MENDELIAN INHERITANCE - JUdoctorsPattern Baldness In Humans: A Sex Influenced Trait Baldness is an...
Transcript of MENDELIAN INHERITANCE - JUdoctorsPattern Baldness In Humans: A Sex Influenced Trait Baldness is an...
台大農藝系 遺傳學 601 20000
Chapter 1 slide 1
MENDELIAN
INHERITANCEMGL - 7
March. 14th 2013
Mohammed El-Khateeb
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-Chromosome = 5%
of the human genome
Approximately 160
million bp (160Mb).
• > 700 genes
identified, most of
them are Recessive
• Few of them are
Dominant
xX
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 (X-
linked dominant type)
• Incontinentia Pigmenti
• Congenital Generalized Hypertrichosis CGH:
• X-linked hypophoshatemic (Vitamin D-resistant rickets).
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
Incontinentia pigmenti
X-Linked Dominant ExampleCongenital 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 RisksIn 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 Phenotype
Adrenoleukodystrophy Atrophy of the adrenal gland; maternalDeterioration; death 1-5 Y after onset
Color Blindness Green (60-75%); Red (25 – 40%) Fabry disease MD α-Galactozidase A deficiency
Cardiac and Renal , Death G-6-P-D Benign, can cause sever fetal anemia
Due to certain food and drugs Hemophilia A Lack of factor VIII Hemophilia B “Christmas Disease” lack of factor IX Ichethiosis Skin disorder causing large, dark scales
on extremities Lynch-Nyhan S MD Hypoxanthine guanine
Phosphoribisyl transferase (HGPRT)Deficiency: MR, Self-mutilationEarly death
Muscular dystrophy Many types
X-linked recessive formsHemophilia A - factor VIIIHemophilia 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
Group of disorderssome 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
Muscular Dystrophy
Enzyme deficiency onset 1 year of age
Most common form X-linked recessive
1/6,000 males rare in females
Ichthyosis
X-Linked Color Blindness in Humans
• Human eye detects only three colors-red, greenand blue
• Affected woman passes the X-linked recessivetrait to her sons but not to her daughters
• Affected man passes the trait to his grandsonsthrough his daughters but never to his sons
• Pattern of inheritance exhibited by X-linkedrecessive characteristics
• 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
Color Blind
Red–green color blindness is inherited as an X-linked recessive trait in humans
Normal subjects see an 8 Color blind subjects see
a 3
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
Color Blind
Y-Linked Inheritance
Y-linked
X
X
X
Y
X X X Y
Father’s Gametes
Mother’s
Gametes
X X X Y
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 TraitsFemales
• Two X chromosomes
• Inherited from both parents
• Three possible genotypes
• XpXp
• XpXm
• XmXm
• Heterozygotes are carriers of recessive traits.
• Females transmit their X randomly to either their sons or daughters
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
Males are more likely to be afflicted than females regarding X-linked traits
Male-Determining Region SRY
on the Y Chromosome
X-Chromosome
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
The Lyon Hypothesis of X Inactivation
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 (7-
10 days after fertilization)
• around 24 cell
• 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
X Chromosome Inactivation
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 fine-grained 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.
– 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.
• 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.
– 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
cenXi
Xa
cenXist RNA
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
At an early stage of
embryonic development
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
Fig 7.4
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
Promotes compaction
Prevents compaction
Mammalian X-inactivation involves the
interaction of 2 overlapping genes.
Human sex chromosomes
(includes Mic2 gene)
Organization of Human Sex Chromosomes
Y
X
pseudoautosomalregions
(short arms)
sex-limitedregions
pseudoautosomal regions
(long arms)
Many genes
escape inactivation
Xce – X chromosome
inactivation center
Length: 153,692,391 bp
Gene Count: 1228
Length: 50,286,555 bp
Gene Count: 160
Why is One X Chromosome
Inactivated?
CausesXist (X-inactive specific transcript)
expressed from and binds to
inactive X chromosome
Methylation of specific cytidine
residues
Late replication
EffectsDosage compensation between the
sexes
mCpG
Sex Linkage
X-linkage;
Hemizygous
genes
Y-linkage;
Hemizygous
genesPseudo-
autosomal
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
Regions wheresweat glandsare absent.
Anhidrotic ectodermal dysplasia in a heterozygous woman
Xb
active
XB
active
spotting gene - autosomal