of males with mental
retardation
 Fragile X syndrome:
syndrome mental retardation, distinctive
facial appearance, hypermobile joints, and increased
testicular volume in postpubertal males

113
 The Fragile X Story

 The degree of mental retardation tends to be milder

and more variable in females than in males
 The X chromosomes exhibit breaks and gaps near
the tip of the long arm when cultured in a medium
that is deficient in folic acid

114
Boys with fragile X syndrome. Note the long faces,
prominent jaws, and large ears and the similar
characteristics of children from different ethnic groups:
European (A), Asian (B), and Latin American (C).
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An X chromosome from
a male with fragile X
syndrome, showing an
elongated, condensed
region near the tip of
the long arm.

116
 The Fragile X Story
 The prevalence is higher in males (1/4000) than in
females (1/8000)
 Normal transmitting males (NTM): males who have
affected descendants but are not affected themselves
 The mothers of NTM had a much lower percentage of
affected sons than did the daughters of these males
 Daughters of NTM were never affected with the disorder,
but these women’s sons could be affected

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A pedigree showing the
inheritance of the fragile X
syndrome. Females who carry a
premutation (50 to 230 CGG
repeats) are shown by dotted
lines. Affected individuals are
represented by solid symbols. A
normal transmitting male, who
carries a premutation of 70 to 90
repeat units, is designated NTM.
Note that the number of repeats
increases each time the mutation
is passed through another female.
Also, only 5% of the NTM’s sisters
are affected, and only 9% of his
brothers are affected, but 40% of
his grandsons and 16% of his
granddaughters are affected. This
is the Sherman paradox.

118
 The Fragile X Story
 FMR1 gene is the disease’s gene, 5’UTR contains a CGG
repeat unit
 6~50 copies in normal persons, 200~1000 or more in
persons with fragile X syndrome (a full mutation)
 An intermediate number of repeats, ranging
approximately from 50 to 200 copies, is seen in normal
transmitting males and their female offspring

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 The Fragile X Story
 Expansion: When the female transmit the gene to their
offspring, there is an expansion from the premutation of 50
to 200 repeats to the full mutation of more than 200
repeats
 These expansions do not occur in male transmission
 Premutations tend to become larger in successive
generations, and larger premutations are more likely to
expand to a full mutation

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 The Fragile X Story
 Males with the premutation do not have affected
daughters because repeat expansion occurs in
female transmission
 Grandsons and great-grandsons of NTM are more
likely to be affected than are brothers because of
progressive repeat expansion through successive
generations of female permutation carriers

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A pedigree showing the
inheritance of the fragile X
syndrome. Females who carry a
premutation (50 to 230 CGG
repeats) are shown by dotted
lines. Affected individuals are
represented by solid symbols. A
normal transmitting male, who
carries a premutation of 70 to 90
repeat units, is designated NTM.
Note that the number of repeats
increases each time the mutation
is passed through another female.
Also, only 5% of the NTM’s sisters
are affected, and only 9% of his
brothers are affected, but 40% of
his grandsons and 16% of his
granddaughters are affected. This
is the Sherman paradox.

122
 The Fragile X Story
 The highest FMR1 mRNA expression levels are in the
brain
 Persons with normal and premutation FMR1 genes both
produce mRNA
 While those with full mutations have no FMR1 mRNA in
their cells, indicating that transcription of the gene has
been eliminated

123
 The Fragile X Story
 mRNA production is elevated in those with
premutations, and this mRNA has toxic effects
 1/3 of males with premutations develop a neurological
disease characterized by ataxia and tremors in later life.
 20% of females with FMR1 premutations experience
premature ovarian

124
 The Fragile X Story
 For persons with full mutations, the CGG repeat is heavily
methylated
 And the degree of methylation, which is likely to influence
transcription of FMR1, is correlated with severity of
expression of the disorder
 ＜ 5% of the diseased are caused by other loss-of
function point mutations in FMR1

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 The Fragile X Story
 The protein product of FMR1, FMRP, may be involved in
transporting mRNA from the nucleus to the cytoplasm, and
regulating the translation of mRNA
 Another fragile site is also associated with an expansion of
CGG repeat in the 5′ region of gene FMR2, subsequent
hypermethylation, and results in mental retardation
 The CGG repeat at this locus can expand when
transmitted through either males or females

126
 Summary

 X-inactivation happens in females, it is random,

fixed, and incomplete
 The recurrence risks for X-linked recessive
inheritance are complex. No father-to-son
transmission happens and skipped generations exist

127
 Summary

 Mitochondrial DNA is maternally inherited and has a

high mutation rate
 Genomic imprinting and anticipation are
nontraditional modes of inheritance, yet important
for several diseases

128
 Study Question No. 1

 Females have been observed with five X

chromosomes in each somatic cell. How many Barr
bodies would such females have?
 There are four Barr bodies, always one less than the
number of X chromosomes.

129
 Study Question No. 2

 Explain why 8% to 10% of female carriers of the DMD

gene have muscle weakness.
 This is most likely a result of X inactivation. The
heterozygotes with muscle weakness are the ones with
relatively large proportions of active X chromosomes
containing the mutant allele.

130
 Study Question No. 3
 For X-linked recessive disorders, the ratio of
affected males to affected females in populations
increases as the disease frequency decreases.
Explain this in terms of gene and genotype
frequencies.
 The disease frequency in males is q, and in females it
is q2. The male-to-female ratio is thus q/q2 or 1/q. Thus,
as q decreases, the male-to-female ratio increases.

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 Study Question No.4
 Figure 5-18 shows the inheritance of hemophilia A in a family.
What is the risk that the male in generation IV is affected with
hemophilia A? What is the risk that the female in generation IV
is a heterozygous carrier? What is the risk that she is affected
by the disorder?

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 Because the male’s grandfather is affected with the disorder, his
mother must be a carrier. His father is phenotypically normal and
therefore does not have the disease gene. Thus, the male in
question has a 50% risk of developing hemophilia A. His sister’s
risk of being a heterozygous carrier is also 50%. Her risk of being
affected with the disorder is close to zero (barring a new mutation
on the X chromosome transmitted by her father).
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 Study Question No.5

 Pedigrees for autosomal dominant and X-linked

dominant diseases are sometimes difficult to
distinguish. Name as many features as you can
that would help to tell them apart.

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 Male-to-male transmission can be observed in autosomal dominant inheritance, but it is
not observed in X-linked dominant inheritance. Thus, males affected with X-linked
dominant disorders must always have affected mothers, unless a new mutation has
occurred.
 Males and females are affected in approximately equal proportions in autosomal
dominant inheritance, but there are twice as many affected females as males in X-linked
dominant inheritance (unless the disorder is lethal prenatally in males, in which case only
affected females are seen).
 In X-linked dominant inheritance, all of the sons of an affected male are normal, and all
of the daughters are affected. In X-linked dominant diseases, heterozygous females tend
to be more mildly affected than are hemizygous males.
 In autosomal dominant inheritance, there is usually no difference in severity of
expression between male and female heterozygotes.

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 Study Question No.6
 How would you distinguish mitochondrial inheritance from
other modes of inheritance?
 In mitochondrial inheritance, the disease can be inherited only
from an affected mother. In contrast to all other types of
inheritance, no descendants of affected fathers can be affected.
Note that males with an X-linked recessive disease who mate
with normal females cannot transmit the disease to their
offspring, but their grandsons can be affected with the disease.

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 Study Question No.7

 A man with Becker muscular dystrophy marries a

phenotypically normal woman. On average, what
percentage of their male offspring will be affected
and what percentage of their female offspring will be
affected by this disorder?

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 Because Becker muscular dystrophy is relatively rare, it is
reasonable to assume that the woman is a normal homozygote.
Thus, she can transmit only normal X chromosomes to her
offspring. Her male offspring, having received a Y chromosome
from the father and a normal X from the mother, will all be
unaffected. All female offspring of this mating will receive a
mutated X chromosome from the father and all will be
heterozygous carriers of the disorder.

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 Study Question No.8

 A female carrier of a Duchenne muscular

dystrophy mutation marries a phenotypically
normal man. On average, what percentage of
their male offspring will be affected and what
percentage of their female offspring will be
affected with the disorder?

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 If the man is phenotypically normal, his X chromosome
cannot carry a Duchenne muscular dystrophy mutation.
The female will transmit her mutation-carrying
chromosome to half of her offspring, on average. Thus,
half of the sons will be affected with the disorder, and
half of the daughters will be heterozygous carriers.

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 Study Question No.9
 A boy and his brother both have hemophilia A. If there is
no family history of hemophilia A in previous generations,
what is the probability that the boys’ aunt (the mother’s
sister) is a heterozygous carrier of the disease gene?
 The boys’ mother must be a heterozygous carrier for a factor
VIII mutation. Thus, one of the mother’s parents must also
have carried the mutation. Consequently, the probability that
the mother’s sister is a carrier is 1/2.

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 Study Question No.10
 It is possible to create a zygote from two copies of
the maternal genome alone. In amphibians, the
zygote will develop and mature into an adult without
fertilization by a sperm cell (this process is known
as parthenogenesis). The same experiment has been
attempted in mice, but it always results in early
prenatal death. Explain this.

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 This is explained by genomic imprinting. For normal
development, differential expression of genes inherited
from the father and mother is necessary. If the
expression pattern from only one parent is inherited, the
embryo cannot develop normally and dies. The
experiment works in amphibians because genomic
imprinting does not occur in these animals.

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