Lecture 28 Flashcards
What are mutations? What are inherited mutations known as? What are non inherited mutations known as?
Mutations are permanent changes to the DNA sequence, inherited mutations are known as germline mutations and are passed on via the gamete. Non inheritable mutations are known as somatic mutations as they occur in somatic cells.
How do mutations allow for evolution to occur? Why can mutations be beneficial in some cases but neutral in others? What effect do most mutations have?
Mutations introduce new genes to be selected for or against by evolution. They could be beneficial, harmful or neutral to an organism. Mutation effects are also affected by the environment (e.g diet and toxins) or other genes, causing them to sometimes be neutral when in other cases they could be beneficial or harmful. Most mutations are neutral.
What types of mutations are there?
Silent mutations: no effect on phenotype, typically due to being in an intergenic (between genes) or intron region, can also occur occasionally in exons though if the change does not cause a change in the amino acid produced (e.g redundancy of the base code).
Missense mutations: change an amino acid and as such alters the protein’s ability to function (sickle cell anaemia is an example).
Frameshift mutations: either insertion or deletion of a base, leads to affecting all amino acids after the change due to changing the reading order, leading to a truncated protein and is known as a nonsense mutation.
What is triplet repeat expansion? What are two examples?
Some genes contain triplet repeat stretches (e.g 23 CAGs in a row), occasionally these repeats undergo catastrophic expansion which leads to dysfunction. Two examples are Huntingtons and fragile X
What is a chromosome re-arrangement? What are some examples of these?
A mutation in which parts of the chromosomes have been changed or transferred e.g translocation, inversions and aneuploidy.
What is a monogenic disorder?
A disorder which results due to the result of a single gene.
What are the two types of hemophilia and what are the differences? How are they inherited?
Heamophilia A and haemophilia B.
Both are disorders in blood clotting which lead to high risk of death from uncontrolled bleeding, pain and tissue damage from internal bleeding and both are treated by intravenous infusion of the missing protein. Haemophilia A is the most common and affects 1/5000 males worldwide, resulting from impaired or abent clotting factor VIII.
The only difference between the two is the haemophilia B affects factor XI (otherwise indistinguishable).
Having one intact copy protects against the disease but the both of the disorder versions are X linked recessive, as such males are far more affected than women. Interestingly about 30% of cases are sporadic (no family history of the disease).
What is huntington disease? How is it inherited? How does it cause damage?
A disorder which onsets in midlife (roughly 30-50) which leads to a progressive tremor, involuntary movements and neurodegeneration. It has no effective treatment.
Huntington disease is autosomal dominant (chromosome 4), meaning it can be gotten from mum or dad and if a parent has the disease it will lead to a 50% chance of the offspring having it. The gene codes for the huntingtin (HTT) gene and is caused by expansion of a CAG triplet repeat in this HTT gene (a long polyglutamine tract) and this causes the protein to be unstable and fragment, clumping in nerve cells and damaging them.
How can we test for huntington disease?
Polymerase chain reaction can be used to determine the length of the CAG repeat, this can determine roughly when the disease will strike or risk to offspring.
10-35 repeats is normal
27-35 carries a risk of descendants developing huntingtons
36-40 has a risk of developing the disease.
with 40+ copies the disease will develop.
What can a descendants genetic test for huntingtons disease reveal? Why is this a dilemma?
As the child would have to have inherited the disorder from their parents it will also reveal if one of the parents has the disorder. Not everyone wants to know if they have huntingtons.
What is cystic fibrosis? How is it inherited
A disorder which causes symptoms like: lung infections, pancreatic insufficiency, congenital absence of vas deferens in males and salty tasting skin. These symptoms range from moderate to severe. The more severe the more frequent the infections and hospitalisation and reduced life expectancy.
It is an autosomal recessive trait, caused by a reduced function to a chloride ion transporter (the CFTR gene, cystic fibrosis transmembrane regulator), this leads to thickening of cell secretions. Many mutations can lead to this disease, the most common is a mutation which leads to the channel not folding correctly and hence making it unable to reach the membrane. Another possibility is the inability of the channel to open properly but some function is still maintained.
How are potential disease genes found?
The genome is sequenced and mapped to the human genome reference and novel variants are found, if they are then predicted to be harmful they will be validated and tested.
What are polygenic disorders? How do we find genes which cause these?
Disorders caused by several genes acting together or environmental factors interacting with genes. To understand these we need to understand gene product function and interaction with each other, the range of normal variation and the environmental risk factors.
We compare our cases of individuals with our control individual genomes and identify the variations, shared varients which are not in the control are checked and from this we can determine the genes and mechanism of the disease.
What does genetic determinism refer to?
In polygenic diseases having a disease related variation does not mean you will get the disease, theses diseases come about through a combination of variants and the environment and different sufferers may have different disease mechanisms, showing that most genetic disorders are probabilistic and not deterministic.
