Genetics, Lecture #7:

Mendelian InheritanceRevision: the possibilities of inheritance (the genotype that the offspring may have) can be predicted if we know the parents genotype:

1> Both parents are homozygous Dominant (AA),, All offspring will be homozygous Dominant (100% AA).

2> One parent is homozygous Dominant (AA) & the other is heterozygous (Aa),, the offspring genotype is 50% homozygous Dominant (AA) & 50% heterozygous.

3> One parent is homozygous Dominant (AA) & the other is homozygous recessive (aa),, All the offspring will be heterozygous (100% Aa).

4> Both parents are heterozygous (Aa),, the possibilities of the offspring's genotype is 25%AA, 50%Aa, 25%aa.

NEW TOPIC: talking about Sex-linked disorders:-It is caused by a gene located on a sex chromosome; the X chromosome (mainly) or the Y chromosome.Y-linked trait s / Disorders : -these are only found in MALES, as females do not carry this chromosome (except in certain conditions that Dr. said he will talk about later).

•- 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 (hemizygous) and females are XX (homozygous):

We have 3 X chromosomes & 1 Y chromosome, so the prevalence of a sex linked disease that is linked to the Y chromosome is 1 of 4 = 1/4.

-Two sex chromosomes are very different in size(Y is about ¼ the size of the X).

-They are not genetically equivalent (X & Y chromosome are different in their size, number of genes they carry and many other differences).

Traits associated with genes on the X chromosome- X-linked

Traits associated with genes on Y chromosome- Y-linked

- On the X Chromosome, about 700 genes have been identified; the vast majority of them are Recessive (x-linked recessive), & Few of them are Dominant.

-In X-linked inheritance, MALES are at RISK,Since they have 1 X chromosome, and 1 copy Of the affected gene is enough for the diseaseTo appear.Exapmle 1: Mother is a carrier & father is normalThe offspring:-Males: 50% normal (inherited normal X from mother) 50% affected (inherited affected X from mother)-Females: 50% normal 50% carrier (one affected X from mother & normal X from father).

Example 2:The father carries the affected gene on X ch.(affected) while the mother is NORMAL:-the father will give his SONS the Y-ch,so, all sons will be NORMAL.-the father will give all his DAUGHTERSThe affected X ch,, so all his daughters willBe CARRIERS. (assuming that this is an X- linkedrecessive inheritance).

Example 3:

-The MOTHER carries the affected gene on one of her X chromosomes.-in any pregnancy, we have 50% chance of havinga male & 50% of having a female:

1. In the 50% male, there is 50% possibility ofGetting the affected X from mother> affected male,And 50% chance of getting normal X >normal male

2. in the 50% female, the father always will give a normal X, and there is 50% possibility of getting the affected X from mother > CARRIER,and 50% chance of getting normal X >NORMAL.

-Like the autosomal inheritance, X-linked inheritance can be DOMINANT OR RECESSIVE.

1) X-linked Dominant Disorders:(Remember: ONE COPY of the affected allele is enough for the disease to appear in the phenotype).

*Affected males will produce all affected daughters (because they will definitely give them the X ch with affected gene), but NO affected sons (because they will definitely give them Y ch , NOT X).

*50% chance that a heterozygous affected female (XA Xa) will pass trait to either son or daughter (50% of giving her offspring an affected XA allele)*Homozygous females pass on trait to all offspring (All the offspring will be affected).*On average, twice as many females afflicted as males (since females have 2 X chromosomes). *Expressed in females with one copy (because it is a dominant trait).*Males are often more severely affected (because they do not have a second X ch., if a female has one affected allele on X (XA),she will have a normal allele on the other X to COMPENSATE (Xa)).*Typically, associated with miscarriage or lethality in males.

Slide 10:The presentation of X-linked dominant inheritance in a FAMILY PEDIGREE:Points to notice :

1. (from generation I > II) An affected MALE (XBY) has passed the affected XB to ALL HIS DAUGHTERS but NOT to his SON.

2. (from generation II > III) An affected heterozygous female (XBXb) has passed the affected allele to one son & two daughters,,50% of her offspring were affected. (both sons and daughters can be affected).

Q: How can we differentiate between autosomal dominant & X-linked dominant inheritance in a family pedigree?

A: 1.In both, there is NO SKIPPING of generations (the disease is passed in all generations).

2.a> If an affected male has passed the disease to his DAUGHTERS but NOT to his SONS > X-linked dominant. b> If an affected male has passed the disease to BOTH his DAUGHTERS & SONS > Autosomal dominant.(This is the only way to differentiate between them)

3. In females, X-linked dominant & autosomal dominant look the same in a family pedigree, we cannot differentiate between them.

The father is affected (XAY)-The daughters will inherit the

XA & be affected-The SONS will inherit the Y

from father & will be NORMAL

The mother is affected (XAXa)-25% unaffected son XaY

-25% affected son XAY-25% unaffected female XaXa

-25% affected female XAXa

Examples of diseases that are inherited as an X-linked Dominant :

(There are very few X-linked dominant traits) • 1. Dwarfing conditions due to X-linked dominant

conditions include another form of chondrodysplasia punctata (X-linked dominant type).

• 2.Incontinentia Pigmenti :-an X-linked dominant,genetic disease.-in males, it is very lethal >Male - death in uterus during pregnancy.-NO homozygous females, because males DIE very early, & there will be no male that carries the affected gene who would reproduce.- a heterozygous female will survive & show characteristic clinical features: - rash & hyper-pigmentation (pigment swirls on skin of arms & legs), hair and tooth loss, seizures.

• 3.Congenital Generalized Hypertrichosis CGH:-also known as: werewolf or wolfman syndrome.- it is an abnormal growth of hair all over the body, including the face.

• 4.X-linked hypophoshatemic (Vitamin D-resistant rickets).

(Note again, that the affected Father passes the disease to his DAUGHTERS ONLY, while an affected may pass the disease to her DAUGHTERS OR SONS.)

• 5. Congenital Bilateral Ptosis: Droopy Eyelids (appearance of being sleepy, cannot raise the eyelids).(Locus of affected gene: Xq24-Xq27.1)

2) 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 (XaY) and homozygous (XaXa)

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(carrier) mothers have a 50%

chance of being afflictedExample: An affected HEMIZYGOUS father (XbY) & a CARRIER (XBXb) mother, the possibilities of the offspring are:

XB Xb

Xb XBXb

Carrier daughter

XbXb

Affected daughter

Y XBYNormal son

XbYAffected son

-an affected father will give the Y ch to his sons,

So, all his sons will be UN-AFFECTED.-an affected father will give the abnormalAllele on X ch to all his daughters, so All his daughters will be CARRIERS.

-a carrier mother has 50% chance of giving anAffected allele (Xa) to her children:

50% AFFECTED son 50% CARRIER daughter

-a carrier mother has 50% chance of giving A normal allele (XA) to her children:

50% unaffected son 50% unaffected daughter

- A homozygous mother (XbXb) will always give an affected allele to her sons or daughters, so ALL her SONS will be AFFECTED, and ALL her DAUGHTERS will be CARRIERS.

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%

The family pedigree of an X-linked recessive disease looksSIMILAR to that of an autosomalRecessive disease: -a carrier female may give

the disease to her SON (50% chance of being affected)But her daughters are CARRIERS(50% chance)-an affected male may has a Carrier daughter, but his sons are NOT affected.

Pitfalls in Recognizing X-Linked Recessive Inheritance and Providing Genetic Counseling(factors that may complicate the recognition of inheritance pattern, when we draw a pedigree):• Small Families. Small family size and few male children

may make the pattern of an X-linked recessive disorder difficult to diagnose. ( no enough number of family members to draw a pedigree)

• 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).

EXAMPLES of diseases that are inherited as X-linked recessive:Adrenoleukodystrophy, Color Blindness, Fabry disease,G-6-P-D

� Hemophilia A, Hemophilia B ,Ichethiosis ,Lynch-Nyhan S andMuscular dystrophy

i)-The most famous of them is Haemophilia:X-linked recessive forms:1. Hemophilia A - factor VIII deficiency.2. Hemophilia B - factor IX deficiency

Also known as “Christmas Disease”

-Incidence of Hemophilia A: 1/10,000 males & 1/100 million in females >>> it is more common in MALES, Very rare in females.Why? It requires two affected gene copies in a female for the disease to appear, but only 1 affected copy is needed in a male for the disease to appear.(dr. did not discuss the pathology in slide 22)

-the most famous pedigree shows the prevalence of hemophilia in many royal European families that resulted from intermarriage between them (slide 23):- the disease started from Queen Victoria, she was a carrier of hemophilia. She had an affected son who got married from the german royal family & spread the disease to it. Her daughter, who was a carrier, was married to a member of the Russian family & spread the disease to this royal family. The intermarriage had spread the disease to greek,Spanish…(about 6-7)royal families in Europe.

ii) Muscular Dystrophy:it comprises a group of disorders:

a) Some are X-linked recessive:Duchene muscular dystrophy (DMD)Becker muscular dystrophy (BMD)(Dr. said that both, DMD & BMD are common in Jordan)

b) some autosomal recessive -Phenotype: progressive skeletal muscle weakness and muscle wasting (atrophy).

- Most common form: Duchennes Muscular Dystrophy* it is X-linked recessive*1 in 3500 males afflicted, age on onset between 1 and 6 yrs *confined to wheel chair by age 12 & die by age 20 (because of respiratory failure).

Summary: Rules for X-linked conditions:

X-linked recessive : -Males have the condition-Females are carriers-If a male has the allele:1.All daughters are carriers2.All sons are normal-If a female has the allele1.½ daughters are carriers2,½ sons have the condition

X-linked dominant : -If a male has the allele:1.All daughters have the condition2.All sons are normal-If a female has the allele:½ offspring have the condition (whether sons or daughters)

iii) Ichthyosis:

-Enzyme deficiency, onset at 1 year of age. -Most common form: X-linked recessive -1/6,000 males, rare in females -presentation:  thickened, scaly or flaky skin. In many types there is cracked skin , which is said to resemble the scales on fish.(Dr.: In Jordan, there has been report of at least 6 families with this disease, 4 of which from west bank).

Iv) X- Linked Color Blindness in Humans:• Human eye detects only three colors: red, green and

blue.• 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

• 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.

-Red–green color blindness is inherited as an X-linked recessive trait in humans:

Note: -P generation= parents.-(a): the daughters have normal vision, but they are carriers of color blindness gene.-(b): daughters are carriers, sons are affected.

Ishihara plates are used to test the subjects for color blindness (as in testing the vision for getting a driving license). It tests the different types of color blindness ( 'red-green', 'blue-green' & yellow-red'):(Please refer to slide 30 on computer to be able to see the plates colored ) 1. Normal subjects see an 8 (RED colored), Color blind

subjects see a 3.2. Normal subjects see a 6 (BLUE colored), Color blind

subjects can’t see any number.3. Normal subjects see a 7 (GREEN colored), Color blind

subjects can’t See any number.4. Normal subjects see a 35 (RED colored), Color blind

subjects see either a 3 or a 5 depending on the type of color blindness.

Y-Linked Inheritance:

Y is a small chromosome. It contains few genes. These genes are important for sex determination.

Slide 32: a mother always gives X chromosomes to her offspring. While a father gives an X (50% chance of having a daughter) or a Y (50% chance of having a son).

-Y-Chromrosome = contains 70Mb (million bases,,dr said "mega"), compared to X; it contains 160 MB (almost the double).- Few dozen genes (Holandric) are found on Y [holandric genes: genes that are carried on Y ch. & belong to the MALE characteristics].-Male differentiation genes, the most important is: Testis-specific spermatogenesis factor-Minor Histocompatibility genes (HY) [it code for HY antigen, but it have nothing to do with major histocompatibility antigens, it was used before the HLA to check for gender (male has HY, a female does not).-Several housekeeping genes (they are typically constitutive genes that are required for the maintenance of basic cellular function, and are expressed in all cells of an organism under normal and patho-physiological conditions, important for the structure & morphology.)-Transmission strictly from father to son.-Y- linked traits are VERY RARE, but can be seen in individuals- recognizing a pedigree that is for a Y-linked trait is very simple; ONLY MALES are affected, no female affected, & the trait is seen in each generation in the pedigree (slide 35).

- an example of a Y-linked trait is :Hypertrichosis Pinnae; Hairy ears, can happen later in life, more common in India & east Asia, less common in middle east.Sex-Limited, Sex-Influenced traits:• Sex-Limited: Autosomal genes (carried on autosomal

ch.), but it affect a structure/process/behavior found only in one sex due to anatomical differences.

Example: Inherited Uterine (seen only in females) or Testicular defects (only in males).• Sex-Influenced: Autosomal genes

-Example: Baldness الصلع, Dominant in males and recessive in females, carrier females have thinner hair.

(a female may have thin hair, but she is NEVER completely bald).

-An obvious example is seen in birds, where the males ( rooster, peacock..) are always prettier & have more beautiful colors than females (example from dr.)-characteristic may appear in both sexes but expression of the phenotype differs.- slide 39 shows the different stages of baldness, they show various dergrees of hair loss.

(NOTE: dr did not mention the details in slides 38-39-, please refer to them for completion of ideas.)

Summary for X-linked traits:

Note: Males are more likely to be afflicted than females regarding X-linked traits

Male-Determining Region SRY on the Y Chromosome:

Males • One X chromosome • Inherited from mother• Two possible

genotypes• XpY (paternal X).• XmY (maternal X).• 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 • XmXm (remember: uniparental disomy)• Heterozygotes are

carriers of recessive traits.

• Females transmit their X randomly to either their sons or daughters

- It is a gene located on Y chromosome. It codes for a SRY protein. This sex-determining region Y (SRY) protein causes a fetus to develop as a male.

- (slide 41) During meiosis in male (spermatogenesis to produce gametes), crossover may happen between X & Y before they separate (exchange of some of their genes). This CROSS OVER may happen in either:(1) COMMONLY, in the homologous area (where

are the pseudo-autosomal genes, that are found in BOTH X & Y), so the SRY remains in Y chromosome & gets transmitted to a son with XY.

(2) In RARE occasions, the crossover may happen at the SRY sequence, so it gets transferred to the X chromosome>> the X has SRY, & the Y does NOT have it..

-when fertilization happens with a normal egg with X:(a) X (with SRY)+ X = XX MALE (the genotype seen in cytogenetics /chromosomal analysis is for a female but the phenotype is a male, because of SRY which is Male-determining).(b) Y (without SRY) + X = XY FEMALE (the genotype is for a male but the phenotype is a female, because she/he has NO SRY) - this case is known as Feminizing XY (with gonadal dysgenesis), male determinant or sex reversed..-Such cases exist. However, they are VERY RARE because crossover in the non homologous areas of X & Y rarely happens. NOTE: In the 22 autosomal chromosomes, the 2 chromosomes are HOMOLOGOUS (have similar gene alleles) across their entire length, while in the sex chromosomes, the X & Y are homologous ONLY at the site of the pseudoautosomal chromosomes.

NOW, talking about the concentration compensation:# A normal female has two X ch.s, while a male has 1 X only, so theoretically , a female should has double the amount of any protein/molecule that is produced by a gene in X ch. (e.g. G6PD). In reality, the amount of any molecule/protein/enzyme

that is produced by an X ch. Located gene is EQUAL in males & females.The reason behind this is the Inactivation of one of X ch in female somatic cells.

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 (Progency: the daughter cells that result from the division of a "mother" cell): all have same inactivated X chromosome as the original (mother cell), creating mosaic individual (has some cells with inactivated paternal X, & other cells with inactivated maternal X)

- The female will be mosaic for any X-linked types of enzymes, example:

Melanin is a protein, whose gene is found on X chromosome.It has many types (Iso-forms). A female has TWO isoforms of this protein (some cells have active Xp & produce one isoform. Other cells have active Xm & produce another isoform) , while a male has only one isoforms.

X-inactivation is an epigenetic process. (meaning that the environmental factors will affect & determine the process of inactivation of, NOT the genes that are found in X). (epigenetics is the study of heritable changes in gene activity that are not caused by changes in the DNA sequence, but the environment where the gene is found will determine its activity.)

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 cells -Lyonization happens early in fetal development when it is divided into 24 cells. If it was delayed & did not

happen, the female will have double the amount of X-linked proteins/enzymes & an abnormality will be seen. (Dr said that inactivation occurs within 24 hours).

� -The Lyon hypothesis states that one X chromosome in the cell is randomly inactivated early in the embryonic development of females ( it is an arbitrary process, the paternal or the maternal X could be inactivated)

�

- In the cells of an organ of a female, some Cells have an inactivated Paternal X, & otherCells have an inactivated Maternal X.This organ is MOSAIC with two different Lines of cells.-Inactivation results in (dosage Compensation).

-What is controlling this inactivation process?

The X inactivation center, it is located on Xq 13 (1 Mb). The XIST X Inactive Specific Transcript. The gene is transcribed only from the inactive X –chromosome: At location Xq 13, there is a gene called XIST. It is

transcribed into mRNA (but not translated). This non coding mRNA will wrap itself around the X to be inactivated & coat it completely. Also, methylation of X happens (adding CH3 group), so this X cannot be transcribed or translated; it becomes INACTIVE.

This X inactivation is reversed only in the process of gametes production in females during fertilization, so that each 1n egg that is produced will get an ACTIVE X chromosome (reactivation of the inactive X).

(slides 45-46 were not discussed in details).

NOTE: If there is an abnormality in one of the X chromosomes, the X with the abnormality will be inactivated (translocated X for eg.). Generally, preservation of the

normal X happens, and inactivation happens for the X with abnormality.

• 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.

(so as NOT to inactivate a part on an autosomal ch. With the X ch.)• In an unbalanced X-autosome translocation, the

translocated X 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.

-slide 51: * a small region is homologous between X & Y chromosomes. It carries the Pseudoautosomal genes. These genes are found in two regions at the tips of X & Y ch.s ( pseudoautosomal region 1 & pseudoautosomal region 2), & here the X & Y behave like the autosomal chromosomes.* at the middle, Y has a differential region that carries Y-linked genes & SRY. It is different from the differential region of X that carries X-linked genes.

Sequence Homologies of the X and Y Chromosomes:-15% of the X Chromosome to be inactivated escape Inactivation.-the location of genes that escape the inactivation: at the tips of q and p arms of X (at pseudoautosomal regions), because they have homologous genes at Y ch., so we need them to stay active.

-The genes that will NOT be inactivated are: Steroid sulfatase enzyme. Xg blood group. (Xg antigen= RBC surface antigen) Kallman Syndrome ( hypogonadism, inability to perceive

odor) Housekeeping genes

X-INACTIVATION involves the following:• G6PD• Melanine • Anhidrotic Ectodermal Dysplasia• Calico Cat Fur Color• Barr Bodies

Anhidrotic Ectodermal Dysplasia (slide 56): - it affects FEMALES only.- some areas of skin have NO sweat glands & do not sweat at all, while other areas have sweat glands.

-this is due to Random Inactivation of one X chromosome, resulting in MOSAICISM.Calico Cat Fur Color (slide 57):

-some of the genes that determine a cat's color are X-linked, it will give the cat an orange tabby or a blck fur colour.

-a male cat has only 1 X, so it will have EITHER a black OR an orange tabby fur (with the original white fur).* a male is wither white-black OR orange-white.- a female cat has some lines of cells with active X B > will have some black fur, & other cells with active X b > will have orange fur.* this female cat with white-black-orange fur is called Calico Cat (ONLY in female cats).