single-gene inheritance - ju medicine › ... › 2018 › 01 › patterns-of-inheri… · •...
TRANSCRIPT
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Single-Gene Inheritance
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Importance of Family History
• Understanding
the past is the
key to
predicting the
future.
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OBJECTIVES• Construct and interpret pedigrees using standard
nomenclature
• Describe the general features of Mendelian patterns of
single gene inheritance.
• Identify the mode of inheritance of traits discussed in
lecture.
• Describe aspects of phenotypic expression, using traits
discussed in lecture as examples.
• Understand basic concepts of probability.
• Recognize the pattern of inheritance of a trait segregating in
a family.
• Apply basic concepts of probability and principles of
Mendelian inheritance to calculate the probabilities that
offspring of specified mating types will be affected and
unaffected.
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Concept 14.3: Inheritance patterns are often
more complex than predicted by simple
Mendelian genetics
• The relationship between genotype and
phenotype is rarely as simple as in the pea
plant characters Mendel studied
• Many heritable characters are not determined
by only one gene with two alleles
• However, the basic principles of segregation
and independent assortment apply even to
more complex patterns of inheritance
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Extending Mendelian Genetics for a Single
Gene
• Inheritance of characters by a single gene may
deviate from simple Mendelian patterns in the
following situations:
– When alleles are not completely dominant or
recessive
– When a gene has more than two alleles
– When a gene produces multiple phenotypes
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Degrees of Dominance
• Complete dominance occurs when phenotypes
of the heterozygote and dominant homozygote are
identical
• In incomplete dominance, the phenotype of F1
hybrids is somewhere between the phenotypes of
the two parental varieties
• In codominance, two dominant alleles affect the
phenotype in separate, distinguishable ways
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• A dominant allele does not subdue a recessive
allele; alleles don’t interact that way
• Alleles are simply variations in a gene’s
nucleotide sequence
• For any character, dominance/recessiveness
relationships of alleles depend on the level at
which we examine the phenotype
The Relation Between Dominance and
Phenotype
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• Tay-Sachs disease is fatal; a dysfunctional
enzyme causes an accumulation of lipids in the
brain
– At the organismal level, the allele is recessive
– At the biochemical level, the phenotype (i.e.,
the enzyme activity level) is incompletely
dominant
– At the molecular level, the alleles are
codominant
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Frequency of Dominant Alleles
• Dominant alleles are not necessarily more
common in populations than recessive alleles
• For example, Polydactyly one baby out of 400 in
the United States is born with extra fingers or toes
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• The allele for this unusual trait is dominant to the
allele for the more common trait of five digits per
appendage
• In this example, the recessive allele is far more
prevalent than the population’s dominant allele
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Multiple Alleles
• Most genes exist in populations in more than two allelic forms
• For example, the four phenotypes of the ABO blood group in humans are determined by three alleles for the enzyme (I) that attaches A or B carbohydrates to red blood cells: IA, IB, and i.
• The enzyme encoded by the IA allele adds the A carbohydrate, whereas the enzyme encoded by the IB allele adds the B carbohydrate; the enzyme encoded by the i allele adds neither
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Figure 14.11
Carbohydrate
Allele
(a) The three alleles for the ABO blood groups and theircarbohydrates
(b) Blood group genotypes and phenotypes
Genotype
Red blood cellappearance
Phenotype(blood group)
A
A
B
B AB
none
O
IA IB i
iiIAIBIAIA or IAi IBIB or IBi
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Pleiotropy
• Most genes have multiple phenotypic effects, a
property called pleiotropy
• For example, pleiotropic alleles are responsible for
the multiple symptoms of certain hereditary
diseases, such as cystic fibrosis and sickle-cell
disease
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Extending Mendelian Genetics for Two or
More Genes
• Some traits may be determined by two or more
genes
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Epistasis
• In epistasis, a gene at one locus alters the phenotypic expression of a gene at a second locus
• For example, in Labrador retrievers and many other mammals, coat color depends on two genes
• One gene determines the pigment color (with alleles B for black and b for brown)
• The other gene (with alleles C for color and cfor no color) determines whether the pigment will be deposited in the hair
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Figure 14.12
Sperm
Eggs
9 : 3 : 4
1/41/4
1/41/4
1/4
1/4
1/4
1/4
BbEe BbEe
BE
BE
bE
bE
Be
Be
be
be
BBEE BbEE BBEe BbEe
BbEE bbEE BbEe bbEe
BBEe BbEe BBee Bbee
BbEe bbEe Bbee bbee
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Polygenic Inheritance
• Quantitative characters are those that vary in the
population along a continuum
• Quantitative variation usually indicates polygenic
inheritance, an additive effect of two or more
genes on a single phenotype
• Skin color in humans is an example of polygenic
inheritance
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Figure 14.13
Eggs
Sperm
Phenotypes:
Number ofdark-skin alleles: 0 1 2 3 4 5 6
1/81/8
1/81/8
1/81/8
1/81/8
1/8
1/8
1/8
1/8
1/8
1/8
1/8
1/8
1/646/64
15/6420/64
15/646/64
1/64
AaBbCc AaBbCc
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Nature and Nurture: The Environmental
Impact on Phenotype
• Another departure from Mendelian genetics
arises when the phenotype for a character
depends on environment as well as genotype
• The norm of reaction is the phenotypic range
of a genotype influenced by the environment
• For example, hydrangea flowers of the same
genotype range from blue-violet to pink,
depending on soil acidity
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• Norms of reaction are generally broadest for
polygenic characters
• Such characters are called multifactorial
because genetic and environmental factors
collectively influence phenotype
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Integrating a Mendelian View of Heredity
and Variation
• An organism’s phenotype includes its physical
appearance, internal anatomy, physiology, and
behavior
• An organism’s phenotype reflects its overall
genotype and unique environmental history
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Concept 14.4: Many human traits follow
Mendelian patterns of inheritance
• Humans are not good subjects for genetic
research
– Generation time is too long
– Parents produce relatively few offspring
– Breeding experiments are unacceptable
• However, basic Mendelian genetics endures
as the foundation of human genetics
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Pedigree Analysis
• A pedigree is a family tree that describes the
interrelationships of parents and children
across generations
• Inheritance patterns of particular traits can be
traced and described using pedigrees
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• Pedigrees can also be used to make
predictions about future offspring
• We can use the multiplication and addition
rules to predict the probability of specific
phenotypes
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Concept 14.4: Many human traits follow
Mendelian patterns of inheritance
• Humans are not good subjects for genetic
research
– Generation time is too long
– Parents produce relatively few offspring
– Breeding experiments are unacceptable
• However, basic Mendelian genetics endures
as the foundation of human genetics
© 2011 Pearson Education, Inc.
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Pedigree Analysis
• A pedigree is a family tree that describes the
interrelationships of parents and children
across generations
• Inheritance patterns of particular traits can be
traced and described using pedigrees
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• Pedigrees can also be used to make
predictions about future offspring
• We can use the multiplication and addition
rules to predict the probability of specific
phenotypes
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Sample Pedigree
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IMPORTANT TERMS
locus codominant compound heterozygote
allele dominant carrier (obligate heterozygote)
genotype recessive genetic heterogeneity
phenotype homozygous pleiotropy
autosomal heterozygous age of onset
X-linked hemizygous sex-limited
penetrance expressivity sex-influenced
pedigree proband imprinting
trinucleotide repeat
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A pedigree is a concise summary of the medical family
history; it is the symbolic language of clinical genetics and
human genetics research.
• It is an easy, fast, and efficient means of recording a wealth of
information about the family.
• Standardization of symbols is essential to facilitate
communication - See Robin Bennett’s article referenced in
resources at the end of the syllabus for more details if
interested.
• Nomenclature is an evolving process.
• Several ethical and legal dilemmas - Potential for
discrimination, issues of privacy raised, and need for
guidelines.
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Designation of generations and
individuals
1. Each horizontal line is a generation
2. Place the oldest generation at the top
3. Use Roman numerals to identify generations
4. Use Arabic numbers to identify individuals within a generation
5. List siblings from oldest to youngest, from left to right
6. Male partner is usually placed to the left of the female partner
7. Record full name, current age and date of birth, or age at death for each
individual
8. Record race and ethnic origin of each individual
9. Note health problems and/or cause of death for each individual
10.There are appropriate symbols to use for both adoption and assisted-
reproductive technologies
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• The proband is an affected individual coming to
medical attention independently of other
• family members. The proband is designated
with an arrow in the pedigree, and there may be
more than one proband per family.
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Medical status and results of genetic
evaluation/testing of family members
1. Shading or fill (hatches, dots, etc.) is used to
denote medical status or symptoms of
individuals. A key/legend is used to define
meaning
2. Results of an evaluation (E) are recorded below
the symbol and a key/legend
defines the notations. Currently this is the least
standardized pedigree
nomenclature
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The Gene is the Unit of Inheritance
The location of a gene on a chromosome is its locus.
Alternative forms of a gene at a particular locus are
referred to as alleles.
An individual’s genotype (genetic composition) at a
particular locus is defined by the nature of the alleles at that
locus
If both alleles are identical, then the individual is
homozygous at the locus. Homozygosity may refer to the
presence of two normal or two mutant alleles.
If the alleles differ, then the individual is heterozygous at the
locus. If two different mutant alleles are present, then the
individual is a compound heterozygote.
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A A A a a a a1 a2
homozygote heterozygote homozygote compound
A allele a allele heterozygote
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The genotype at a particular locus and the environment
in which it is expressed determines the phenotype or
observed characteristics of an individual.
Traits that are determined by loci on one of the 22
autosomes are autosomal. Traits determined by loci
on the X chromosome are X-linked, and those
determined by loci on the Y chromosome are Y-
linked.
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Gregor Mendel’s Laws of
Inheritance
– Law of Unit Inheritance - parental characteristics do
not blend because there is a unit of inheritance.
Mendel’s “units” are now known as genes or alleles.
– Law of Segregation - the two alleles at a particular
locus segregate into different gametes.
– Law of Independent Assortment - alleles at different
loci are transmitted independently of each other.
Linkage is an exception to this rule.
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Dominant and Recessive Inheritance
– Nomenclature: For dominant traits the capital letter (e.g. A) represents
the mutant allele and the small letter (e.g. a) represents the normal
allele. For recessive traits, the small letter (e.g. a) represents the mutant
allele and the capital letter (e.g. A) represents the normal allele.
– Autosomal dominant traits are those traits in which the phenotype of
the heterozygote and the homozygote for the dominant allele are the
same, i.e., Aa and AA have the same phenotype where A=dominant
allele. These traits are expressed when only one copy of the dominant
allele is present. In practice, if the heterozygote expresses the trait, then
the trait is classified as dominant, even if the phenotype of the
homozygote (AA) and heterozygote (Aa) are different.
– Autosomal recessive traits are those traits in which the phenotype is
expressed only if homozygous for the recessive allele, i.e., aa where
a=recessive allele. Two copies of the recessive allele are necessary for
expression.
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Dominant and Recessive Inheritance
– If the heterozygote (AB) has a different phenotype than either of the
homozygotes (AA or BB), then the alleles are said to be codominant.
– X-linked dominant traits are those expressed when either males or
females have one copy of the dominant allele, i.e., XAY or XAXa where
A=dominant allele.
– X-linked recessive traits are those expressed in males who carry one
copy of the recessive allele (i.e., are hemizygous, XaY where
a=recessive allele). Two copies of the recessive allele are generally
required for females to express the trait, i.e., XaXa.
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Types of Genetic Disease
• Chromosomal
• Single gene (Mendelian)
• Multifactorial
• Teratogenic
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Examples and Features of
Autosomal Dominant Inheritance
Unaffected
individual
a a
Affected
individual
A a
A=mutant allele
a=normal allele
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Examples
• familial hypercholesterolemia
• Huntington disease
• neurofibromatosis type I (NF1)
• myotonic dystrophy
• Marfan syndrome
• achondroplasia
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Dominantly Inherited Disorders
• Some human disorders are
caused by dominant alleles
• Dominant alleles that cause a
lethal disease are rare and
arise by mutation
• Achondroplasia is a form of
dwarfism caused by a rare
dominant allele
© 2011 Pearson Education, Inc.
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Figure 14.17
Parents
DwarfDd
Sperm
Eggs
DdDwarf
ddNormal
DdDwarf
ddNormal
D
d
d
d
Normaldd
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From www.hopkinsmedicine.org From www.sciencemuseum.org.uk
Achondroplasia
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Neurofibromatosis Type 1
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Neurofibromatosis Type 1
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Neurofibromatosis Type 1
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Features of Autosomal Dominant
Inheritance1. Vertical transmission – direct transmission from
grandparent to parent to child without skipping generations
2. Both sexes affected in 1:1 ratio
3. Both sexes may transmit the trait
4. Heterozygotes much more common than homozygotes
5. May see variable expressivity and variable age of onset
6. Homozygotes usually more seriously affected than heterozygotes
7. May be due to new mutation
8. Gene product is usually a structural (non-enzymatic) protein
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Autosomal Dominant Pedigree
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Transmission probabilities and the
use of the Punnett square
1. If one parent has the disorder (assumed to be Aa) and the
other does not (aa) then there is a 50% chance that the
child will inherit the disorder and a 50% chance that they
will not.
2. If both parents have the disorder (assumed to be Aa x Aa)
then there is a 75% chance that their children will inherit the
disorder, and a 25% chance that they will not.
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Examples and Features of Autosomal
Recessive Inheritance
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Recessively Inherited Disorders
• Many genetic disorders are inherited in a
recessive manner
• These range from relatively mild to life-
threatening
© 2011 Pearson Education, Inc.
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Examples
• cystic fibrosis
• sickle cell anemia
• Tay-Sachs disease
• Phenylketonuria
• most inborn errors of metabolism
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The Behavior of Recessive Alleles
• Recessively inherited disorders show up only in
individuals homozygous for the allele
• Carriers are heterozygous individuals who
carry the recessive allele but are phenotypically
normal; most individuals with recessive
disorders are born to carrier parents
• Albinism is a recessive condition characterized
by a lack of pigmentation in skin and hair and
eyes
© 2011 Pearson Education, Inc.© 2011 Pearson Education, Inc.
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Cystic Fibrosis
• Cystic fibrosis is the most common lethal
genetic disease in the United States, striking
one out of every 2,500 people of European
descent
• The cystic fibrosis allele results in defective or
absent chloride transport channels in plasma
membranes leading to a buildup of chloride
ions outside the cell
• Symptoms include mucus buildup in some
internal organs and abnormal absorption of
nutrients in the small intestine
© 2011 Pearson Education, Inc.
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Photos from
www.cff.org
Cystic fibrosis (CF)
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Figure 14.16
Parents
NormalAa
Sperm
Eggs
NormalAa
AANormal
AaNormal(carrier)
AaNormal(carrier)
aaAlbino
A
A
a
a
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• If a recessive allele that causes a disease is
rare, then the chance of two carriers meeting
and mating is low
• Consanguineous matings (i.e., matings
between close relatives) increase the chance
of mating between two carriers of the same
rare allele
• Most societies and cultures have laws or
taboos against marriages between close
relatives
© 2011 Pearson Education, Inc.
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Sickle-Cell Disease: A Genetic Disorder with
Evolutionary Implications
• Sickle-cell disease affects one out of 400
African-Americans
• The disease is caused by the substitution of a
single amino acid in the hemoglobin protein in
red blood cells
• In homozygous individuals, all hemoglobin is
abnormal (sickle-cell)
• Symptoms include physical weakness, pain,
organ damage, and even paralysis
© 2011 Pearson Education, Inc.
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Fig. 14-UN1
© 2011 Pearson Education, Inc.
• Heterozygotes (said to have sickle-cell trait) are
usually healthy but may suffer some symptoms
• About one out of ten African Americans has
sickle cell trait, an unusually high frequency of
an allele with detrimental effects in
homozygotes
• Heterozygotes are less susceptible to the
malaria parasite, so there is an advantage to
being heterozygous
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Sickle Cell Anemia
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Carrier, unaffected
A a
Autosomal Recessive
A=normal allele
a=mutant allele
Affected
a a
Unaffected, not a carrier
A A
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Autosomal Recessive Pedigree
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Autosomal Recessive Pedigree
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Features of Autosomal Recessive
Inheritance
1. Horizontal transmission – affected
individuals usually within the same
sibship or generation
2. Both sexes affected in 1:1 ratio
3. Both sexes may equally transmit the
mutant allele
4. May observe consanguinity
5. Gene product is usually an enzymatic
protein
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Transmission probabilities and
use of the Punnett square
If both parents are carriers (Aa x Aa) then there is 25% chance that the child will have the disorder (aa)
50% chance that the child will be a carrier (Aa), and
25% chance that the child will be neither affected nor a
carrier (AA).
Thus the chance that an unaffected child of carrier
parents is also a carrier is two in three.
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Affected homozygotes are commonly the offspring of two
heterozygote carriers.
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XA Y XA Xa Xa Xa
Sex Linkage and X-Inactivation
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Dosage compensation
1. For autosomal traits, two doses lead to a normal
phenotype, while one dose or more than two doses
often have clinical significance
2. For X-linked traits two doses in females and one dose in
males both lead to a normal phenotype
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X-inactivation in females allows compensation for
this difference in dosage for X-linked traits
• Lyon hypothesis
• In early embryonic life (3-7 days after fertilization) one X
chromosome is inactivated. The inactive X chromosome is
condensed in a Barr body.
• Inactivation of the maternal or paternal X chromosome is random,
but once it occurs, the same X will be inactive in all descendants of
a particular cell.
• Some genes on the inactive X chromosome remain active, i.e.,
escape inactivation. These include the genes in the
pseudoautosomal region that have matching genes on the Y
chromosome, genes outside the pseudoautosomal region that have
related copies on the Y chromosomes, and others.
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X-Inactivation
• Allows dosage compensation between
males and females for genes on the X
chromosome
• In females, early in embryonic life, one of
the X chromosomes is inactivated
• The process is random and clonal
• Some genes escape X-inactivation
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• A gene that is located on either sex chromosome
is called a sex-linked gene
• Genes on the Y chromosome are called Y-linked
genes; there are few of these
• Genes on the X chromosome are called X-linked
genes
© 2011 Pearson Education, Inc.
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Inheritance of X-Linked Genes
• X chromosome have genes for many
characters unrelated to sex, whereas the Y
chromosome mainly encodes genes related
to sex determination
© 2011 Pearson Education, Inc.
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• X-linked genes follow specific patterns of
inheritance
• For a recessive X-linked trait to be expressed
– A female needs two copies of the allele
(homozygous)
– A male needs only one copy of the allele
(hemizygous)
• X-linked recessive disorders are much more
common in males than in females
© 2011 Pearson Education, Inc.
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Figure 15.7
Eggs Eggs Eggs
Sperm Sperm Sperm
(a) (b) (c)
XNXN XnY XNXn XNY XNXn XnY
Xn Y XN Y YXn
Xn Xn
XN
XN
XN XNXNXn XNY
XNY
XNY XNY
XnY XnYXNXn XNXn
XNXnXNXN
XnXn
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• Some disorders caused by recessive alleles on
the X chromosome in humans
– Color blindness (mostly X-linked) (Red-green
color blindness)
– Duchenne muscular dystrophy
(dystrophy muscle weakness and loss of muscle tissue)
– Hemophilia
© 2011 Pearson Education, Inc.
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X Inactivation in Female Mammals
• In mammalian females, one of the two X
chromosomes in each cell is randomly inactivated
during embryonic development
• The inactive X condenses into a Barr body
© 2011 Pearson Education, Inc.
•If a female is heterozygous for a particular gene located on the X chromosome, she will be a mosaic for that character
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Examples and Features of X-Linked
Recessive Inheritance
Examples:
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Duchenne muscular dystrophy
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X-Linked Recessive Pedigree
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Features of X-Linked Recessive Inheritance
1. Diagonal inheritance – affected males related
through females of the maternal line
2. Absence of male-to-male transmission
3. Incidence of trait much higher in males than
females
4. Full expression in hemizygous males
5. No or mild expression in carrier females due to
X-inactivation
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Transmission probabilities and use of the
Punnett square
1. A son never inherits the disorder from his father.
2. All daughters of a male with the disorder are obligate
carriers.
3. Sons of carrier females have a 50% chance of inheriting
the disorder.
4. Daughters of carrier females have a 50% chance of
being carriers too.
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Examples and Features of X-Linked
Dominant Inheritance
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X-Linked Dominant Pedigree
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Features of X-Linked Dominant
Inheritance
1. Twice as many females with the disorder
as males
2. Absence of male-to-male transmission
3. Males with the disorder transmit it to all
daughters and no sons
4. Females usually have more mild and
variable expression due to X-inactivation
5. Few disorders classified as X-linked
dominant
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Transmission probabilities and use of the
Punnett square
1. A son never inherits the disorder from his father
2. All daughters of male with the disorder will also
have the disorder
3. Sons of affected females have a 50% chance of
inheriting the disorder
4. Daughters of affected females also have a 50%
chance of inheriting the disorder
5. Can distinguish between autosomal and X-linked
dominant by looking at offspring of affected
males
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Phenotypic Expression
1. Penetrance
2. Expressivity
3. Variable age of onset
4. Pleiotropy
5. Genetic heterogeneity
6. Sex-limited
7. Sex-influenced
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Penetrance
• Penetrance refers to the all or none expression of a
mutant genotype. It usually refers to dominant traits in
heterozygotes, and means that even though an
individual has inherited the mutant allele, there may be
no expression of the phenotype. If a condition is
expressed in less than 100 % of persons who have one
copy of the mutant allele, it is said to have reduced
penetrance.
If a condition/feature is expressed in less than 100% of
individuals who carry the responsible allele, then it is
said to have reduced penetrance
• The probability of expression of the phenotype given the
genotype
• Term used for dominant conditions
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Retinoblastoma, a malignant
eye tumor. About 10% of
individuals who transmit the
mutant allele are unaffected.
Therefore, the mutant allele
is 90% penetrant.
Retinoblastoma
Reduced Penetrance
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Reduced Penetrance
Deafness in Waardenburg syndrome
Waardenburg syndrome, a
congenital sensorineural
deafness, heterochromia,
displacement of the inner canthi,
white forelock, and other
features. Since only about 20%
of people with Waardenburg
syndrome are deaf, this shows
reduced penetrance of this
feature of this syndrome
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Variable Expressivity
• The extent to which a trait is expressed
• If expression ranges from mild to severe then it is said to
have variable expressivity
• However, it is never completely unexpressed
– Eg. Neurofibromatosis & myotonic dystrophy
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Variable age of onset refers to the variation in the time to
phenotypic expression of mutant gene (s). Example: the onset
of Huntington disease is typically in the 40’s, however, age of
onset may range from the 20’s to 60’s.
A mutant gene is said to be pleiotropic when it produces a
wide range of phenotypic effects. Example: Marfan syndrome
involves the skeletal, cardiovascular, and ocular systems.
Variable age of onset & pleiotropy
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Anticipation: Earlier Age of
Onset & Increasing Severity
Myotonic dystrophy
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Genetic heterogeneity
locus heterogeneity
PAX3 on 2q
Auto dom HL
GJB2 on 13q
Auto rec HL
a1 a2
At the CF locus on 7q
a1 = ΔF508 allele
a2 = S549R allele
allelic heterogeneity
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Genetic heterogeneity
Allelic heterogeneity refers to two or more different
mutant alleles at the same genetic locus (Example:
Duchenne and (the less severe) Becker muscular
dystrophy; cystic fibrosis).
a1 a2
At the CF locus on 7q
a1 = ΔF508 allele
a2 = S549R allele
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Genetic heterogeneity
Locus heterogeneity is when mutations at two
different genetic loci result in similar phenotypes
(Example: congenital deafness). In some cases, the
mode of inheritance of the disorders can vary
PAX3 on 2q
Auto dom HL
GJB2 on 13q
Auto rec HL
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Sex-limited & Sex-influenced
– refers to a phenotype that is autosomally transmitted
but expressed only in one sex. Example: Autosomal
dominant male precocious puberty.
– Sex-influenced refers to autosomally inherited traits
that are expressed differently, in either degree or
frequency, in males and females. Example:
hemochromatosis (autosomal recessive disorder of
increased absorption of dietary iron) is more
commonly found in males due to lower dietary intake
and menstruation in females.
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• Some disorders do not follow Mendelian
patterns of inheritance.
• These disorders are clearly genetic
(inherited) and their inheritance is
classified as non-Mendelian.
• We now understand why some of these
disorders do not follow Mendelian patterns
and examples include: mitochondrial
inheritance, unstable trinucleotide
repeats, and imprinting.
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Trinucleotide Repeats
Some disorders were observed to increase in severity from one
generation to another,
and/or the age of onset of symptoms became earlier in successive
generations.
This was termed anticipation and the mechanism was a mystery since
mutations were presumed to be inherited in a stable manner from
one generation to another.
Furthermore, in some disorders the sex of the parent who passed on
the disorder seemed to influence the severity or age of onset of
symptoms.
This too was a puzzle because in Mendelian traits maternal and
paternal DNA was assumed to be equivalent.
Anticipation and parent of origin effects are now known to be due to a
novel type of dynamic mutation known as unstable trinucleotide
repeats.
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Trinucleotide Repeats
Tandemly repeated trinucleotides (i.e. CGG, CTG) within or adjacent to
a gene that may increase or decrease in number during formation of
egg or sperm cells and thus disrupt the functioning of the gene and
lead to disease
Examples:
• Fragile X Mental Retardation syndrome
• Huntington disease
• myotonic dystrophy
• spinocerebellar ataxia
• Kennedy disease
• Joseph disease
• Friedreich Ataxia
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Trinucleotide Repeat
Expansion
Fragile X MR Syndrome
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FX MR Clinical Features
1. Incidence of about 1 in 5000 males; presumed incidence in females
is about one-half that of males.
2. Most common cause of inherited mental retardation in males.
3. Phenotype in males includes moderate mental retardation, large
head, long face, prominent forehead and chin, protruding and
larger ears, large testes after puberty, speech delay, and loose
joints. Behavior abnormalities include hyperactivity, hand flapping,
hand biting, temper tantrums and sometimes autism spectrum
disorder.
4. Approximately 50% of female carriers of a full mutation have mental
retardation that is usually less severe than in affected males.
5. About 30% of males who carry a premutation will develop Fragile
X-associated tremor/ataxia syndrome (FXTAS) which is
characterized by late-onset, progressive cerebellar ataxia and
intention tremor.
About 20% of females who carry a premutation will develop
premature ovarian failure (POF).
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Genetic Features
A. Atypical X-linked inheritance showing parent of origin effect.
B. In affected males associated with a fragile site at Xq27.3 in 10-40% of
metaphase spreads, however, this cytogenetic testing is no longer used
for diagnostic testing.
C. Amplified ‘CGG’ trinucleotide repeat as well as abnormal methylation
(hypermethylation) of the FMR-1 gene. The normal protein product,
FMRP, is an RNA-binding protein that seems to function as a
nucleocytoplasmic shuttling protein and it binds several mRNAs
including its own. It also seems to affect cytoskeletal structure, synaptic
transmission and neuronal maturation. The FMR-1 gene mutation
results in gene silencing and the loss of function results in suppression
of translation of proteins from its RNA targets.
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Genetic Features
D. Allele sizes (these categories are not absolute):
- Normal alleles: 5-54 repeats
- Premutation alleles: 55-200 repeats (not associated with MR but
there is risk for FXTAS and POF; may expand to full mutation in
female carrier)
- Full mutation alleles: > 200 repeats (affected individuals)
E. Existence of transmitting males who are of normal intelligence but
can transmit the Fragile X chromosome to their daughters. These
daughters are of normal intelligence, however, their children are at
risk for mental retardation.
F. The change from phenotypically normal to affected state (i.e.
expansion of the trinucleotide repeats into the full mutation
range) has only been observed following oogenesis.
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• Huntington’s disease is a degenerative disease
of the nervous system
• The disease destroys cells in the basal ganglia,
the part of the brain that controls movement,
emotion, and cognitive ability
• The disease has no obvious phenotypic effects
until the individual is about 35 to 40 years of age
• Once the deterioration of the nervous system
begins the condition is irreversible and fatal
Huntington’s Disease: A Late-Onset Lethal Disease
© 2011 Pearson Education, Inc.
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Genomic Imprinting
• For a few mammalian traits, the phenotype
depends on which parent passed along the
alleles for those traits
• Such variation in phenotype is called genomic
imprinting
• Genomic imprinting involves the silencing of
certain genes that are “stamped” with an
imprint during gamete production
© 2011 Pearson Education, Inc.
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Figure 15.17
(a) Homozygote
Paternalchromosome
Maternalchromosome
Normal Igf2 alleleis expressed.
Normal Igf2 alleleis not expressed.
Normal-sized mouse(wild type)
Mutant Igf2 alleleinherited from mother
Mutant Igf2 alleleinherited from father
Normal-sized mouse (wild type) Dwarf mouse (mutant)
Normal Igf2 alleleis expressed.
Mutant Igf2 alleleis expressed.
Mutant Igf2 alleleis not expressed.
Normal Igf2 alleleis not expressed.
(b) Heterozygotes
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Figure 15.17a
(a) Homozygote
Paternalchromosome
Maternalchromosome
Normal Igf2 alleleis expressed.
Normal Igf2 alleleis not expressed.
Normal-sized mouse(wild type)
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Figure 15.17b
Mutant Igf2 alleleinherited from mother
Mutant Igf2 alleleinherited from father
Normal-sized mouse (wild type) Dwarf mouse (mutant)
Normal Igf2 alleleis expressed.
Mutant Igf2 alleleis expressed.
Mutant Igf2 alleleis not expressed.
Normal Igf2 alleleis not expressed.
(b) Heterozygotes
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• It appears that imprinting is the result of the
methylation (addition of –CH3) of cysteine
nucleotides
• Genomic imprinting is thought to affect only a
small fraction of mammalian genes
• Most imprinted genes are critical for embryonic
development
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Imprinting
Prader-Willi syndrome Angelman syndrome
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Imprinting
I.Definition: the differential expression of a gene depending on the sex
of the parent from which it is inherited (i.e., the parental origin of the
gene).
Implications:
A.Implies that there is a critical or sensitive period during development
(i.e. during or before gametogenesis) during which the genetic
information is marked or imprinted in order to permit differential
expression based on parental origin.
B.The imprint must persist stably through DNA replication and cell
division in the body cells.
C.The imprint must be capable of affecting gene expression (i.e. turning
genes on or off).
D.Imprinting is not a permanent alteration since it must be erased in the
germ cell line of every individual so that new imprinting may be
introduced.
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Example of Imprinting in HumansPrader-Willi syndrome (PWS) and Angelman syndrome (AS)
1.Both map to and may involve deletions of 15q11-13 but they have
distinct phenotypes.
2.PWS is characterized by obesity, voracious appetite, and mental
retardation, whereas, Angelman is characterized by gait ataxia, smiling
facies and happy demeanor, and mental retardation.
3.Deletions are found in about 50-60% of cases of PWS and AS.
4.If the deletion is paternally derived (only maternal 15q11-13 present)
then PWS.
5.If the deletion is maternally derived (only paternal 15q11-13 present)
then AS.
6.Some cases of PWS (about 30%) have been attributed to maternal
uniparental disomy and some cases of AS (about 5%) have been
attributed to paternal uniparental disomy. About 10-15% of cases of AS
are caused by a single gene mutation in the UBE3A gene. Other causes
of PWS and AS include defects in the imprinting center, chromosomal
translocation within the PWS/AS critical region, and unknown cause.
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PWS & AS both involve chromo 15q11-13
Deletions account for ~ 70% cases of PWS & AS
• If paternal deletion of 15q11-13 → PWS
• If maternal deletion of 15q11-13 → AS
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Causes of PWS and AS
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Inheritance of Organelle Genes
• Extranuclear genes (or cytoplasmicgenes) are found in Mitochondria
• Extranuclear genes are inherited maternally because the zygote’s cytoplasm comes from the egg
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• Some defects in mitochondrial genes prevent cells from
making enough ATP and result in diseases that affect the
muscular and nervous systems
– For example, mitochondrial myopathy (myopathy is a
muscular disease) and Leber’s hereditary optic neuropathy (damage to nerves)
© 2011 Pearson Education, Inc.
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