Chapter 15: DNA damage, repair and mutation

Question 1

What is a chromosomal mutations, insertional mutation and a point mutation? (TYPES OF MUTATIONS)

Answer 1

Chromosomal mutations: gain or loss of all or part of a chromosome
Insertional mutations: insertion of large regions of DNA, e.g. transposable elements
Point mutations: changes in a single nucleotide or addition/deletion of one or more nucleotides

Question 2

What is tautomerization?

Answer 2

The spontaneous isomerization of a nitrogen base from its normal keto form to an alternative hydrogen-bonding enol (or imino) form.

Question 3

What is ionization?

Answer 3

The process by which an atom in DNA acquires a negative or positive charge.

Question 4

What type of error in DNA replication does tautomerization and ionization create?

Answer 4

Mismatch of base pair forms: leading to a base substitution that may be either a transition or a transversion.

Question 5

What is the difference between transition and transversion of base pairs?

Answer 5

Transitions are interchanges of two-ring purines (A G), or of one-ring pyrimidines (C T): they therefore involve bases of similar shape. Transversions are interchanges of purine for pyrimidine bases, which therefore involve exchange of one-ring & two-ring structures. (A C and (G T)

Question 6

What are the types of spontaneous mutations?

Answer 6

Error in DNA recplication
1. tautomerization
2. ionization
3. Indels
Chemical change to DNA 🧬 Cellular environment:
1. Depurination
2. Deamination
3. Oxidatie damage

Question 7

What is the difference between synonymous and neutral mutation?

Answer 7

Synonymous: (GENE LEVEL) also called silent mutation mutations change the sequence of a codon but do not change the encoded amino acid because of degeneracy of the genetic code
Neutral: (ORGANISMAL LEVEL) broad category (includes synonymous) , neutral mutations are changes to DNA sequence that do not affect the ability of an organism to survive and reproduce.

Question 8

What is the difference between missense (conservative vs. non-conservative) and nonsense mutation?

Answer 8

missense: change the sequence of a codon to one that codes for a different amino acid. Conservative mutations: mutant codon encodes a chemically similar amino acid
Non-conservative mutations: mutant codon encodes a chemically different amino acid

nonsense: often result from the change of a single base that changes an amino acid-coding codon into a stop codon. Effect depends on distance from the 3′ end of the ORF
Can trigger nonsense-mediated decay (NMD), which completely degrades the mRNA

Question 9

What is a trinucleotide-repeat disease and what is the cause?

Answer 9

A disease caused by a kind of mutation where the number of three-nucleotide repeats is increased over a stable threshold.
Example: Fragile X syndrome results from an increase in the number of CGG repeats in the 5′ UTR of the FMR1 (fragile X mental retardation) gene. Normal individuals have fewer than 45 CGG repeats, but Fragile X syndrome occurs when the number of CGG repeats expands to at least 200.

Question 10

Where do trinucleotide-repeats take place on DNA and how can affect the genome?

Answer 10

Expansion could occur in the 5′ UTR, exons, introns, or the 3′ UTR. Expansion in
the 5′ or 3′ UTR could affect translation or stability of the mRNA, expansion in exons
could affect the sequence of the encoded protein, and expansion in introns could affect
splicing of the pre-mRNA.

Question 11

With regards to trinucleotide-repeats what does it mean for ancestors to carry premutations?

Answer 11

For this reason, these ancestors are said to carry premutations. The repeats in these premutation alleles are not sufficient to cause the disease phenotype, but they are much more prone to expansion than normal alleles, and so they lead to even greater expansion in their offspring. They have a number of repeats in between the normal and critical range.

Question 12

What are the 2 types of point mutations?

Answer 12

Base substitution: translation vs. transversion
Base deletion or insertion

Question 13

What is the cause and consequence of a frameshift mutation?

Answer 13

Caused by an insertion or deletion
Change the translation reading frame for all codons downstream of the mutation

Question 14

What types of effects on gene function can point mutations have ?

Answer 14

Wild type function (mutation has no effect on gene function)

Loss-of-function (gene function is partially or completely lost)
* HYPOMORPHIC: Weak/partial – protein retains some function or is produced at a reduced level
* NULL: Protein is non-functional or not produced

Gain-of-function (gene function is increased or novel)
* HYPERMORPHIC: Protein is hyperactive
* ECTOPIC: More protein made or made in wrong time/place
* NEOMORPHIC: Protein gains new function

Question 15

Describe the loss of function and gain of function mutation of Ras?

Answer 15

Gain of function: locks Ras into GTP bound form, excess cell division and proliferation = tumour
Loss of function: Mutant form is always off, stays bound to GDP or does not complete its normal function - even in the presence of GDP

Question 16

How can point mutations in non-coding regions affect gene function?

Answer 16

Mutations in non-coding regions can disrupt:
Transcription
Splicing (new cryptic splice site created or normal splice site destroyed)
Stability
Translation
Function

Question 17

Describe the BAP1 mutation (synonymous mutation that causes error in splice site)?

Answer 17

Synonymous mutation: both make glycine
BUT affect splicing: single point mutation affect splice donor site and skips the exon = frameshift and early stop codon

Question 18

When does it matter that these forms can exist or not (tautomeric or ionized)? i.e. when do they have an impact?

Answer 18

During DNA replication, the arrangement of bonds might change during interphase when DNA is not being replicated, but that doesn’t really matter. What really matters is if that form occurs when the polymerase is coming along and copying the DNA,
The base that’s being copied happens to be in an alternate form. At the moment that the DNA polymerase is adding the new base, the DNA polymerase is going to make a mistake.

Question 19

How do spontaneous mutations cause INDELS?

Answer 19

Strand slippage during DNA replication leads to indels. Whether slippage generates an insertion or deletion depends on which strand loops out.