What is meant by a duplication mutation
a piece of DNA that is abnormally copied one or more times
What is meant by a frameshift mutation
addition or loss of DNA bases changes a gene’s reading frame (insertions, deletions and duplications can all be frameshift mutations)
What is meant by a repeat expansion
: nucleotides repeats are short DNA sequences that are repeated multiple times in a row e.g trinucleotide repeat. These are often repeat expansions i.e a mutation increases the number of times that short DNA sequence is repeated e.g Huntington’s Disease
What can point mutations cause
o Point mutations (change in one DNA base) can cause:
Missense: substitution of one amino acid for another
Nonsense: the formation of a stop codon
Silent: altered codon corresponds to the same amino acid
Describe post-translational modification
the new protein requires modification to give it a three-dimensional structure and to prepare it for its final role in the body. This occurs primarily in the endoplasmic reticulum and golgi apparatus.
Why are mutations in coding regions important
- Mutations in coding regions are more important – they may result in the production of a defective protein.
Describe the inheritability of sickle cell disease
This is dependent on the genes of their mother. As the sickle cell gene is recessive, both copies must be inherited in order to have sickle cell disease.
If their mother is sickle cell trait, their risk of inheriting both mutant copies and being affected is 50%.
Assuming their mother does not have any sickle genes (i.e. not sickle cell trait), there is no possibility of being affected.
Compare deletion and stop codon mutations
Both result in a loss of function of the protein (a chloride ion transporter)
Describe cystic fibrosis
The deletion of the 3 nucleotides in the first example is the F508 mutation. It is the most common mutation causing one of the most common monogenic conditions in the Caucasian population. This condition is characterised by pancreatic insufficiency needing enzyme replacement, thick mucous pulmonary secretions causing bronchiectasis, failure to thrive in children with most patients requiring lung transplantation.
Describe Tay-Sachs disease
The baby is born. He developed normal motor skills in the first few months of life but at 5 months old became progressively weaker, hypotonic, hyperreflexic. Seizures were also observed and the infant was not responsive to visual stimuli. MRI head showed macrocephaly.
‘a 4bp insertion in exon 10’
3. Autosomal recessive
Describe Marfan syndrome
- Generally loss of function mutations are recessive meaning some of the protein can be made – but in Marfan they are dominant. No protein can be made meaning this is a ‘null mutation’.
‘mutation in the Fibrillin 1 gene on chromosome 15)’
A 30-year old man comes has been referred by his GP due to an ‘early diastolic murmur’ that was picked up on a routine examination. His GP noted the patient to be particularly tall, had a wide arm-span and suspected that the patient may have an ‘autosomal dominant’ condition and helpfully referred him also to the Genetics Service.
Describe Huntington’s disease
- Trinucleotide repeat expansion
- Autosomal dominant
- Anticipation – a longer repeat may result in earlier onset of symptoms
Describe T1DM
- Type 1 diabetes mellitus (unusual to present at 23-years of age) or maybe maturity onset diabetes of the young (MODY).
- Autosomal dominant
- Type 1 MODY
Describe type 1 mody
A report showed an ‘insertion of a single nucleotide causing a frameshift mutation in the Hepatocyte Nuclear Factor-1 gene (HNF-1)’.
What are HNFs
HNFs are transcription factors that play an important role in the development and function of -cells of the pancreas. They control appropriate expression of -cell genes required for adequate -cell functioning. Mutations in HNF-1A result in abnormal insulin secretion. Patients have increased insulin sensitivity and have marked sensitivity to the hypoglycaemic effects of sulphonylureas. In one study, 70% of patients previously treated with insulin were successfully coverted to sulphonylureas.
What are the pros of GWAS
- Paving the way for the future of ‘genomic medicine’ where we may be able to genetically re-programme those with a disease back to health
- GWAS is a non-candidate-driven approach meaning it can pick up a wider selection of loci associated with a disease and not just those that are known to cause a disease. Contrast this to contrast to gene-specific candidate-driven studies which rely on previous knowledge in choosing a particular gene to study.
What are the cons of GWAS
- Very expensive to sequence the whole genome, so most GWAS studies focus on a small area of the genome known as single-nucleotide polymorphisms (SNPs) – we may be missing key areas of the genome without recognizing it.
- Disease risk is not solely related to genetic susceptibility. The impact of diet, the environment, social status is not accounted for in GWAS studies.
- May have negative effects on attaining health insurance or jobs in the future i.e if a company identifies an individual as possessing a number of ‘high risk’ mutations they may not offer them cover or employment.
- As yet, the therapeutic benefits of knowledge gained in GWAS studies is unclear. We cannot yet re-programme cells.
- Effect sizes are very small. How significant are these findings in reality?
What is meant by the common-disease-common-variant hypothesis
- Assumption that for all common diseases there must be a common genetic basis i.e many people will have the disease alleles
- This hypothesis is the basis for GWAS studies
- May be used to predict risk of certain diseases in sub-populations and then used to target these groups with preventative measures or increased screening
