X-LINKED INHERITANCE
X-LINKED RECESSIVE INHERITANCE
X-LINKED DOMINANT INHERITANCE
dr. Retno Sutomo, Ph.D., Sp.A.
X-LINKED RECESSIVE INHERITANCE
Carrier mother
Segregation of X-linked recessive allele
Affected father
Segregation of X-linked recessive allele
Pedigree of X-linked recessive inheritance
X-linked recessive inheritance:
Features
 Affects mainly males
 Affected males are usually born to
unaffected parents
 Transmission through carrier females
 No male-to-male transmission
 All daughters of affected males are carriers
X-linked recessive disorders
Complication to X linked pedigree
De novo mutation
De novo mutation in DMD
X-linked recessive disease in female
is it possible?
1.
2.
3.
4.
5.
Mating of an affected father and a carrier mother
Non-random X inactivation
Female with single X chromosome
Translocation of X chromosome
Androgen insensitivity syndrome (AIS)
X-linked recessive disorder in female
Affected male + carrier female
Mother’s gametes
Father’s gametes
Xm
X
Xm Xm Xm XmX
Y
XmY
XY
Usually lethal
X-linked recessive disorder in female
Female with single X chromosome
45, X0
 Turner’s syndrome
X-linked recessive disorder in female
Non-random X inactivation
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Only one X chromosome is active in each cell, other X
chromosome/chromosomes is/are inactivated
Normally, inactivation of X chromosome occurs randomly (by chance) 
random (balanced) X inactivation
The chance for each X chromosome being inactivated in each cell is 50%
 In normal female (46, XX), mutation in one X chromosome will be compensated
by another active X chromosome
In certain condition, most cells activate the defective X chromosome and only
few cells activate the normal one  non-random (imbalanced, skewed) X
inactivation
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
X-linked recessive disorder in female
Translocation of X chromosome
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Translocation of X chromosome segments to autosomes
The translocated X chromosome defective/non-functional
Mimics individual with single X chromosome for the
associated gene
X-linked recessive disorder in female
Androgen insensitivity syndrome
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Phenotypically female but genotypically male (pseudo female)
Non-responsiveness of androgen receptor to androgen
stimulation
 No development of male sex characters
Duchene muscular dystrophy (DMD) in Vietnamese “girl”
 Karyotipe: 46, XY  boy
 Carries mutation in androgen receptor gene
X-LINKED DOMINANT
INHERITANCE
X-linked dominant inheritance
Characteristics
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Affects either sex, F > M
Females are often less severely affected than males
The child of an affected female has a 50% chance of being
affected, regardless the sex
For an affected male, all his daughters are affected, but none of
his sons
The pedigree resembles autosomal dominant inheritance, except
no male to male transmission
 excess of affected females

X-linked dominant pedigree
Which one is X-inked dominant inheritance?
X-linked dominant
autosomal dominant
X-linked dominant inheritance
Characteristics

In some disorders the condition appears to be lethal in
affected males
 Ex:
focal dermal hypoplasia (Goltz syndrome), incontinentia
pigmenti
 There will be fewer males than expected, half of the females
will be affected and all surviving males will be unaffected

Some XLD disorders affects girls almost exclusively and
usually occurs sporadically, since affected females do
not reproduce
 Ex:
Rett syndrome  gene mapped to Xq24
X-linked dominant pedigree  lethality in male
Father’s gametes
Mother’s gametes
Xm
X
X
XXm
XX
Y
XmY
XY
POLIFACTORIAL INHERITANCE
Mendelian versus Galtonian
 Mendel  discontinuous characters
 Tall vs dwarf
 Green peas vs yellow peas
 Etc
 Galton  continuous characters
 Body height
 Intelligence
 etc
Polifactorial inheritance
Environment + genetic factors
Galtonians
Regression to mean
Extremely tall fathers tend to have sons shorter than
themselves, extremely short fathers tend to have sons taller
than themselves
 "Tallness" or "shortness" is not similar to Mendel's pea
experiments
 The height of the father and the average height of the son are
related, but the average height of the son always regresses
toward the mean
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RA Fisher (1918):continuous characters governed by a
large number of independent mendelian factors (polygenic
characters)
Polygenic characters
Polyfactorial characters
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Tradition in human genetics
 Mendelian genetics
 Non-mendelian genetics
The spectacular advances of 1970-1990 were entirely in
mendelian genetics
Investigation of nonmendelian characters remained largely
limited to statistical studies of family resemblances
Poor advancement of study
on multifactorial characters
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Complex statistical methodology
Feeling of a poor investment of research effort compared
to mapping and cloning genes for mendelian characters
Many studies concerned sensitive areas of behavioral
genetics
 such
as the heritability of IQ  violent controversies and a
distastefully confrontational style of argument often reigned
Multifactorial inheritance
Characteristics
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Several, but not an unlimited number, loci are involved in the
expression of the trait
There is no dominance or recessivity at each locus
The loci act in concert in an additive fashion, each adding or
detracting a small amount from the phenotype.
The environment interacts with the genotype to produce the final
phenotype.
Multifactorial inheritance
Characteristics

Most affected children have normal parents

Most geniuses come from normal parents, most mentally challenged
come from normal parents
Recurrence risk increases with the number of affected children
in a family
 Recurrence risk increases with severity of the defect

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A more severely affected parent is more likely to produce an affected
child
Consanguinity slightly increases the risk for an affected child
Multifactorial determination of disease
The balance between angels and devils
Influence of environment on phenotypic distribution
INBREEDING
Inbreeding
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Mating between related individuals
Consanguinity  "mixing of the blood.“
Although some plants successfully self-fertilize (the most
extreme case of inbreeding), biological mechanisms
encourage cross-fertilization
Inbreeding in human
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In general, inbreeding in human populations is rare
Many customs and laws prevent marriages between
closely related individuals
when two partners are related their chance to have a
baby with a disease or birth defect is higher than the
background risk in the general population.
Effect of inbreeding
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Many genetic diseases are recessive  only people inherit two
disease alleles develop the disease
All individuals carry several single alleles for genetic diseases
Close relatives have more genes in common than unrelated
individuals
 higher chance of inbred parents have the same disease alleles
 higher risk for their child inherits homozygous for a recessive disease
Case study
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At any locus the chance that cousins share an allele inherited from a
common parent is one-eighth
If each parent has one copy of the allele % offspring to inherit this
allele from both parents = 1/4
Thus, the risk the offspring inherit two copies of the same allele is
1/8 × 1/4, or 1/32, about 3 percent
Overall, the risk associated with having a child affected with a
recessive disease as a result of a first cousin mating is
approximately 3 percent, in addition to a baseline risk of 3 to 4 % all
couples face
Inbreeding coefficient (F)
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Probability that two genes at any locus in one individual are
identical by descent (common ancestor)
The larger the F the more closely related the parents are
Homozygosity
 Allozygosity  two alleles are alike but unrelated (not copies of
the same ancestral allele)
 Autozygosity  two alleles have identity by descent (i.e., are
copies of the same ancestral allele)
Thus, inbreeding coefficient:
 The probability of autozygosity
 May range from zero (no inbreeding) to one (it is certain an
individual is autozygous)
Any benefit of inbreeding?

Improve specific characteristics

Facilitate genetic study  gene mapping
Any benefit of inbreeding?
Improve specific characteristics
Inbreeding commonly practiced in animal breeding to
enhance specific characteristics (e.g. milk production)
 But, if genes controlling unselected traits are also
influenced  deleterious effects
 Moreover, inbreeding results in decreased genetic
diversity

Any benefit of inbreeding?
Valuable resource for genetic study
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Inbred populations  relatively homogeneous in both genetics and
environment  rich resource for genetic studies
Homozygosity mapping  identify several recessive mutations in
inbred groups
 Search for regions of alleles at genetic loci that are linked to one
another and are homozygous
 In affected individual  the two alleles at the disease locus will
have descended from a common ancestor
 Tightly linked markers (identifiable DNA segments) surrounding
the disease locus tend to come from the same ancestral
chromosome and identical on both homologous chromosomes.
Finally…….
Human inbreeding
Just don’t do it!