Download MENDELIAN INHERITANCE

Mohammed El-Khateeb
MENDELIAN
INHERITANCE
MGL - 7
March. 14th 2013
台大農藝系 遺傳學 601
20000
Chapter 1 slide 1
Sex-Linked
Disorders
X
Y
Y-linked Traits
• The Y chromosome is small and
therefore does not contain many
genes
• Y linked diseases are very rare
• Only passed from father to son.
• Example: Male infertility
Sex-linked inheritance
 Males are XY and females are XX
 Two sex chromosomes are very different in size
Y about ¼ the size of the X
 They are not genetically equivalent
 Traits associated with genes on the X
chromosome
- X-linked
 Traits associated with genes on Y chromosome
- Y-linked
X Chromosomes Inheritance
X
x
• X-Chromosome = 5%
•
•
of the human genome
Approximately 160
million bp (160Mb).
> 700 genes
identified, most of
them are Recessive
Few of them are
Dominant
X-Linked Disorders: Males are at Risk
X-linked Inheritance
Rules for X-linked conditions
• X-linked recessive
 Males have the condition
 Females are carriers
 If a male has the allele
• All daughters are carriers
• All sons are normal
 If a female has the allele
• ½ daughters are carriers
• ½ sons have the condition
• X-linked dominant
– If a male has the allele
• All daughters have the condition
• All sons are normal
– If a female has the allele
• ½ offspring have the condition (whether sons or daughters)
X-linked Dominant Disorders
• Affected males will produce all affected
•
•
•
•
•
•
daughters, but no affected sons.
50% chance that a heterozygous affected female
will pass trait to either son or daughter.
Homozygous females pass on trait to all
offspring.
On average, twice as many females afflicted as
males
Expressed in females with one copy.
Males are often more severely affected.
Typically associated with miscarriage or lethality
in males.
X-Linked Dominant
X-Linked Dominant Inheritance
X-Linked Dominant Inheritance
There are very few X-linked dominant traits.
• Dwarfing conditions due to X-linked dominant conditions
include another form of chondrodysplasia punctata (Xlinked dominant type)
• Incontinentia Pigmenti
• Congenital Generalized Hypertrichosis CGH:
• X-linked hypophoshatemic (Vitamin D-resistant rickets).
Incontinentia pigmenti
 X-linked dominant trait
 Heterozygous female - pigment swirls
on skin, hair and tooth loss, seizures
 Male - death in uterus
 No homozygous females because no males
reproduce
X-Linked Dominant Example
Congenital Bilateral Ptosis: Droopy Eyelids
Locus: Xq24-Xq27.1
X-linked Recessive Disorders
•
•
•
•
•
•
•
•
Abnormal disorder-causing allele is recessive and is located
on the X-chromosome
Normal, wild type allele is dominant
Affects hemizygous males and homozygous females.
Expressed phenotype much more common in males
Affected males get the mutant allele from their mothers
Affected males transmit the mutant allele to all daughters,
but not to sons
Daughters of affected males are usually heterozygous – thus
unaffected
Sons of heterozygous mothers have a 50% chance of being
afflicted
X-Linked Recessive Inheritance
X-linked Recessive Inheritance:
Recurrence Risks
In the usual mating between a heterozygous
affected female and a normal male, the risks
for offspring are as follows:





25% chance affected male
25% chance normal male
25% chance carrier female (normal)
25% chance non-carrier female (normal)
Total risk for an affected child: 25%
X-linked Recessive
X-Linked Recessive Inheritance
Pitfalls in Recognizing X-Linked Recessive Inheritance
and Providing Genetic Counseling
 Small Families. Small family size and few male children
may make the pattern of an X-linked recessive disorder
difficult to diagnose.
 New Mutation. An affected male may be the first person
in the family with the condition, due to a mutation
arising for the first time . sperm, egg or embryo.
 Germline Mosaicism. A new mutation may arise in
testis or ovary, resulting in a parent who can pass on
the condition or the carrier state to children, without
being either affected (in the case of a male parent) or a
carrier (in the case of a female parent).
X-linked Recessive Disorders
TRAIT
 Adrenoleukodystrophy
 Color Blindness
 Fabry disease
 G-6-P-D
 Hemophilia A
 Hemophilia B
 Ichethiosis
 Lynch-Nyhan S
 Muscular dystrophy
Phenotype
Atrophy of the adrenal gland; maternal
Deterioration; death 1-5 Y after onset
Green (60-75%); Red (25 – 40%)
MD α-Galactozidase A deficiency
Cardiac and Renal , Death
Benign, can cause sever fetal anemia
Due to certain food and drugs
Lack of factor VIII
“Christmas Disease” lack of factor IX
Skin disorder causing large, dark scales
on extremities
MD Hypoxanthine guanine
Phosphoribisyl transferase (HGPRT)
Deficiency: MR, Self-mutilation
Early death
Many types
X-linked recessive forms
Hemophilia A - factor VIII
Hemophilia B - factor IX
“Christmas Disease”
Hemophilia A
1/10,000 males
1/100 million females
Why? - requires two copies in
female - only 1 in male
Hemophilia
•It is a rare blood disorder.
•The blood does not clot.
• A hemophiliac will bleed
“freely”, while a normal
person will eventually stop
bleeding because a scab
forms.
•Hemophiliacs require
medical intervention to stop
the flow of blood.
•Usually they are given
clotting factors, which help
them form scabs.
•Hemophilia is inherited.
•About 1 out of 5,000 males
are born with hemophilia each
year.
Intermarriage caused the disease hemophilia to spread
through the royal families of Europe
Muscular Dystrophy
Group of disorders
some X-linked recessive
Duchene muscular dystrophy (DMD)
Becker muscular dystrophy (BMD)
some autosomal recessive
Phenotype
- progressive weakness and muscle wasting
Most common form:
Duchennes Muscular Dystrophy
-X-linked recessive
-1 in 3500 males afflicted
- age on onset between 1 and 6 yrs
- confined to wheel chair by age 12
- death by age 20
Ichthyosis
 Enzyme deficiency
onset 1 year of age
 Most common form Xlinked recessive
 1/6,000 males rare in
females
X-Linked Color Blindness in Humans
• Human eye detects only three colors-red, green
and blue
• Affected woman passes the X-linked recessive
trait to her sons but not to her daughters
• Affected man passes the trait to his grandsons
through his daughters but never to his sons
• Pattern of inheritance exhibited by X-linked
recessive characteristics
Color Blind
• The human eye has two types of
receptors that detect light:
 Rods detect differences in the
intensity of light
 Cones detect colors
 There are 3 types of cones,
which detect red, blue & green
wavelengths of light
Red–green color blindness is inherited as
an X-linked recessive trait in humans
Color Blind
Normal subjects see an 8 Color blind subjects see
a3
Normal subjects see a 6 Color blind subjects can’t
see any number
Normal subjects see a 7 Color blind subjects can’t
See any number
Normal subjects see a 35 Color blind subjects see
either a 3 or a 5 depending on the type of color
blindness
Y-Linked Inheritance
Y-linked
Father’s Gametes
Mother’s
Gametes
X
Y
X
XX
XY
X
XX
XY
Y Chromosome Inheritance
 Y-Chromrosome = 70Mb
 Few dozen genes (Holandric) are
found on Y
 Male differentiation genes
 Testis-specific spermatogenesis
factor
 Minor Histocompatibility genes (HY)
 Several housekeeping genes
 Transmission strictly from father to son
Y-linked traits
• - Related to genes unique to the Y chromosome
- are present only in males (no afflicted females)
- passed directly from fathers to sons
hemizygous – always expressed
• Very rare - only about 3 dozen Y-linked traits
known
- Often associated with infertility
• One important gene
- TDF – testis determining factor
- Also known as SRY
- Sex determining region of the Y chromosome
Y-Linked Traits
HYPERTRICHOSIS PINNAE AURIS
(Hairy ears), Y-LINKED??
Hypertrichosis Pinnae.
• Hairy ears
• Can happen later in life.
• Y-linked
Sex-Limited, Sex-Influenced
• Sex-Limited: Autosomal genes
– Affects a structure/process/behavior found
only in one sex due to anatomical differences,
Inherited Uterine or Testicular defects
• Sex-Influenced: Autosomal genes
Baldness, Dominant in males and
recessive in females, carrier females
have thinner hair
Sex-influenced traits
• characteristic may appear in both sexes but
expression of the phenotype differs.
• Example: Early balding (pattern baldness) in humans.
Heterozygous men (b+/b) lose their hair;
heteroyzgous women do not have significant hair
loss.
• Homozygous men or women (b/b) become bald. The
trait is therefore dominant in men, recessive in
women. (We used b to designate the mutant baldness
allele even though the allele is dominant in males.)
Pattern Baldness In Humans: A Sex Influenced Trait
Baldness is an autosomal trait and is apparently influenced by sex hormones
after people reach 30 years of age or older.
In men the gene is dominant, while in women it is recessive. A man needs
only one allele (B) for the baldness trait to be expressed, while a bald woman
must be homozygous for the trait (BB).
What are the probabilities for the children for a bald man and
woman with no history of baldness in the family?
SUMMARY: X-linked Traits
Males
• One X chromosome
• Inherited from mother
• Two possible genotypes
•XpY
•XmY
• Have trait or do not have
trait
• Hemizygous
• Males transmit their X to
their daughters, Y to their
sons
Females
• Two X chromosomes
• Inherited from both
parents
• Three possible genotypes
• XpXp
• XpXm
• Xm X m
• Heterozygotes are
carriers of recessive
traits.
• Females transmit their X
randomly to either their
sons or daughters
Males are more likely to be afflicted than females
regarding X-linked traits
Male-Determining Region SRY
on the Y Chromosome
X-Chromosome
Inactivation
The Lyon Hypothesis of X Inactivation
• Proposed by Mary Lyon and Liane Russell (1961)
• Which X is inactivated? Inactivation of X chromosome
occurs randomly in somatic cells during
embryogenesis
• Progeny of cells all have same inactivated X
chromosome as original, creating mosaic individual
X-inactivation is an
epigenetic process.
• Because of X-inactivation
every female is a mosaic of
cell lines with different active
X chromosomes
• Early in the development of
female, one X-chromosome
is inactivated at random (710 days after fertilization)
• around 24 cell
X Chromosome Inactivation
• Mechanism of X Chromosome inactivation
• XIC – X chromosome Inactivation Center
• XIC controls expression of the XIST gene
• XIST: X-inactive-specific transcript
• XIST produces a non-coding 17 kb RNA molecule
• “Coats” the entire local X-chromosome – cis-acting
Dosage Compensation
•
•
How can females have 2 X’s and
males only 1 without running into
gene dosage problems?
Lyon hypothesis (1961): placental
mammals randomly inactivate all but
1 X at the 200-400 cell embryo stage
(blastocyst). The inactivated X's
become Barr bodies: late-replicating
condensed chromatin sitting on the
nuclear membrane (heterochromatin).
– Number of Barr bodies is always 1
less than the number of X’s: Seen in
XXY, XXX, etc.
•
why are females rarely colorblind?
Many retinal precursor cells present at
time of inactivation, so get a finegrained mosaicism--brain fills in
colors
After SRY
•
The testes produce two hormones: testosterone and anti-Mullerian hormone (also known as Mullerian
Inhibiting Substance, MIS) at about week 6. Together these hormones cause development of male
structures and regression of female structures.
•
Testosterone is a steroid hormone; which binds to a receptor in the cytoplasm and then moves to the
nucleus to stimulate transcription.
–
•
In target tissues, some testosterone is converted to dihydro form by 5-alpha reductase. Dihydrotestosterone
controls male external genitalia development.
–
•
A person with 5-alpha reductase deficiency can appear female until puberty, when the testosterone level gets high
enough to stimulate development of eh male external geneialia: the penis grows. Common in a village in the
Domincan Republic. Technically, they are male pseudohermaphrodites (have testes but some female characteristics).
Called “guevedoce ”, which is probably a corruption of “heuvos a doce”, meaning “eggs (i.e. testicles) at 12”.
Although they grew up as girls, once this happens they develop normal heterosexual interest in girls (or at least most of
them do I suppose).
Anti-Mullerian hormone is also secreted by the testes. It is a peptide hormone which causes the Mullerian
ducts to regress.
–
•
Receptor defects cause “testicular feminization” (better known as androgen insensitivity). A chromosomal male
develops female external genitalia and vagina but no uterus, female breast development (often "voluptuously
feminine" -OMIM). The testes are internal (undescended) and can become cancerous. Can also cause spinal bulbar
syndrome: atrophy of lower back muscles.
If AMH is absent or its receptor is defective, you get a male with a rudimentary uterus and fallopian tubes (but no
ovaries or vagina).
Amusing bit of history: Aristotle taught that gender was determined by the state of the semen: hot semen
produced a male child and cold semen generated a female child.
X Inactivation Center (XIC)
•  (XIC) located near the centromere, Contains 12 genes
 7 genes code for proteins 5 genes code for untranslated RNA
(Rougeulle et al., 2003)
 X chromosome lacking Xist gene cannot be inactivated
 XIST contained no "open reading frames" (no codons to encode AA)
 XIST is transcribed but not translated.
 Xist gene Encodes a large RNA molecule
 RNA Coats Xi from the XIC near the centromere outward along
the X chromosome
 High levels of DNA methylation (CH3) (Chadwick et al., 2003)
 Low levels of histone substitution of the acetyl group (CH3CO)
for a H atom in a -OH group
cen
Xist/Tsix in XIC Xq13.2
Xa
Xist RNA
cen
cen
Xi
X - Inactivation
• The inactivation is random, either paternal or
maternal X may be inactivated in any cell
• A structurally abnormal X-chromosome is always
inactivated
• In balanced X-autosome translocation, the
normal X chromosome is inactivated so that
inactivation does not involve an autosome
• In an unbalanced X-autosome translocation, the
translocated chromosome is inactivated
• A few genes on the inactivated X
chromosome are expressed in the
somatic cells of adult female mammals
– Pseudoautosomal genes
(Dosage compensation in this case is
unnecessary because these genes are
located both on the X and Y)
– Up to a 25% of X genes in humans may
escape full inactivation
• The mechanism is not understood
Fig 7.4
The epithelial cells
derived from this
embryonic cell will
produce a patch of
white fur
While those from
this will produce a
patch of black fur
At an early stage of
embryonic development
X - Inactivation
 The Lyon hypothesis states that
one X chromosome in
the cell is randomly inactivated
early in the embryonic
development of females
 Inactivation results in 'dosage
compensation',
 The X inactivation center is
located on Xq 13 ( 1 Mb). The
XIST X Inactive Specific
Transcript. gene is transcribed
only from the inactive X chromosome.
X - Inactivation
• Pseudo autosomal region on short arms of X and
Y chromosomes heal" same gene loci, they pair
during meiosis with exchange of segments
• The inactivation is incomplete: 1/3 of genes on
Short arm and 5% of genes on long arm escape
inactivation (deletion of short arm causes more
significant consequences)
• Reactivation of the previously inactivated X
chromosome OCCURS during oogenesis
Mammalian X-inactivation involves the
interaction of 2 overlapping genes.
Promotes compaction
Prevents compaction
Human sex chromosomes
(includes Mic2 gene)
Organization of Human Sex Chromosomes
pseudoautosomal
regions
(short arms)
Many genes
escape inactivation
sex-limited
regions
Y
Xce – X chromosome
inactivation center
pseudoautosomal
regions
(long arms)
Length: 153,692,391 bp
Gene Count: 1228
Length: 50,286,555 bp
Gene Count: 160
X
Why is One X Chromosome
Inactivated?
Causes
Xist (X-inactive specific transcript)
expressed from and binds to
inactive X chromosome
Methylation of specific cytidine
residues
Late replication
mCpG
Effects
Dosage compensation between the
sexes
Sex Linkage
X-linkage;
Hemizygous
genes
Pseudoautosomal
Y-linkage;
Hemizygous
genes
Sequence
Homologies of the
X and Y
Chromosomes
• 15% ox X Chr. Escape
Inactivation
• Tips of P and q arms
escape inactivation
• Steroid sulfatase
• Xg blood group
• Kallman Syndrome
( hypogonadism inability
to perceive odor)
• Housekeeping genes
X-INACTIVATION
• G6PD
• Melanine
• Anhidrotic Ectodermal Dysplasia
• Calico Cat Fur Color
• Barr Bodies
Mosaicism Reveals the Random Inactivation
of one X chromosome
Anhidrotic ectodermal
dysplasia in a
heterozygous woman
Regions where
sweat glands
are absent.
spotting gene - autosomal
Xb
active
XB
active