Genetics 2

Question 1

Describe characteristics of monogenic diseases, give examples

Answer 1

Clear inheritance
No environment (?)
Individually rare

Huntington disease
Cystic fibrosis
Haemophilia

Question 2

Describe characteristics of polygenic diseases, give examples

Answer 2

No clear inheritance
Environment essential
Common

Type 2 diabetes
Schizophrenia
Crohn’s disease

Question 3

What is Mendelian inheritance

Answer 3

The process whereby individuals inherit and transmit to their offspring one out of the two alleles present in homologous chromosomes

Question 4

What is an allele

Answer 4

Alleles: Alternate forms of a gene or DNA sequence at the same chromosome location (locus)
Different alleles may be described as mutations or polymorphisms

Question 5

What are homologous chromosomes

Answer 5

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

Question 6

What are the differences between mutations and polymorphisms

Answer 6

A mutation is any heritable change in the DNA sequence

A polymorphism is a mutation present in >1% of a population

Usually still called mutations if they cause monogenic disease

Polymorphisms may contribute to complex diseases
The difference between describing a DNA sequence change as a mutation or a polymorphism may be based on the frequency and/or whether it has a functional effect on a gene product.

Question 7

How should we describe to patients that they have a mutation

Answer 7

The preferred term when talking to patients is ‘altered form of a gene that causes disease’. The term “mutation” should be used with great care as it has many negative connotations outside of this context.

Question 8

What is a missense mutation

Answer 8

A point mutation, substitution of one base for another, resulting in a new amino acid.
Synonymous mutations are single base substitutions which result in the same amino acid being coded for

Question 9

What is a nonsense mutation

Answer 9

A point mutation, the base inserted results in the triplet encoding a stop codon- acts like a deletion in the gene.

Question 10

Describe nonsense-mediated decay

Answer 10

In normal translation, ribosomes move along the mRNA displacing exon junction complex proteins, until it reaches the stop codon. If the stop codon is inserted prematurely due to a nonsense mutation, a truncated protein will be produced, however, if the stop codon is inserted before the presence of another EJC, the EJC will trigger the degradation of this mRNA, this is mRNA surveillance. Could be why 3’UTR codes for a long exon

Question 11

What is a frameshift mutation

Answer 11

Insertion or deletion of nucleotides. If not a multiple of 3, a frameshift mutation will occur, reading frame of bases is then changed from this protein, cannot fold correctly, hence cells can detect it and degrade it. Also, a stop codon is normally encoded shortly after the frameshift, hence no protein is produced normally.

Question 12

Why do we take family histories

Answer 12

To identify genetic disease in a family
To identify inheritance patterns
To aid diagnosis
To assist in management of conditions
To identify relatives at risk of disease

Question 13

Symbols for pedigree diagrams

Answer 13

Build up the tree from the ‘bottom’
starting with the affected person and siblings
Record names, dates of birth

Square = Male, Circle = Female
Filled-in = Affected
Lines link related individuals
Choose one parentAsk about siblings and their children,then parents
Put a sloping line through the symbol(from the bottom left hand corner) if the person has died
Record names, dates of birth and maiden names
Ask for miscarriages, stillbirths or deathsin each partnership

Question 14

What are the mendelian inheritance patterns

Answer 14

Autosomal Dominant
Autosomal Recessive
X-linked dominant – Rare
X-linked Recessive
Mitochondrial – Genetics 3

Question 15

Describe autosomal dominant diseases

Answer 15

At least one affected parent

Transmitted by M or F

M or F affected

Vertical transmission
50% risk of each child being affected

Question 16

What is an example of an autosomal dominant disease

Answer 16

First described by Dr George Huntington in 1872

Motor, cognitive, and psychiatric dysfunction: ‘hyperkinesia’ https://www.youtube.com/watch?v=JzAPh2v-SCQ

Mean age of onset is 35 to 44 years

Median survival time is 15 to 18 years after onset

Treatment can ease symptoms, but no cure
The HTT gene on Chr 4 encodes a protein called huntingtin
HD patients inherit one copy of a mutated form of the huntingtin gene

Altered gene encodes a toxic form of the protein that forms ‘clumps’

Cell death in the basal ganglia, leading to symptoms

Question 17

How does HD change down the generations

Answer 17

Age of onset decreases

Severity increases
(also seen in myotonic dystrophy)

Huntington Disease is caused by an unstable CAG triplet repeat: the number of repeats may expand with each generation

10-35 repeats: unaffected
27-35 repeats: unaffected, but at risk of having affected child
35-40 repeats: sometimes affected, sometimes not
40-120 repeats: affected

Question 18

Describe autosomal recessive diseases

Answer 18

No affected parent

Transmitted by M or F

M or F affected

Usually no family history

25% risk of each child being affected

50% chance of each child being a carrier

Question 19

Example of an autosomal recessive condition

Answer 19

A chronic, life-threatening condition
https://www.youtube.com/channel/UC6SBFFcVKYY3skUinIZWzkw

Thick mucus in lungs  breathing problems, infections

Blockages in pancreas affect digestive enzymes
https://www.youtube.com/watch?v=4MaEFDjhgz8

Treatment: daily enzymes and physiotherapy

In the UK, 1 person in 22 is a CF carrier (no symptoms)

Question 20

Molecular basis of cystic fibrosis

Answer 20

The CFTR gene on Chr 7 encodes the CF transmembrane conductance regulator (CFTR) protein
CF patients inherit two copies of a mutated form of the CFTR gene

Absence of functional CFTR protein affects chloride ion channel function in epithelial cells

Disruption of salt /water regulation causes thick mucus and leads to symptoms
Again, note symptoms are dependent on expression pattern of gene – in this case all organs with epithelium that is usually coated in watery mucus
Affects folding of the CFTR protein and prevents it from moving to its correct place in the cell membrane

Question 21

Give an example where the same gene causes different symptoms

Answer 21

Congenital absence of the vas deferens (CAVD) is a condition in which thevasa deferentia fail to form properly

Causes infertility (azoospermia)

Affects around 1 : 2500 men

Most cases of CAVD are caused by mutations in the CFTR gene

Question 22

Describe X-linked recessive conditions

Answer 22

No affected parents

Transmitted by carrier F

Only M affected
Cn never be transmitted from father to son- son inherits X chromosome from Mother
Sons have a 50% risk of being affected

Daughters have a 50% chance of being carriers

Question 23

What is an example of an X-linked recessive condition

Answer 23

Haemophilia
A blood-clotting disorder

Affected people bruise easily and bleed for longer

Two main types, A and B, which together affect about 6500 people in the UK

Can be successfully treated with injections of clotting factor

Question 24

Describe the molecular basis of Haemophilia

Answer 24

The F8 gene on Chr X encodes a protein called coagulation factor VIII
Boys with Haemophilia A inherit one copy of a mutated form of the F8 gene

Lack of functioning Factor VIII causes symptoms of disorder

Question 25

What is Haemophilia B

Answer 25

Haemophilia B is caused by mutations in the F9 gene, also on the X chromosome F9 gene codes for coagulation factor IX Symptoms are identical to Haemophilia A Much rarer than Haemophilia A

Question 26

Describe the concept of genetic heterogeneity

Answer 26

Same gene, different mutations, different symptoms – e.g., cystic fibrosis and CAVD are both caused by mutations in the CFTR gene Same disease, different genes – e.g., Haemophilia A/B Same disease, different genes, different inheritance patterns – e.g., different forms of epidermolysis bullosa can be AD or AR

Question 27

What is meant by the penetrance of a character

Answer 27

The proportion of people with the relevant genotype who display the character.

Question 28

Describe the pitfalls of Mendelian inheritance

Answer 28

Incomplete penetrance – symptoms are not always present in an individual with a disease-causing mutation- may be a non-penetrant carrier of an autosomal dominant condition. Variable expressivity – disease severity may vary between individuals with the same disease-causing mutation Phenocopy – having the same disease but with a different underlying cause Epistasis – interaction between disease gene mutations and other modifier genes can affect phenotype

Question 29

Explain the difference between incomplete penetrance and variable expressivity

Answer 29

Incomplete penetrance and variable expressivity are phenomena associated only with dominant inheritance, never with recessive inheritance. Incomplete penetrance – eg, if an obligate carrier of a dominant disease does not show symptoms (eg HTT gene with intermediate number of CAG repeats (25-30) sometimes does/not cause symptoms of HD). Not to be confused with variable expressivity – in which patients with same genotype have different severity of symptoms. One example of variable expressivity is Marfan syndrome. Phenocopy –eg. Common Obesity has a high frequency in the general population and may complicate looking for inheritance patterns for rare monogenic obesity. Epistasis, eg. modifier genes that affect the severity of CF

Question 30

Describe the continuum of penetrance

Answer 30

Full penetrant conditions ( mendelian) | Low penetrance conditions ( multifactorial diseases).

Question 31

Differences between dominant and recessive diseases

Answer 31

Dominant conditions are usually caused by mutations that result in presence of a toxic protein (e.g., HD) – effects of the mutated gene ‘mask’ normal copy Recessive conditions are caused by mutations that result in absence of a functional protein (e.g., CF, haemophilia) – effects of the mutated gene only seen because normal copy is absent Co-dominant conditions: effects of both mutated and normal genes apparent in people with both (e.g., sickle cell trait)

Question 32

Implications for therapy of dominant and recessive diseases

Answer 32

Dominant (and co-dominant) conditions – need to neutralise the effects of the toxic protein or ‘switch off’ the mutant gene, “unmasking” the normal gene Recessive conditions – need to restore activity of the missing protein, by replacing the gene or protein product, or even affected tissues Dominant – require drug therapies, perhaps one day possible to use RNAi to block expression of mutant gene. Recessive – need to replace missing gene (gene therapy, eg. SCID, best for diseases where just one or two easily accessible tissues affected) or protein (eg. enzyme replacement therapy) or cells (eg. bone marrow transplants for SCID, other blood diseases)