Human disease genetics

Question 1

What is a mutation

Answer 1

a permanent change to the DNA sequence

Question 2

Why are vast majority of mutations neutral and have no effect at all

Answer 2

Because our genome is very large but the functional part is very small so there is a bigger chance of mutation occurring at a non-functional part of genome

Question 3

Relate different ways in which mutations can be inherited

Answer 3

Germline mutations are inheritable. This is when mutations occur in cells that produce gametes and therefore can be inherited by the next generation

Question 4

Silent mutation - define & where does it occur

Answer 4

Mutation with no effect on phenotype
Often occur in non-coding regions such as the intergenic regions and introns
Can occur in exons but can also cause no effect due to the redundancy of the genetic code

Question 5

Missense mutations

Answer 5

Mutation that causes a change in amino acid due to changing a base that often does not produce serious phenotype alterations
Can change the sequence of protein and thus altering the protein’s ability to function
Can also have no effect if the amino acid changed was replace by a very similar one that does not alter the protein’s ability to function

Question 6

Frameshift mutations

Answer 6

Insertion or deletion of a single base in a coding region that changes the readout of DNA so that the resulting protein is altered from that point on

Question 7

Nonsense mutation/truncated mutation

Answer 7

Special case of point mutation when the base change results in the formation of a STOP codon resulting in truncated protein

Question 8

Sickle cell anaemia is caused by what type of mutation

Answer 8

missense mutation

Question 9

Triplet repeat expansion

Answer 9

Where a region containing triplet repeats undergo a catastrophic expansion that can alter protein function of destabilise a chromosome

Question 10

Point mutation (single nucleotide polymorphism)

Answer 10

Single base change to NA sequence

Can result in change to amino acid but are mostly ‘silent’

Question 11

Loss of function mutation

Answer 11

A mutation in the organism’s DNA resulting in the formation of either a protein that non longer functions, or complete loss of protein

Question 12

Gain of function mutation

Answer 12

When the DNA sequence is altered so the protein becomes more active or takes on a new function

Question 13

Example of loss of function mutation

Answer 13

Cystic fibrosis

Question 14

Example of gain of function mutation

Answer 14

Huntington’s disease (triplet expansion)

Question 15

somatic mutations

Answer 15

Changes to the DNA sequence of non-germline cells that are only inherited by daughter cells after division

Question 16

Example of monogenic diseases

Answer 16

Haemophila A and B
Huntington Disease
Cystic fibrosis

Question 17

What is haemophilia

Answer 17

disorders of blood clotting

Question 18

Haemophilia A - effect, cause

Answer 18

Affects 1/5000 males worldwide
Results form impaired or absent clotting factor VIII which is most commonly caused by a mutation of inversion in Factor VIII gene on the X-chromosome

Question 19

Haemophilia B - cause, what happens if untreated and treatment

Answer 19

Defect of blood clotting factor XI
If untreated, there is high risk of death from uncontrolled bleeding
Treatment by intravenous infusion of missing protein

Question 20

Both Haemophilia A and B are what type of disorders

Answer 20

X-linked recessive disorders (1 intact copy protects against disease)

Question 21

Why are women rarely affected by haemophilia

Answer 21

Because women have 2 X-chromosomes

Question 22

Sons of women who are carriers of Haemophilia have what probability of inheriting the disease

Answer 22

0.5

Question 23

Genetic cause of Huntington Disease

Answer 23

Mapped to chromosome 4 - autosomal
Caused by expansion of a CAG triplet repeat in HTT gene (Huntington gene) which codes for glutamine (protein has long polyglutamine tract which cause it to become unstable)

Question 24

Symptoms of Huntington’s Disease (3)

Answer 24

Progressive tumor
Involuntary movements
Neurodegeneration

Question 25

When does Huntington's Disease normally develop

Answer 25

Onset in mid-life - usually 30-50

Question 26

Treatment for Huntington's Disease

Answer 26

No effective treatment

Question 27

Inheritance of Huntington's Disease

Answer 27

``` Autosomal dominant (not sex-linked) 1 copy of the infected gene can cause disease, having a normal copy of the same gene is NOT protective Only affected people can pass on the gene ```

Question 28

Genetic testing for Huntington's Disease

Answer 28

PCR used to determine length of CAG | Variation in length of repeat determines whether or not one will develop the disease

Question 29

10-35 copies of the CAG repeat

Answer 29

Normal

Question 30

How many copies of CAG repeats indicate risk of descendants developing Huntington's Disease

Answer 30

27-35

Question 31

36-40 copies of CAG repeat

Answer 31

risk of developing disease

Question 32

How many copies of CAG repeats indicate that Huntington's disease will develop

Answer 32

40+ copies

Question 33

Cause of Cystic Fibrosis

Answer 33

Can be caused by many different mutations in CFTR gene (Cystic fibrosis transmembrane regulator) which is an chloride ion transporter Most common = 3 base pair deletion/deltaF508 deletion (protein is abnormally processed, mislabeled so is not directed to the cell membrane and become degraded)

Question 34

What does the reduced function of CFTR protein cause

Answer 34

thickening of cell secretions

Question 35

State a method used for screening for Cystic Fibrosis

Answer 35

Increased saltiness of sweat causedy by CF mutation

Question 36

Symptoms of Cystic fibrosis (5)

Answer 36

``` Lung infections Pancreatic insufficiency Congenital absence of vas deferens in males Salty tasting skin Thick mucus ```

Question 37

Inheritance of Cystic fibrosis

Answer 37

Autosomal recessive (not sex linked) - one copy of normal gene can protect from inheriting the disease

Question 38

State a X-linked recessive disorder

Answer 38

Haemophilia A and B

Question 39

What are polygenic disorders

Answer 39

Disorders that involve several genes acting together or environmental factors interacting with genes

Question 40

Technique used to find polygenic disorders

Answer 40

Association study - where the DNA of people with disease and people without disease are sequenced and variants are identified

Question 41

Examples of polygenic disease (8)

Answer 41

``` Ischaemic heart disease Asthma Hypertension Some cancers Diabetes Multiple sclerosis Bipolar disorder Rheumatoid arthritis ```

Question 42

Genetic determinism

Answer 42

- In polygenic disease, having a disease-related variation does not mean you will get the disease, such diseases come about through a combination of variants and the environment - Most genetic disorders are probabilistic not deterministic

Question 43

Synteny

Answer 43

When genes are present in the same order on chromosome of different species, indicating a common ancestor

Question 44

CNV (copy number variant)

Answer 44

Site in the genome at which individuals of the same species have different number of copies of a gene or genetic region instead of the standard 2 copies

Question 45

InDel

Answer 45

Variation in genome arising from insertion or deletion of base pair

Question 46

SNP (Single Nucleotide Polymorphism)

Answer 46

Site at which individuals of he same species have a different base pair in their genome

Question 47

Outline sources of variation between individual human genomes (3)

Answer 47

CNV, InDel, SNP

Question 48

What can't we learn from the human genome sequence

Answer 48

function of a gene

Question 49

How can we make mutants

Answer 49

by treating organisms with radiation or chemicals

Question 50

Reasons for selected model organisms for genetics (3)

Answer 50

closely related to us have rapid life cycles can be domesticated

Question 51

What is a transgenic animal

Answer 51

model organism that has been engineered to carry an extra copy of DNA or transgene by random integration

Question 52

Example of mouse disease model

Answer 52

Cystic fibrosis

Question 53

Disadvantages of the mouse disease model for cystic fibrosis

Answer 53

- Pancreatic disease not replicated - Males not infertile - Mouse died of gastrointestinal complications whereas humans die of lung disease - Lung disease only develops after long term exposure to pathogens

Question 54

Advantages of the mouse disease model for cystic fibrosis

Answer 54

Able to test therapies on mice - Drug therapy (treat the chronic symptoms) - Gene therapy (repair or replace the damaged CFTR protein)

Question 55

Define totipotent

Answer 55

Able to give rise to any cell type

Question 56

Homologous recombination

Answer 56

when the targeted gene recombines with the targeting vector and is removed

Question 57

Homologue

Answer 57

Gene that share similar sequence and function

Question 58

knockout mouse

Answer 58

mouse engineered by homologous recombination to lack a particular gene

Question 59

Model organism

Answer 59

an animal used by geneticists to link genotype to phenotype, using reverse and forward genetics

Question 60

Null

Answer 60

a non-functional gene allele

Question 61

Reverse genetics

Answer 61

when we disrupt the function of a known gene in order to work out what its purpose is

Question 62

Differentiation

Answer 62

The process by which cells become adapted ad tied to one function

Question 63

iPS cell

Answer 63

a pluripotent cell made by manipulating a differentiated cell