INTERNATIONAL UNIVERSITY FOR SCIENCE & TECHNOLOGY

GENETICS lecture course

Dr. A. Rahmo

PhD. Biochemistry and Molecular biology USC

GENETICS COURSE LECTURES1- INTRODUCTION2- MONOGENIC INHERITANCE (ONE GENE) 3- MONOGENIC INHERITANCE (TWO GENES)4- PEDIGREE ANALYSIS 5- BEYOND CLASSICAL (MENDELIAN) GENETICS6- EXAM7-POLYGENIC INHERITANCE7-POLYGENIC INHERITANCE8- CYTOGENETICS9- MOLECULAR GENETICS OF PROCARYOTES10- MOLECULAR GENETICS OF EUCARYOTES11- ONCOGENETICS12- EXAM13- TESTING & TREATMENT OF GENETIC DISEASES 14- POPULATION GENETICS15- REVIEW

PEDIGREE ANALYSIS

Classical (Mendelian) GeneticsClassical (Mendelian) Genetics

Pedigreessymbolic representations of family

relationships and inheritance of a trait

Normal female

Normal male

Single bar indicates mating

Pedigreessymbolic representations of family

relationships and inheritance of a trait

Normal parents and normal offspring

Single parent means partner is not significant for the analysis

Double bar indicates consanguineous mating

Fraternal twins (not identical)

Identical twins

Number of children62

Pedigreessymbolic representations of family

relationships and inheritance of a trait

Affected

Heterozygote

Female X-linked carrier

Dead Aborted or stillborn

The Royal Egyptian family

Effect of consanguinity

A Pedigree with Consanguinity

Effect of consanguinity

DD Dd Dd DD

DdDD

DDDdDdDD

Dd ddDD

Consanguinity increases the risk of sharing a common ancestral mutation

Congenital Insensitivity to Pain

(congenital analgesia): is one or more rare conditions where a person cannot feel (and has never felt) physical pain

Sclerosteosis

autosomal recessive

A rare genetic disorder characterized by syndactyly (condition where two or more digits are fused together) andthickening and overgrowth of bone. interferance with a process which plays a key role in the regulation of bone formation.

Albinism

Autosomal Traits

Autosomal Recessive Inheritance

Brachydactyly

Autosomal Dominant Inheritance

"shortness of the fingers and toes" (digits)

Achondroplasia

Autosomal Dominant

is a bone-growth disorder responsible for 70% of dwarfism cases, the limbs are disproportionally short compared to the trunk (abdominal area), with the head larger than normal and characteristic facial features.

Chands Syndrome

CHAND is an acronym for Curly Hair-Ankyloblepharon-Nail Dysplasia syndrome. This combination of anomalies belongs to the group of ectodermal dysplasias and has been ectodermal dysplasias and has been described in less than five patients.

Autosomal recessive

Tay-Sachs Disease

Autosomal Recessive; Lethal before reproduction

known as infantile TaySachs disease, it causes a relentless deterioration of mental and physical abilities that commences around six months of age and usually results in death by the age of four.

Freckles

Autosomal Dominant

Freckles are clusters of concentrated melanin which are most often visible on people with a fair complexion.

X-linked Recessive Traits

Always expressed in hemizygous males Female homozygotes show the trait but female heterozygotes do not Affected males: Inherited from affected or heterozygous mother Affected females : affected fathers and affected or heterozygous mothers

Possible genotypesPossible genotypesX+Y Hemizygous wild type maleXmY Hemizygous mutant male

X+X+ Homozyogus wild femaleX+Xm Heterozygous female carrierXmXm Homozygous mutant female

Ichtyosis

X-linked Recessive Inheritance

All types of ichthyosis have dry, thickened, scaly or flaky skin.[1]In many types the skin is said to resemble the scales on a fish

HEMOPHILIA A

(clotting factor VIII deficiency)

Colorblindness is a defect of vision affecting the ability to distinguish colors, occurring mostly in males. Color blindness is caused by a defect in the retina or in other nerve portions of the eye. Also known as dichromatism, this disease

Colorblindness

as dichromatism, this disease consists of the inability to differentiate between reds and greens.

X-linked recessive

X-linked dominant trait

Affected femaleAffected femaleAffected maleAffected male

What does the pattern look like?

Normal maleNormal maleNormal femaleNormal female

Example with male survival

X-linked dominant, male lethalWhat does the pattern look like?

Affected femaleAffected female

Normal maleNormal male

Normal femaleNormal female

Example with male lethality

X-linked dominant recurrence risks

X1 X2

Mother

X1

Y

X1X1 X1X2

X1Y X2Y

Daughters 50% normal50% affected

Sons50% normal50% affected

Congenital Generalized Hypertrichosis

X-linked Dominant Inheritance

describes hair growth on the body in an amount considered abnormal. Extensive cases of hypertrichosis have informally been called werewolf syndrome.

Incontinentia pigmenti

Linear blisters on leg

Linear blisters in newborn girls Crops followed by scarring Small teeth Eye abnormalities Patchy hair loss Only girls are affected Males are typically not affected

Linear erosions on soles X-linked dominant(male lethal condition)

Potentially confusing in X-linked pedigree analysis

Male lethal X-linked conditions New mutations may be hard to recognize as X-linked Sex-limited conditions may look X-linked With carrier mother and affected father can see male

to male inheritance

Y-linked Traits

Genes on the Y chromosome Very rare Transmitted male to male No affected females Currently, identified Y-linked traits

involve infertility and are not transmitted

Example: Y chromosome infertilitytransmitted

Example: Y chromosome infertility

Codominant Alleles

Offspring from Parents with Blood Type A and Blood Type B

Punnett squares

ABO blood typing: co-dominant alleles

A/- B/- B/- BB

BBB/-ABA/--/-

AB BBA/-

Inconclusive

EXERCISESWhat type of inheritance is present in this Pedigree?

Genetic PredictionsEllens brother Michael has sickle cell anemia, an autosomal recessive disease. - What is the probability that Ellens child has a sickle cell anemia allele?

Ellen and Michaels parents must be heterozygous

EXERCISES

S s

S

s

SS Ss

Ss ss

Ellen is not affected andcannot be ss

Probability Ellen is a carrier = 2/3Probability child inherits sickle cell allele = Probability child carries sickle cell allele from Ellen

= 2/3 x 1/2 = 1/3

Question #1

1 2

EXERCISES

1 2

Write the genotypes in every possible place.If individuals 1 and 2 marry, what is the probability that their first child will be sick?

Question #2

PKU is a human hereditary disease resulting from inability of the body to process the chemical phenylalanine (contained in protein that we eat).

It is caused by a recessive allele with simple Mendelian inheritance.

Some couple wants to have children. The man has a sister with PKU

EXERCISES

Some couple wants to have children. The man has a sister with PKU and the woman has a brother with PKU. There are no other known cases in their families.

What is the probability that their first child will have PKU ?

Question #2-Solution Highlights

P/p P/p P/p P/p

EXERCISES

p/p p/pP/- P/-

P the normal allelep the mutant allele

Answer: 1/9

Question #3

The disease is rare.

EXERCISES

1 2 3 4 5 6 7 8 9 10

a. What is the most likely mode of inheritance ?

b. What would be the outcomes of the cousin marriages 1 x 9, 1 x 4, 2 x 3, and 2 x 8 ?

a. Observations: After the disease is introduced into the family in generation #2, it

appears in every generation dominant! Fathers do not transmit the phenotype to their sons

X-linked!

b. The outcomes:

Question #3-Solution HighlightsEXERCISES

b. The outcomes: 1 x 9: 1 must be A/a

9 must be A/a 1 x 4: 1 must be A/a

4 must be a/a 2 x 3: 2 must be a/a

3 must be A/a 2 x 8: 2 must be a/a

8 must be a/a

Same

All normal

What is the probability that a clinically unaffected sibling of a child with an autosomal recessive disease is a carrier for that disorder ?

EXERCISES

What is the probability that the consultand III-3 is a carrier of Duchenne muscular dystrophy ?

1 1/2 2 1/4

EXERCISES

3 1/8 4 1/9 5 1/18

EXERCISES

EXERCISES

EXERCISES

EXERCISES

EXERCISES

Solutions to the exercises

Definition of Probability

The probability of an event equals the number of times it happens divided by the number of opportunities.

These numbers can be determined by experiment or by knowledge of the system.

For instance, rolling a die (singular of dice). The chance of

REVIEW OF PROBABILITY RULES

For instance, rolling a die (singular of dice). The chance of rolling a 2 is 1/6, because there is a 2 on one face and a total of 6 faces. So, assuming the die is balanced, a 2 will come up 1 time in 6.

It is also possible to determine probability by experiment: if the die were unbalanced (loaded = cheating), you could roll it hundreds or thousands of times to get the actual probability of getting a 2. For a fair die, the experimentally determined number should be quite close to 1/6, especially with many rolls.

The AND Rule of Probability

The probability of 2 independent events both happening is the product of their individual probabilities.

Called the AND rule because this event happens AND that event happens.

For example, what is the probability of rolling a 2 on one die and a 2 For example, what is the probability of rolling a 2 on one die and a 2 on a second die? For each event, the probability is 1/6, so the probability of both happening is 1/6 x 1/6 = 1/36.

Note that the events have to be independent: they cant affect each others probability of occurring. An example of non-independence: you have a hat with a red ball and a green ball in it. The probability of drawing out the red ball is 1/2, same as the chance of drawing a green ball. However, once you draw the red ball out, the chance of getting another red ball is 0 and the chance of a green ball is 1.

The OR Rule of Probability

The probability that either one of 2 different events willoccur is the sum of their separate probabilities.

For example, the chance of rolling either a 2 or a 3 on a die is 1/6 + 1/6 = 1/3.

The NOT Rule of Probability The chance of an event not happening is 1 minus the chance of it The chance of an event not happening is 1 minus the chance of it

happening.

For example, the chance of not getting a 2 on a die is 1 - 1/6 = 5/6.

This rule can be very useful. Sometimes complicated problems are greatly simplified by examining them backwards.

Combining the Rules

More complicated situations involve combining the AND and OR rules.

It is very important to keep track of the individuals involved and not allow them to be confused. This is the source of most peoples problems with probability.peoples problems with probability.

What is the chance of rolling 2 dice and getting a 2 and a 5? The trick is, there are 2 ways to accomplish this: a 2 on die A and a 5 on die B, or a 5 on die A and a 2 on die B. Each possibility has a 1/36 chance of occurring, and you want either one or the other of the 2 events, so the final probabilty is 1/36 + 1/36 = 2/36 = 1/18.