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MTM > L14 - Mechanisms and effects of mutations > Flashcards

L14 - Mechanisms and effects of mutations Flashcards

1
Q

What are microsatellites?

A

Tandem repeats of 2-6 base pairs

- <100 bp in total length

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2
Q

What are minisatellites?

A

Variable number tandem repeats of 10-60 base pairs

- Can span several kb

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3
Q

How can variation in the genome occur?

A
  • Alterations in the sequence of bases in a specific section of DNA
  • Single nucleotide polymorphisms
  • Small deletions or duplications (few bases)
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4
Q

What can variation in the genome lead to?

A

Altered effects of a protein or control of genes

  • Normal human variation (i.e. eye colour)
  • Differences in response to medication (effect of antidepressants)
  • Influence likelihood of disease (diabetes)
  • Directly result in a genetic condition (sickle cell disease)
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5
Q

How can a genome variant be classified?

A

Classified by size, frequency and clinical effects

  1. Large - small
  2. Common - rare
  3. Non-pathogenic - pathogenic
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6
Q

What is the definition of a mutation?

A

An alteration or change in the genetic material

  • Harmful in clinical use
  • From exposure to mutagenic agents but more arise spontaneously through errors in DNA replication/ repair
  • More likely to be recognised if effects are detrimental
  • Alters gene function and phenotype
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7
Q

What is polymorphism?

A
  • Non-harmful
  • Sequence variant is in non-functional DNA
  • Sequence variant is within gene but does not change aa
  • Sequence variant changes aa but does not alter protein function
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8
Q

What is a single nucleotide polymorphism?

A
  • A change in a single base at a particular position
  • Occur throughout the genome
  • Most common type of genome variation
  • The base change has to be a frequency of >1%
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9
Q

How can the genome be examined?

A
  1. Bases
    - Sequencing
    - Microarray analysis
  2. Large blocks of DNA
    - Microarray analysis
    - Fluorescence in situ hybridisation (FISH)
  3. Chromosomal
    - Light microscopy
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10
Q

Describe the process of DNA sequencing

A
  1. Amplify v small amounts of target DNA (usually by PCR)
  2. DNA is used as a template to generate a set of fragments that differ in length from each other by a single base
  3. The fragments are then separated by size, and the bases at the end are identified, recreating the original sequence of the DNA
    (Dideoxy or chain termination method)
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11
Q

Why sequence DNA?

A
  1. Sequencing determines the exact POSITION of the mutation within the gene
  2. Determines the TYPE of the mutation (including single base changes)
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12
Q

What is the Sanger sequencing method?

A

A method of DNA sequencing based on the selective incorporation of chain-terminating dideoxynucleotides by DNA polymerase during in vitro DNA replication `

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13
Q

When do mutations occur?

A
  1. Cell division

2. From intrinsic and extrinsic attacks on DNA

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14
Q

What are the different endogenous mechanisms that can cause DNA damage?

A
  1. Depurination
  2. Deamination
  3. Reactive oxygen
  4. Methylation of ctyosines
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15
Q

What is depurination?

A

Spontaneous fission of link between purine base and sugar

  • Causes loss of adenine or guanine from helix
  • Deletion of base or incorrect nucleotide in new strand
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16
Q

What is deamination?

A

Cytosine deaminates into uracil

- Causing substitution of an A in new strand

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17
Q

What is reactive oxygen endogenous mechanism?

A

Attack purine/ pyrimidine rings

18
Q

What is methylation of cytosines?

A

Methylation of cytosines at CpG dinucleotides spontaneous deamination of 5-methyl-cytosine to thymine

19
Q

What are the different exogenous (extracellular agents) mechanisms that damage DNA?

A
  1. UV light
  2. Environmental chemicals
  3. Ionising radiation
20
Q

How dose UV light damage DNA?

A

Cross-linking of adjacent thymines on a DNA strand to form a stable dimer

21
Q

How do environmental chemicals damage DNA?

A

Interpolate into DNA or cause DNA breaks or chromosome aneuploidy

22
Q

What is aneuploidy?

A

The presence of an abnormal number of chromosomes in a cell

23
Q

How does ionising radiation damage DNA?

A

Causes breaks in DNA

24
Q

How can DNA replication errors be corrected?

A
  1. Proof reading from DNA rep machinery
    - DNA polymerase adds base, checks it, excises it if wrong and move on
  2. DNA mismatch repair
    - Backup system which corrects 99% of residual errors from replication machinery
25
Q

What happens if there is a mutation in the mismatch repair gene?

A

Mutations in the mismatch repair genes lead to accumulation of somatic mutations and so predispose to cancers

26
Q

How can endogenous damage to DNA due to thymine dimers and chemical adducts be corrects?

A
  • Mismatch identified

- Usually repaired by excision repair mechanisms (1300 genes involved)

27
Q

How can damage to DNA due to ionising radiation and reactive oxygen species be corrected?

A

DNA double strand breaks repaired either by:

  • The accurate method of using a sister DNA molc (homologous recomb)
  • End-joining broken ends (error prone - resulting in deletion of nucleotides at repair site)
28
Q

What are the different types of mutations possible?

A
  1. Inversion
  2. Insertion
  3. Deletion
  4. Substitution
  5. Translocation
  6. Non-disjunction
29
Q

What are the different effects of mutations possible?

A
  1. Missense
  2. Nonsense
  3. Frameshift
  4. Silent
  5. Beneficial
  6. Neutral
30
Q

What is a nonsense mutation?

A

The triplet for an aa is replaced with a triplet which is a STOP codon

31
Q

What is a missense mutation?

A

The triplet for an aa is replaced with a triplet for a different aa –> ppc different 1o structure which will alter the 2o, 3o and 4o structures
- Changes to a codon for another aa

32
Q

What is a silent mutation?

A

The triplet for an aa is replaced with a triplet for the same aa

33
Q

What is a frameshift mutation?

A

A base within the triplet for an aa is deleted/ inserted

34
Q

What is a splice-site mutation?

A

A change that results in altered RNA sequence

35
Q

What can mutations at splice sites cause?

A

Mutations at splice sites can cause exon skipping (or incorporation of intron sequence into mRNA)

36
Q

What are copy number variants?

A

[The number of copies of a particular gene varies between individuals]
Small arrays of triplet repeats in coding sequences of genes are prone to expand in number and disrupt the function of the gene

37
Q

What could be the effects of copy number variants?

A
  1. Short tandem repeats can mispair and cause pathogenic deletions and insertions which cause a frameshift
  2. Expansion of the number of short tandem repeats within or in the vicinity of a gene can affect gene expression
  3. Repeats can predispose to large deletions and duplications
38
Q

What is the repeat codon present in myotonic-dystrophy?

A

CTG

39
Q

What is the repeat codon present in Huntingtons disease?

A

CAG (glutamine)

40
Q

How do larger deletions and insertions of copy number variants occur?

A
  • Usually caused by unequal crossing-over between repeat sequences
  • May affect a gene, several genes or section of a chromosome
  • Clinical effects depend on genes involved and gene dosage
    1. Misalignment of large blocks of repeats with v similar sequence
    2. Unequal crossing-over between chromatids
    3. Results in deletion of segment of duplication of segment
41
Q

What are the different possible variations/ mutations in genes?

A
  1. Mendelian inheritance
    - Single gene
  2. Copy number variation
    - Chromosomal segment (or whole chromosome) and so affect thousands of genes
  3. Multifactorial inheritance
    - Several variants of genes acting with environmental influences

MTM (33 decks)

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