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