Human disease genetics Flashcards
What is a mutation
a permanent change to the DNA sequence
Why are vast majority of mutations neutral and have no effect at all
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
Relate different ways in which mutations can be inherited
Germline mutations are inheritable. This is when mutations occur in cells that produce gametes and therefore can be inherited by the next generation
Silent mutation - define & where does it occur
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
Missense mutations
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
Frameshift mutations
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
Nonsense mutation/truncated mutation
Special case of point mutation when the base change results in the formation of a STOP codon resulting in truncated protein
Sickle cell anaemia is caused by what type of mutation
missense mutation
Triplet repeat expansion
Where a region containing triplet repeats undergo a catastrophic expansion that can alter protein function of destabilise a chromosome
Point mutation (single nucleotide polymorphism)
Single base change to NA sequence
Can result in change to amino acid but are mostly ‘silent’
Loss of function mutation
A mutation in the organism’s DNA resulting in the formation of either a protein that non longer functions, or complete loss of protein
Gain of function mutation
When the DNA sequence is altered so the protein becomes more active or takes on a new function
Example of loss of function mutation
Cystic fibrosis
Example of gain of function mutation
Huntington’s disease (triplet expansion)
somatic mutations
Changes to the DNA sequence of non-germline cells that are only inherited by daughter cells after division
Example of monogenic diseases
Haemophila A and B
Huntington Disease
Cystic fibrosis
What is haemophilia
disorders of blood clotting
Haemophilia A - effect, cause
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
Haemophilia B - cause, what happens if untreated and treatment
Defect of blood clotting factor XI
If untreated, there is high risk of death from uncontrolled bleeding
Treatment by intravenous infusion of missing protein
Both Haemophilia A and B are what type of disorders
X-linked recessive disorders (1 intact copy protects against disease)
Why are women rarely affected by haemophilia
Because women have 2 X-chromosomes
Sons of women who are carriers of Haemophilia have what probability of inheriting the disease
0.5
Genetic cause of Huntington Disease
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)
Symptoms of Huntington’s Disease (3)
Progressive tumor
Involuntary movements
Neurodegeneration
When does Huntington’s Disease normally develop
Onset in mid-life - usually 30-50
Treatment for Huntington’s Disease
No effective treatment
Inheritance of Huntington’s Disease
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
Genetic testing for Huntington’s Disease
PCR used to determine length of CAG
Variation in length of repeat determines whether or not one will develop the disease
10-35 copies of the CAG repeat
Normal
How many copies of CAG repeats indicate risk of descendants developing Huntington’s Disease
27-35
36-40 copies of CAG repeat
risk of developing disease
How many copies of CAG repeats indicate that Huntington’s disease will develop
40+ copies
Cause of Cystic Fibrosis
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)
What does the reduced function of CFTR protein cause
thickening of cell secretions
State a method used for screening for Cystic Fibrosis
Increased saltiness of sweat causedy by CF mutation
Symptoms of Cystic fibrosis (5)
Lung infections Pancreatic insufficiency Congenital absence of vas deferens in males Salty tasting skin Thick mucus
Inheritance of Cystic fibrosis
Autosomal recessive (not sex linked) - one copy of normal gene can protect from inheriting the disease
State a X-linked recessive disorder
Haemophilia A and B
What are polygenic disorders
Disorders that involve several genes acting together or environmental factors interacting with genes
Technique used to find polygenic disorders
Association study - where the DNA of people with disease and people without disease are sequenced and variants are identified
Examples of polygenic disease (8)
Ischaemic heart disease Asthma Hypertension Some cancers Diabetes Multiple sclerosis Bipolar disorder Rheumatoid arthritis
Genetic determinism
- 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
Synteny
When genes are present in the same order on chromosome of different species, indicating a common ancestor
CNV (copy number variant)
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
InDel
Variation in genome arising from insertion or deletion of base pair
SNP (Single Nucleotide Polymorphism)
Site at which individuals of he same species have a different base pair in their genome
Outline sources of variation between individual human genomes (3)
CNV, InDel, SNP
What can’t we learn from the human genome sequence
function of a gene
How can we make mutants
by treating organisms with radiation or chemicals
Reasons for selected model organisms for genetics (3)
closely related to us
have rapid life cycles
can be domesticated
What is a transgenic animal
model organism that has been engineered to carry an extra copy of DNA or transgene by random integration
Example of mouse disease model
Cystic fibrosis
Disadvantages of the mouse disease model for cystic fibrosis
- 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
Advantages of the mouse disease model for cystic fibrosis
Able to test therapies on mice
- Drug therapy (treat the chronic symptoms)
- Gene therapy (repair or replace the damaged CFTR protein)
Define totipotent
Able to give rise to any cell type
Homologous recombination
when the targeted gene recombines with the targeting vector and is removed
Homologue
Gene that share similar sequence and function
knockout mouse
mouse engineered by homologous recombination to lack a particular gene
Model organism
an animal used by geneticists to link genotype to phenotype, using reverse and forward genetics
Null
a non-functional gene allele
Reverse genetics
when we disrupt the function of a known gene in order to work out what its purpose is
Differentiation
The process by which cells become adapted ad tied to one function
iPS cell
a pluripotent cell made by manipulating a differentiated cell
