Download The genes on the X and Y chromosomes: Sex linkage inheritance

The genes on the X and Y chromosomes:
* 122 genes (May 2007) have been mapped to the Y chromosome.
- Many of the Y chromosome genes contain the instructions to make the baby develop as a male
rather than a female
- Without the presence of the Y chromosome genes, the baby will develop into a female
* In rare cases, a male baby is born with his cells containing 47 chromosomes: made up of 44
autosomes, two X chromosome copies and the Y chromosome (Klinefelter (XXY)
syndrome) Despite the presence of the two copies of the X chromosomes in the cells, the baby still
develops as a male because of the instructions issued by the Y chromosome genes
The genes on the X chromosome
* Unlike the Y chromosome, the X chromosome is ‘gene rich’ with 1021 genes
mapped to it (May 2007).
* Many of the X chromosome genes are very important for growth and
development;
Example:
- the genes that contain the instructions for a major protein in muscles
(dystrophin)
- several proteins that control clotting in the blood and
- a number of genes involved in the development of intelligence.
Sex linkage inheritance
* Sex linkage is the phenotypic expression of an allele related to the sex chromosome of the
individual.
- This mode of inheritance is in contrast to the inheritance of traits on autosomal
chromosomes, where both sexes have the same probability of inheritance.
- Since humans have many more genes on the X than the Y, there are many more X-linked
traits than Y-linked traits.
* Disease caused by genes on the X chromosome are said to be X-linked and specific
genetic conditions may result: hemophilia, muscular dystrophy and fragile X syndrome.
* Most X-linked disease is recessive, although there are also a few X-linked dominant
diseases.
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X inactivation is a special feature of female development:
* In mammals, the female is the homozygous sex, with two X chromosomes (XX), while the male is
heterozygous, with one X and one Y chromosome (XY).
- In the early 1962s Dr Mary Lyon who first hypothesized that one X chromosome in each
somatic cell of the female is inactivated.
- This would result in dosage compensation, that means an equalization of X-linked gene
products in males and females. This system of ‘switching off’ of one of the X chromosome copies is
seen in all mammals and is often called lyonization.
* The Lyon hypothesis stated that X inactivation occurs very early in female embryonic
- development (at late blastocyst stage in humans),
that X chromosome contributed by the father is inactivated in some cells, where as in other
cells the X chromosome contributed by the mother is inactivated.
- Each cell chooses one of the two X chromosomes at random to be inactivated, so the
maternally and paternally derived X chromosomes will each be inactivated in about half of the
embryo's cells
* The maternal and paternal X chromosomes are both active in the zygote and in early
embryonic cells. X inactivation then take place, resulting in cells having either an active
paternal X or an active maternal X chromosome. Females are thus X chromosome
mosaics, as shown in the tissue sample at the bottom of the figure.
Once X chromosome is inactivated in a cell, it will remain inactive in all descendants of that cell
* As a result of X-inactivation, all normal females have two distinct populations of cells: one
population has an active paternally derived X- chromosome, and the other is an active
maternally derived X chromosome.
* With two populations of cells, females are mosaics for the X chromosome. Males are not
mosaics but are hemizygous for the X chromosome.
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* In each body cell (somatic cell) of the developing baby girl, one of the X
chromosomes becomes very shortened and condensed so that most of its
genes are not able to be ‘read’ by the cells. An examination of female cells
under a microscope reveals a dark body in the cell (called a Barr body) or sex
chromatin body near the membrane of the interphase nucleus which is
inactivated X chromosome.
X- Linked Recessive Inheritance:
* X-linked recessive traits are expressed in all heterogametics and homogametics that are
homozygous for the recessive allele.
- Because females inherit two copies of the X chromosome, they can be homozygous for a
disease allele at a given locus, heterozygous, or homozygous for the normal allele at the locus
- In females, an X-linked recessive trait behaves much like an autosomal recessive trait.
However only one X chromosome is active in an individual somatic cell. This means that about
half of the cells in a heterozygous female will express the disease allele and half will express the
normal allele. Thus as with autosomal recessive trait, the heterozygote will produce about
50% of the normal level of the gene product, and this is sufficient for a normal phenotype
* The situation is different in males, who are hemizygous for the X chromosome.
* If a male inherits a recessive disease gene on the X chromosome, he will be affected by the
disease because the Y chromosome does not carry a normal allele to compensate for the
effects of the disease gene.
- In males they express the trait when they inherit one mutant allele, gene frequency (q). In
contrast, a female must inherit two mutant alleles, a less frequent event since the mutant allele
is rare in the population.
- The incidence of recessive X-linked phenotypes in females is the square of that in
males (q 2). If 1 in 20 males in a human population are green color blind , then 1 in 400
females in the population are expected to be color blind, gene frequency= ( 1/20)*(1/20)
* Since a father can transmit only a Y chromosome to his son, X- linked genes are not
passed from father to son.
* An X- linked disease allele can be transmitted through a series of phenotypically normal
heterozygous females, causing the appearance of “skipped” generations.
* The gene is passed from an affected father to all his daughters, who act as carriers transmit it to
approximately half of their sons, who are affected.
Punnett square representation of the mating of a
heterozygous female who carries an X-linked ressecive
disease gene with a normal male. X1 chromosome with
normal allele; X2 chromosome with disease allele.
Daughters: 50% normal, 50% carriers.
Sons: 50% normal, 50% affected
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Mother
Father
X1
X2
X1
X1X1
X1 X2
Y
X1 Y
X2 Y
- the heterozygous mother is called "carrier" because she has one copy of the recessive allele.
sons will have 50% probability to be affected 50% of unaffected daughters will become carriers like
their mother
Punnett square representation of the
Mother
mating of a normal female with a male
X1
X1
Father
who is affected by an X- linked recessive
X2
X2 X1
X2 X1
disease.
Y
X1 Y
X1 Y
X1 chromosome with normal allele;
X2 chromosome with disease allele.
Daughters: 100% carriers. Sons: 100% normal.
the affected father has one X-linked recessive gene allele,the mother is homozygous for the allele
only daughters (all) will be affected.
Punnett square representation of the
Mother
mating of a carrier female with a male
X1
X2
Father
affected with an X- linked recessive gene
X2
X2X1
X2X2
disease.
Y
X1Y
X2 Y
X1 chromosome with normal allele;
X2 chromosome with disease allele.
Daughters: 50% affected, 50%carriers. Sons: 50% normal, 50% affected disease.
The affected mother is hetrozygous with one copy of the recessive allele : both daughters and
sons will have 50% probability to be affected.
X- Linked Diseases
* Over 400 human traits and diseases seem to be encoded by genes on the X chromosome.
1. Red-green color blindness: was the first human trait proven to be due to a gene on X
chromosome.
* Males are more severely affected than females; in the case of red-green color blindness, Females
who have one copy of the mutant gene (that is, are heterozygous or carriers) are not at all affected
* Among offspring of carrier mothers, 50% of their sons are affected, whereas 50% of their
daughters are carriers.
* Affected fathers cannot pass their mutant X chromosome to their sons, but do pass it to all of
their daughters, who thereby are carriers.
A number of other well-known human conditions behave in this manner, including the two
forms of hemophilia, Duchenne muscular dystrophy, and glucose-6-phosphate dehydogenase
deficiency that predisposes to hemolytic anemia.
2. Hemophilia A
* Hemophilia A is caused by deficient in factor VIII, a key component of the clotting
cascade. Fibrin formation is affected, resulting in prolonged and often sever bleeding
from
wounds and hemorrhages in the joints and muscles. Spontaneous bleeding may
occur.
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* Hemarthroses (bleeding into the joints) are common in joints such as the ankles,
knees, hips, and elbows, resulting in swelling and impaired function.
- Hereditary bleeding disorder caused by deficiency of a coagulation factor.
- In hemophilia A, lack of factor VIII causes classic hemophilia, affect approximately 1 in
5000 to 1 in 10000 males worldwide.
- Other types are caused by deficiency of factor IX or XI. The first two are transmitted by sexlinked heredity; the third has dominant inheritance and occurs in females as well as males.
- Hemophilia characterized by severe anemia or even death. Large bruises of the skin and soft
tissue are often seen, usually following injury. There may also be bleeding in the mouth, nose,
and gastrointestinal tract.
Treatment: Administration of donor- derived factor VIII.
- Drawback: Because infusion contained plasma products from different donors, it was
frequently contaminated by viruses, like hepatitis B and C, also HIV
3. Duchenne Muscular Dystrophy (DMD)
* A progressive weakness and loss of muscle. Muscle tissue degenerates and regenerates
randomly and is replaced by scar tissue and fat.
* Muscles contain a protein called dystrophin, which is necessary for muscles to function
properly.
- People with DMD have a shortage of dystrophin in their muscles due to faulty gene. The lack of
dystrophin leads to muscle fiber damage and a gradual weakening of the muscles.
- The symptoms of DMD are usually seen before the age 5 years, all skeletal muscle degenerates
eventually and most patients with DMD are confined to a wheelchair by 11 years of age.
- The heart and respiratory musculature become impaired, and death results from respiratory or
cardiac failure. Survival beyond age 25 years is uncommon.
- It affects 1 of every 3500 males
- There is no specific treatment Physical therapy, and corrective surgery may help
Can Duchenne's muscular dystrophy affect women who carry the gene?
• Girls and women who carry the DMD gene are usually well and have no symptoms of DMD
themselves.
• A small number of women 8-10% carrying the DMD gene may develop some muscle weakness
themselves
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X- Linked Dominant Inheritance
Are fewer in number and prevalence than the X- linked recessive diseases.
An example:
1. Hypophosphatemic rickets: a disease in which the kidneys are impaired in their
ability to reabsorb phosphate. This results in abnormal ossification of the bones.
2. Incontinentia pigmenti type I: a disorder characterized by abnormal skin
pigmentation, conical or missing teeth, and ocular and neurological abnormalities.
 This disorder is seen only in females.
 It is thought that hemizygous males are so severely affected, they die inutero.
3. Rett Syndrome: a neurodevelopment disorder seen in 1/10000 to 1/ 15000 females and
in smaller proportion of males (some males are lost inutero, while others survive).
 It characterized by mental retardation, and gait ataxia.
 As with autosomal dominant diseases, an individual need inherit only a single copy
of an X- linked dominant disease gene to manifest the disorder
 Because females have two X chromosomes, either can carry the disease gene, they
are about twice as commonly affected as males (unless the disorder is lethal in males).
 Affected father cannot transmit the trait to their sons. All of their daughters must
inherit the disease gene, so all are affected.
 Affected females are usually heterozygotes and thus have a 50% chance of passing
the disease allele to their daughters and sons.
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Y- Linked Inheritance
 The Y chromosome contains relatively few genes. The Y- chromosome cannot carry
any genes whose function is important for health, because females are perfectly
normal without any Y- linked genes.
 Thus any Y- linked genes must code either for non-essential characters or for male
specific functions includes the gene that initiates differentiation of the embryo into
a male. Any defects in Y chromosome associated with male sexual dysfunction.
 Transmission of Y- linked traits is strictly from father to sons.
Mitochondrial inheritance gives a recognizable matrilineal pedigree pattern
 Mitochondrial mutations are a significant cause of human genetic disease.
The mitochondrial genome is small but highly mutable compared to nuclear DNA. The
mutation rate of mtDNA is about 10 times higher than that of nuclear DNA. This is
caused by:
 a lack of DNA repair mechanisms in the mtDNA, and
 possibly by damage from free oxygen radicals released during the oxidative
phosphorylation process.
Mitochondrial inheritance
Mitochondrial encoded diseases have two unusual features:
 Matrilineal inheritance and
 Frequent heteroplasmy( a single cell can harbor some molecules that have an
mtDNA mutation and other molecules that do not).
 In some patients with a mitochondrial disease, every mitochondrial genome carries
the causative mutation is (homoplasmy).
 Thus a mitochondrial inherited condition can affect both sexes, but is passed on only
by affected mothers.
 So small number of maternal mtDNA molecules give rise to all the mitochondrial DNA
of the child.
 Each tissue type requires a certain amount of mitochondria produced ATP for normal
function. Organ systems with large ATP requirements and high thresholds tend to be
the ones most seriously affected by mitochondrial diseases.
 For example, the central nervous system (CNS) consumes about 20% of the body’s
ATP production and therefore affected by mtDNA mutation.
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Mitochondrial disorders can be classified according to the type of mutation that causes
them.
1. Missense mutations (base- pair substitutions, which brings change in single amino
acid) in protein- coding mtDNA genes cause one of the best- known mtDNA diseases
called,
A. “Leber’s hereditary optic neuropathy” (LHON)
Characterized by sudden loss of vision and irreversible loss of sight as a result of optic
nerve death.
 Vision loss typically begins in the third decade of life.
 Heteroplasmy is rare in LHON, so expression tend to be uniform.
 unexpectedly almost all affected patients are male. (the cause of male affected is
unknown, possibly LHON requires both a mitochondrial and X- linked mutation).
B. Mitochondrial Encephalomyopathy (MELAS) caused by a single- base tRNA mutation
in mitochondria, it is heteroplasmic.
2. mtDNA mutation due to insertion or deletion: Example:
1. Kearns- Sayre disease (muscle weakness, cerebellar damage, and heart failure)
2. Pearson syndrome (infantile pancreatic insufficiency, and lactic acidosis).
Mitochondrial mutations are also involved in some common human diseases.
 A mitochondrial deletion causes a form of deafness,
 MELAS mutation is seen in 1-2% of individuals with Type 2 DM, and
 mtDNA defects may also be associated with some cases of Alzheimer disease.
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