MCBG Session 15 - Mutations and Molecular Diagnosis Flashcards
Briefly, state what a mutation is.
Mutation: a change in a DNA sequence
How do mutations arise?
Mutations can result from:
- DNA replication errors made during cell division (mitosis and meiosis)
- Exposure to ionizing radiation (a mutagen)
- Exposure to chemicals (chemical mutagens)
- Infection by viruses
Distinguish between a somatic mutation and a germ line mutation.
- Germ line (genetic or hereditary) mutations occur in the eggs or sperm, affect all cells in the body and can be passed on to offspring.
- A somatic mutation occurs in a body cell and is not passed on to offspring.
Outline the causes and consequences of RNA translation errors.
- The long-term effects on the organism whose cell has made a transcription/translation error will not be the as bad as if the mistake was in the genome itself
- The cell will be making multiple copies of this RNA, and it is unlikely that it will make the same mistake again in exactly the same place
- RNAs are quickly degraded, so the ‘bad’ copy of the RNA will be quickly removed
- RNAs are not inherited molecules passed down from generation to generation. Therefore, making an incorrect copy of an RNA molecule is not going to be as consequential as making a change in the genome, which is lasting and permanent.
Outline mitochondrial somatic mutations.
- Mitochondrial DNA is also prone to somatic mutations, which are not inherited
- Because mitochondrial DNA has a limited ability to repair itself when it is damaged, these mutations tend to build up over time
- A build-up of somatic mutations in mitochondrial DNA has been associated with some forms of cancer and an increased risk of age-related disorders such as heart disease, Alzheimer disease, and Parkinson disease
With reference of autosomal dominant and recessive disorders respectively, outline the possibility of spontaneous mutations.
- In the case of an autosomal dominant disorder (e.g achondroplasia), if a parent is not affected then an affected child must be a spontaneous mutation
- In the case of an autosomal recessive disorder (e.g cystic fibrosis), if it is a spontaneous mutation an affected individual will have suffered a spontaneous mutation of the same gene on both chromosomes very unlikely! (less than 5 cases of spontaneous cystic fibrosis have been described).
- A spontaneous mutation commonly affects one gene (1 in 25 caucasians for cystic fibrosis) producing a heterozygote. An affected child results from two heterozygote parents (1 in 4 children)
Classify germ line mutations with regards to macro and micro mutations.
- Gene
I. Substitution
II. Insertion
III. Deletion
- Chromosomal
I. Structural - deletion, duplication, inversion, translocation
II. Numerical - non-disjunction
Explain how mitosis can produce a chromosomal mutation.
- Errors in mitosis may occur during metaphase, when the chromosomes align at the metaphase plate
- If the duplicate chromosomes do not pair properly at the metaphase plate, the pair will not move properly to each pole during anaphase (anaphase lag).
- This type of error is normally fatal to the daughter cell lacking a copy of a chromosome
- Cells receiving two copies of a chromosome will have an increase in expression of the genes contained on the extra chromosome.
- If the genes function to slow growth, the extra copy may be fatal to the cell. However, if the genes promote growth, the cell may grow uncontrollably, leading to cancer.
- Other effects will depend on the nature of the additional gene
Outline the role of Primodial Germ Cells in oogenesis and spermatogenesis.
- Note that PGCs proliferate hugely through mitosis
- At birth in the female there are approx 1 million Primordial Germ Cells (PGCs) remaining
- At birth in the male there are approx 4 million PGCs remaining
- Once PGCs arrive in the foetal female gonad they differentiate into oogonia and undergo further mitosis.
- Once PGCs arrive in the male gonad they remain there until puberty.
The mutation rate in male gametes is approx. 5x higher than in female gametes. Explain why.
- The number of germline divisions in spermatogenesis vastly exceeds that in oogenesis.
- Spermatogonial germ cells are continually active in adult men and the male mutation rate increase with age (male fertility decreases with age and the miscarriage rate increases)
Why do male and female gametocyte mutations increase with age?
- Male – Spermatozoa are continually made. Older men’s spermatagonia have been exposed to mutagens/radiation for a longer time
- Female – Longer in meiosis arrest?
Hence the IVF embryo aneuploidy rate will overestimate the in vivo rate.
What do you think are the possible outcomes if a very early embryo was exposed to radiation (a mutagen)?
- Death/aborted
- Teratogenesis
- Cancer when born
What features would allow a germ cell mutations to be inheritable?
- It would not be lethal to the gamete
- It would not impair gamete function
- It would not be lethal at fertilisation
- It would allow the production of a viable adult with normal reproductive capacity
Compare and contrast the effect of recessive and dominant mutations.
- In general, recessive mutations cause loss of function and often affect biochemical pathways (not a rule!)
- In general, dominant mutations cause increased function and often cause structural abnormalities (not a rule!)
The fact that most recessive mutations affect biochemical pathways whereas dominant mutations causing structural abnormalities is an observation – but not a rule!
Account for the variation of effects between recessive and dominant mutations.
- A given mutation is much more likely to be deactivating or inactivating than introduce a new function because there are many ways to deactivate or inactivate a protein whereas it is much more difficult to introduce an activating mutation.
- Failure of one allele to produce a protein can be compensated for by the normal allele (if heterozygous).
- Overproduction by a single allele will not be ‘compensated for’ by the other normal allele if heterozygous and will therefore produce an effect – hence it will be dominant
Outline the causes and consequences of somatic mutations.
- Error in mitosis
- Can be genetic (DNA replication error) or less commonly chromosomal
- The affected cell will produce 2 affected cells and if the mutation is not lethal and does not affect mitosis and is not recognised as ‘foreign’ by the immune system then a clone will develop
- In general terms this clone may produce a benign or malignant tumour (a tumour means a swelling)
