Mutations

Question 1

What is a mutation?

Answer 1

Heritable alteration (e.g. change in nucleotide sequence) in a gene or chromosome.

Question 2

What are the 2 types of mutation causes? Give examples of these.

Answer 2

1. Exogenous
   - ionising particles
   - free radicals (e.g. UV light, smoking, air pollution)
   - mutagenic chemicals and anti-cancer agents
2. Endogenous
   - DNA replication defects
   - transposable elements
   - free radicals (e.g. Mitochondrial metabolism, leukocyte inflammation)

Question 3

What are transposable elements?

Answer 3

• Ubiquitous specific supernumerary DNA sequences (>1 gene) always contained within another DNA molecule.
• Can transpose as a discrete unit to random sites in the genome - can insertionally activate target genes, causing mutation.

Question 4

Which genes are more susceptible to TE invasion?

Answer 4

Large genes, e.g. BRCA1/2 and breast cancer

Question 5

What are micromutations? Give examples of these.

Answer 5

Single nucleotide changes.

• deletion
• insertion
• substitution

Question 6

What are the 2 types of nucleotide substitution?

Answer 6

• Transition: change to the same base type (e.g. A to G, T to C).
• Transversion: change to a different base type (e.g. A/G to C/T).

Question 7

Give an example of a disease caused by a single base substitution.

Answer 7

• Sickle cell disease

- Missense mutation: substitution in codon 7 of HBB gene causing 6th aa change from Glu to Val.

Question 8

What kind of mutations can single nucleotide changes cause?

Answer 8

1. Mutations that do not have an effect:
   
   • silent/neutral - no aa change (synonymous)
2. Mutations that change gene products:
   
   • missense mutation - change in aa
3. Mutations that change the amount of gene product:
   
   • affect transcription/translation (e.g. Alter promoter activity, alter translation initiation at AUG, prevent mRNA splicing, reduce mRNA stability)
4. Mutations that change the polypeptide length:
   
   • frameshift mutation
   • stop codon mutation
   • nonsense mutation

Question 9

What is nonsense-mediated decay (NMD)?

Answer 9

A surveillance pathway that eliminates mRNA transcripts containing premature stop codons.

Question 10

Describe a disease caused by missense mutation?

Answer 10

• Thalassemia intermedia: particularly severe form of beta-thalassemia (no or extremely low levels of mutant beta-globin mRNA).
• Mutant transcript produces truncated beta chains - leads to clinical phenotype in heterozygote.

Question 11

Name different types of structural macro mutations.

Answer 11

1. Deletion
2. Duplication
3. Inversion
4. Substitution
5. Translocation

Question 12

Why might inversions/translocations not have a significant effect in somatic cells?

Answer 12

No genetic info loss

Question 13

Suggest a disease where gene translocation does have a large impact.

Answer 13

Certain type of leukaemia caused by a gene translocation between chromosome 9 and 22.

• no significant change for chromosome 9
• gene fusion on chromosome 22 - creates new type of protein continually expressed (normally regulated)

Question 14

Why are DNA transcription/translation errors more common than DNA replication errors?

Answer 14

RNA polymerases don’t proofread like DNA polymerases

Question 15

Why are the effects of transcrption/translation errors not usually significant?

Answer 15

1. Cell makes multiple copies of RNA so unlikely that same mistake will happen again in exactly the same place.
2. RNAs are quickly degraded - ‘bad’ copy of RNA will be quickly removed.
3. RNAs are not inherited molecules passed down from generation to generation - not as consequential as making genome change which is lasting and permanent.

Question 16

What is often the consequence of mtDNA mutation?

Answer 16

Defects in oxidative energy metabolism.

Question 17

Describe the characteristics of diseases caused by germ line mutations in mtDNA.

Answer 17

• Often involve multiple organ systems - effects most pronounced in organs/tissues requiring a lot of energy (e.g. Heart, brain & muscles).
• Symptoms:
  ~ muscle weakness/wasting
  ~ movement problems
  ~ diabetes
  ~ kidney failure
  ~ heart disease
  ~ dementia
  ~ hearing loss and vision abnormalities

Question 18

What is the pedigree pattern of mitochondrial disease?

Answer 18

Maternal line only

Question 19

Why do mtDNA mutations tend to build up over time? What is this progressive accumulation associated with?

Answer 19

• mtDNA has limited ability to repair itself.
• Associated with
  1. Some forms of cancer
  2. Increased risk of age-related disorders, e.g. Heart disease, Alzheimer’s, Parkinson’s
  3. Normal ageing process

Question 20

Why are spontaneous mutations more unlikely to cause autosomal recessive disorders (e.g. CF)?

Answer 20

• A spontaneous mutation of the same gene must occur on both chromosomes - very unlikely (<5 cases of spontaneous CF described).
• A spontaneous mutation commonly affects 1 gene producing a heterozygote - affected individual results from 2 heterozygote parents.

Question 21

How can errors in meiosis cause abnormal chromosomal numbers?

Answer 21

Non-disjunction of chromosomes

Question 22

How can errors in mitosis of germ-line cells cause chromosomal mutation?

Answer 22

Duplicate chromosomes don’t pair properly at metaphase plate - cause anaphase lag:
~ 1 cell lacks chromosome (usually fatal to this daughter cell)
~ 1 cell receives 2 copies of chromosome - increased gene expression:
1/ if gene slows growth, extra copy may be fatal to cell
2/ if gene promotes growth, cell may grow uncontrollably - cancer
3/ other effects will depend on nature of additional gene