Lecture 2- Genetic Transmission

Question 1

Contrast the characteristics of monogenic and complex disorders

Answer 1

• Clear inheritance vs no clear inheritance
• No environment vs environment essential
• Individually rare vs common

Question 2

Give examples of monogenic disorders

Answer 2

Huntington’s
Cystic Fibrosis
Haemophilia

Question 3

Give examples of complex disorders

Answer 3

T2D
Schizophrenia
Crohn’s disease

Question 4

Define mendelian inheritance

Answer 4

• Process where individuals inherit and transmit to their offspring one out of the two alleles present in homologous chromosome

Question 5

Define allele

Answer 5

Alternate forms of a gene or DNA sequence at the same chromosome location (locus)

Question 6

Define homologous chromosome

Answer 6

• Homologous chromosomes are a matching (but non-identical) pair
• One inherited from each parent

Question 7

Define ‘mutation’

Answer 7

Any HERITABLE change in the DNA sequence

Question 8

Define ‘polymorphism’

Answer 8

A mutation present in >1% of a population–> complex disease

Question 9

What are the two classes and four subclasses of mutations?

Answer 9

1) Point Mutation
- Missense: Change in codon to code for different amino acid
- Nonsense: Change in codon that codes for stop codon= premature end of polypeptide
2) Frameshift Mutation
- Insertion: insertion of extra base causing the code to shift out of frame
- Deletion: deletion of a base

Question 10

What is a point mutation?

Answer 10

A single change in the DNA sequence

Question 11

What does a triangle represent in a pedigree diagram?

Answer 11

Miscarriage

Question 12

If you have a small arrow pointing to the square or circle, what does it represent?

Answer 12

The person providing the pedigree information

Question 13

What is consanguineous mating and how is it displayed on a pedigree?

Answer 13

Marriage with blood relative

A double line

Question 14

What are the five types of mendelian inheritance patterns?

Answer 14

1) Autosomal dominan
2) Autosomal recessive
3) X-linked dominant
4) X-linked recessive
5) Mitochondrial

Question 15

Give an example of an autosomal dominant disease

Answer 15

Huntingtons’s disease

Question 16

What are the symptoms of Huntington’s disease and what is its mean age of onset?

Answer 16

• Motor, cognitive and psychiatric dysfunction
• hyperkinesia
• Mean age of onset 35 to 44 years

Question 17

Which gene and protein is involved in Huntington’s disease?

Answer 17

HTT gene on Chr4

Huntingtin protein

Question 18

What does the mutated gene cause?

Answer 18

• Toxic form of huntingtin that forms clumps

- cell death in basal ganglia

Question 19

What does it mean by the ‘genetic anticipation’ of Huntington’s?

Answer 19

As you go down generations:

• age of onset decreases
• severity increases

Question 20

What causes the genetic anticipation of Huntington’s disease?

Answer 20

• Huntington’s Disease is caused by unstable CAG triplet repeats.
• As you go down generation # of repeats increases (>40 repeats for disease)

Question 21

Give an example of an autosomal recessive disease

Answer 21

Cystic Fibrosis

Question 22

Which gene and protein is involved in cystic fibrosis?

Answer 22

• CFTR gene on Chr7

- CF transmembrane conductance regulator protein

Question 23

What happens when you have a mutation on the CFTR gene?

Answer 23

• affects Cl- ion channel function in epithelial cells

- Disruption of Na+/ H2O regulation –> thick mucus

Question 24

What are the symptoms of CF?

Answer 24

• breathing problem, infection (caused by thick mucus in lungs)
• Blockages in pancreas affects digestive enzymes

Question 25

What is the most common mutation causing CF?

Answer 25

Delta F508 (deletion of Phe @ aa 508)

Question 26

Name another condition caused by a mutation in the CTFR gene and give some of its symptoms

Answer 26

- Congenital absence of the vas deferens (CAVD) --> vas deferent fail to form properly - -> azoospermia (infertility)

Question 27

What are the characteristics of X-linked recessive disorders?

Answer 27

- No affected parents - Transmitted by carrier F - Only males affected

Question 28

Give an example of an X-linked disease

Answer 28

Haemophilia

Question 29

What causes haemophilia A?

Answer 29

- Mutation of F8 gene on ChrX | - Loss of functioning Coagulation Factor VIII

Question 30

What causes haemophilia B?

Answer 30

- Mutation of F9 gene on ChrX | - loss of functioning coagulation factor IX

Question 31

Give examples of genetic heterogeneity

Answer 31

1) Same gene, different mutation, different symptoms- cystic fibrosis and CAVD caused by mutation in the CFTR gene 2) Same disease, different gene- Haemophilia A/B 3) Same disease, different genes, different inheritance patterns- Epidermolysis Bullosa (AD/ AR)

Question 32

Define incomplete penetrance

Answer 32

Symptoms not always present in an individual with a disease causing mutation

Question 33

Define variable expressivity

Answer 33

Disease severity may vary between individuals with the same-disease causing mutation

Question 34

Define phenocopy

Answer 34

Having same disease but with different underlying caus

Question 35

Define Epistasis

Answer 35

Interaction between disease gene mutations and other modifier genes which affects phenotype

Question 36

Look at the molecular mechanisms of dominant, recessive and co-dominant conditions

Answer 36

1) Dominant- presence of toxic protein- effects of mutated gene mask normal copy 2) Recessive- absence of functional protein- effects seen when normal copy is absent 3) Co-dominant- both mutated and normal genes apparent (e.g. sickle cell trait)

Question 37

What is the therapy for dominant and co-dominant conditions?

Answer 37

- Neutralise the effects of the toxic protein | - 'switch off' the mutant gene

Question 38

What is the therapy for recessive conditions?

Answer 38

- Restore activity of the missing protein | - replace the gene/ protein/ affected tissue