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1PATH3305 Medical Genetics > Lectures 3 and 4: Mechanisims of Mutation 1 and 2 > Flashcards

Lectures 3 and 4: Mechanisims of Mutation 1 and 2 Flashcards

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1
Q

What is Human Genetic Variation?

A

Variation in structure or sequence of the human genome

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2
Q

Human Genetic Variation AFFECTS WHO?

A
  • Can be both within and among populations

1 – Inter-individual (intra-individual)

2 – Inter-population

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3
Q
  • Multiple mechanisms contributing to Human genetic Variation = 6
A

1- Meiotic recombination

2 – DNA replication and repair

3 – Population effects
…..4 * Random genetic drift
…..5 * Selection (adaptive advantage)
…..6* Migration

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4
Q

reference genome ….

A

A reference genome (also known as a reference assembly) is a digital nucleic acid sequence database, assembled by scientists as a representative example of the set of genes in one idealized individual organism of a species.

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5
Q

Types of Variation…

STRUCTURAL VS SEQUENCE LEVEL = 6

A
  • Structural (>1000bp)
    1 – Copy number (deletions & duplications)
    2 – Positional (insertions, translocations)
    3 – Orientational (inversions)
  • Sequence level (<1000bp)
    4 – Single base substitutions
    5 – Small insertions/deletions/duplications
    6 – Repetitive sequence
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6
Q

Causes of Sequence Variation

A

1 * Homologous DNA recombination during meiosis (allelic and non-allelic)

2 * Retrotransposition

3 * Spontaneous chemical change

4 * Damage due to environmental factors
– Ionising radiation,
– UV radiation
– Chemical mutagens
– Infectious agents (viruses)

5 * Errors of DNA replication and repair
– Proof-reading errors
– Replication slippage
– Replications fork-stalling

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7
Q

Causes of Sequence Variation:

DAMAGE DUE TO ENVIRONMENTAL FACTORS = 4

A

1 – Ionising radiation,

2 – UV radiation

3 – Chemical mutagens

4 – Infectious agents (viruses)

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8
Q

Causes of Sequence Variation:

Errors of DNA replication and repair: 3

A

1 – Proof-reading errors

2 – Replication slippage

3 – Replications fork-stalling

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9
Q

Chemical Stability of DNA: 6

A

1 * DNA is subject to hydrolysis, oxidation, and non-ezymatic methylation ‘in vivo’

2 * Many of these changes interfere with;
…3 – regular base-pairing and/or
…4 – the physical structure of the DNA

5 * The chemical stability of DNA is limited and does play a role in mutagenesis

6 * DNA repair mechanisms counter balance the ongoing change to the genome

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10
Q

Nucleotides known to be modified by;

A
  1. OXIDATIVE DAMAGE
  2. HYDROLYTIC ATTACK
  3. UNCONTROLLED METHYLATION

LOOK AT DIAGRAM IN SLIDE 7

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11
Q

Tautomers: Spontaneous Change

WHAT IS IT?

A

Tautomers are structural isomers of that readily interconvert with the relocation of a proton.

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12
Q

Tautomers: STABLE DNA …TRANSITIONS OCCUR… UNSTABLE TAUTOMERS …

A
  1. Stable DNA bases exist in:
    * Keto form (T and G)
    * Amino form (A and C)

2 * Transitions occur to unstable forms:
* Enol (T and G)
* Imino (A and C)

3 * Unstable tautomers can form unstable pairs:
* T:G
* A:C

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13
Q

PURINES …PYRIMIDINES …STABLE TO UNSTABLE

A

LOOK AT DIAGRAM SLIDE 8

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14
Q

Tautomeric shifts allow

A

Tautomeric shifts allow for irregular base pairing

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15
Q

Tautomeric shifts allow for irregular base pairing

WHAT ARE THEY?

A
  1. Standard base-pairing arrangements
  2. Anomalous base arrangements
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16
Q

Tautomeric shifts allow for irregular base pairing

A

diagram ..understand …on slide 9

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17
Q

Replication embeds change

A
  • the change caused by the tautomeric shift is embedded by the replication machinery
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18
Q

Replication embeds change = 5

A

UNDERSTAND DIAGRAM ON slide 10

  1. Parental DNA
    DNA REPLICATION
  2. …rare enol tautomeric form of guanine (G*)
  3. First-generation progeny (x2)
  4. DNA Replication
  5. SECOND GENERATION PROGENY
    - Wild-type
    - MUTANT
    - Wild-type
    -Wild Type
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19
Q

Mutagens

A
  • agents that cause an increase in the rate of mutation above a spontaneous background (X-rays, UV, chemicals, viruses etc)
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20
Q

MUTAGENS:

  • Mechanisms Include = 8
A

1 – Deamination (spontaneous and induced)

2 – Alkylation

3 – Depurination

4 – Hydroxylation/Oxidation

5 – Base analogs

6 – Intercalating agents

7 – Ultraviolet radiation

8 – Ionising radiation

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21
Q

MUTAGENS = RADIATION EXAMPLES

A
  1. UV (from sunlight)
  2. X-rays (medical uses)
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22
Q

MUTAGENS ..CHEMICAL examples …3

A
  1. Carcinogens (e.g cigarettes)
  2. Processed foods and preservatives
  3. Cosmetics and cleaning products
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23
Q

MUTAGENS …INFECTIOUS AGENTS EXAMPLES = 2

A
  1. Viruses (e.g. HPV)
  2. Bacteria (e.g. Helicobacter)
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24
Q

A deaminating agents…

A

is a role played by a chemical agent which exhibits the capability of causing the loss of an amine functional group on another molecular entity (e.g. DNA or protein).

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25
Q

Mutagens: Deaminating Agents

  • Deamination can occur by various means:
A

– Spontaneous

– Induced

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26
Q

Mutagens: Deaminating Agents…..

  • Methyl-Cytosine becomes T
A
  • Methyl-Cytosine becomes T

– Spontaneous

– C:G becomes T:A

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27
Q

Mutagens: Deaminating Agents…

  • Effects on Methylation?
A

HNO2 is a potent deaminator

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28
Q

Mutagens: Deaminating Agents

A

LOOK AT SLIDE 12

UNDERSTAND A AND B PROCESSES

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29
Q

Induced Deamination = 3

A

1 * Nitrous Acid (HNO2) is a potent driver of oxidative deamination

2 * Hypoxanthine similar to A (imine)
– ‘A:T pair becomes G:C’

3 * Xanthine similar to G (enol)
– ‘G:C pair becomes A:T’

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30
Q

Induced Deamination DIAGRAM

A

UNDERSTAND DIAGRAM …SLIDE 13

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31
Q

Understanding Deamination of 5(^m)C in CpG Islands = 7

A

1 * Predicted that ~4% of the genome should be CpG – reality : 0.8%

2 * Most CpG islands <1800bp long, 60-70% GC (genome average 45-50%)

3 * CpG islands associated with the 5’ end of 40-50% of known genes

4 * Up to 10% of CpG are methylated on the C nucleotide

5 * Methylation can result in repression of expression (tissue-specific methylation
in restricted genes for example)

6* De-amination of the C results in a T nucleotide (so CpG becomes TpG)

7 * Effects of changes variable (from nothing to chronic hemolytic anemia)

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32
Q

Deamination of 5mC in CpG Islands DIAGRAM

A

UNDERSTAND SLIDE 14

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33
Q

Hydroxylamine

A
  • hydroxylates the amino group of cytosine and can lead to G:C to A:T transitions
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34
Q

Hydroxylamine DIAGRAM

A

UNDERSTAND SLIDE 15 DIAGRAM

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35
Q

Mutagens: Alkylating Agents = 4

A

1 * Chemicals that donate alkyl groups to other molecules.

2 * Cause transitions, transversions, frameshifts, and chromosome aberrations

3 * Alkylation of bases can change base-pairing properties (eg GC to AT)

4 * Alkylation can also activate errors during repair processes

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35
Q

Alkylating Agents EQUATION

A

C(n)H(2n+1)

36
Q

Alkylating agents …

Di-(2-chloroethyl) sulfide (mustard gas)

Ethyl methane sulfonate (EMS)

Ethyl ethane sulfonate (EES)

A

EQUATIONS …SLIDE 16

37
Q

Depurination:

  • If not repaired before replicated;
A

Hydrolysis reactions remove purine (A and G) rings by cleaving the N-glycosidic bond that holds them to the sugar

  • If not repaired before replicated;
    1 – any base may be added (commonly an A)

2 – position may be (skipped)deleted

38
Q

DEPURINATION DIAGRAM…

A

DIAGRAM ON SLIDE 17

39
Q

Mutagens: Intercalating Agent: 5

A

1 * Thin, plate-like hydrophobic molecules insert themselves between adjacent base pairs

2 * Generally (+) charged molecules

3 * Mutagenic intercalating agents cause insertions during DNA replication.

4 * Loss of intercalating agent can result in deletion.

5 * Examples:
–Proflavin
–ethidium bromide

40
Q

Mutagens: Intercalating Agent: MUTATION BY ADDITION = 4

A
  1. Template DNA strand
    - Molecule of intercalating agent
  2. NEW DNA STRAND
    - A randomly chosen base is inserted opposite intercalating agent; here the base is G
  3. SUBSEQUENT REPLICATION OF NEW STRAND
  4. RESULT: FRAMESHIFT MUTATION DUE TO INSERTION OF OBE BASE PAIR (CG)
41
Q

Mutagens: Intercalating Agent: MUTATION BY DELETION = 3

A
  1. Template DNA strand
    - Molecule of intercalating agent
  2. NEW DNA STRAND
    - A randomly chosen base is inserted opposite intercalating agent;
  3. Replication of new strand after intercalating agent lost
42
Q

Mutagens: Intercalating Agent DIAGRAMS….

A

UNDERSTAND SLIDE 18

43
Q

Mutagens: Base Analogues = 5

A

1 * Similar structures to regular DNA bases

2 * When incorporated into DNA, they increase frequency of
mis-pairing

……..3
– 2-aminopurine : adenine analogue which pairs with cytosine

……4
– 5-bromouracil : thymine analogue pairs with guanine

44
Q

Mutagens: Base Analogues DIAGRAM

A

UNDERSTAND DIAGRAM ON SLIDE 19

45
Q

Mutagens: UV Irradiation: 3

A

1 * UV (254-260 nm) causes purines and pyrimidines to form abnormal dimer bonds and bulges in the DNA strands

2 * Cross-linking of adjacent thymine dimer formation most common
– Block DNA replication and activates DNA repair mechanisms

3.* Hydrolysis of cytosine to a hydrate may lead to mis pairing during replication

46
Q

Mutagens: UV Irradiation DIAGRAM

A

UNDERSTAND DIAGRAMS ON SLIDE 20

47
Q

Mutagens: Ionising Radiation = 2

A

1 * X-rays, gamma rays, alpha and beta particles and neutrons

2 * Can produce double strand breaks, abasic sites and single strand breaks

48
Q

Mutagens: Ionising Radiation DIAGRAM

A

UNDERSTAND DIAGRAMS ON SLIDE 21

49
Q

DNA Replication

  • DNA polymerase makes errors = 3
A

1 * DNA polymerase makes errors

2 – Approximately 1/10,000-100,000 nucleotides (10^4 – 10^5)

3 – After repair, approximately 1 in 1 billion (10^9) nucleotides

50
Q

DNA Replication

  • Two types of abnormalities need repair: 2
A
  1. Base mismatches
  2. Damage to the structure of the DNA itself, (eg. breaks in the chromosome or pyrimidine dimers)
51
Q

DNA Replication…. mismatch/damage ..HOW IS IT CORRECTED?

A

Several different types of repair system, and most mismatch/damage can be corrected by more than one system

52
Q

Direct DNA Repair = 2

A
  1. SINGLE STRAND BREAKS (ssDNA)
  2. ENZYMATIC REPAIR
53
Q

Direct DNA Repair

  • Single strand breaks (ssDNA) = 3
A
  1. aka DNA “Nicks”
  2. DNA Ligase can rejoin backbone
  3. Requires functional 5’ phosphate and 3’-hydroxyl groups
54
Q

Direct DNA Repair

Enzymatic Repair: 2

A

Highly specific removal of chemical groups

– e.g. removal of Alkyl group by O6-methylguanine-DNA methyltransferase

55
Q

Direct DNA Repair DIAGRAMS

A

LOOK AND UNDERSTAND SLIDE 24

DIAGRAMS ON BOTH DIRECT DNA REPAIRS

56
Q

DNA Repair: Base Excision Repair (BER)…WHAT IS THE PROCESS?

A

1 - base specific DNA glycosalase remove altered base

2 - Now facing an abasic scenario (i.e. no base)

3 - AP endonuclease removes the sugar back bone

4 - DNA polymerase replaces the missing nucleotide

5 - DNA ligase seals the SSDNA break

57
Q

DNA Repair: Base Excision Repair (BER) DIAGRAM

A

UNDERSTAND THE DIAGRAM AND THE PROCESS ON SLIDE 25

58
Q

DNA Repair: Nucleotide Excision Repair (NER) = 4

A
  1. detects and repairs distortions in the DNA helix

2 - Excision nuclease removes nucleotides in and around the distortion

3 - DNA polymerase replaces the missing nucleotides

4 - DNA ligase seals the ssDNA break

59
Q

DNA Repair: Nucleotide Excision Repair (NER) DIAGRAM

A

UNDERSTAND THE DIAGRAM AND THE PROCESS ON SLIDE 26

60
Q

DNA Repair: Mismatch Repair (MMR) = 5

A

1 - Corrects post-replicative base-pair mismatches and insertion/deletion loops

2 - Complex scans DNA for SSB = new strand

3 - Exonuclease removes up to 1000bp of new strand

4 - DNA polymerase replaces the missing nucleotides

5 - DNA ligase seals the ssDNA break

61
Q

DNA Repair: Mismatch Repair (MMR) DIAGRAM

A

UNDERSTAND THE DIAGRAM AND THE PROCESS ON SLIDE 27

62
Q

DNA Replication: Slippage

A

1 * Repeating regions effected, mostly microsatellites

2 * DNA polymerase “slips off” and misaligns with a nearby repeat

3 * Misalignment creates a distortion in the helix which should be detected and repaired by the mismatch repair system

4 * Replication before repair will produce a new allele (expansion more common)

63
Q

DNA Replication: Slippage DIAGRAM

A

UNDERSTAND THE DIAGRAM AND THE PROCESS ON SLIDE 28

64
Q

DNA Repair: Homologous Recombination (HR) = 6

A

1 * ~10 DNA double strand breaks (DSB) per day per cell

2 * Due to radiation, ROS,
broken/stalled replication forks

3 * HR can repair DSBs
….4 * Rare
….5 * High fidelity but not error-free!

6 * Mutations in HR associated genes can be pathogenic

65
Q

DNA Repair: Homologous Recombination (HR) DIAGRAM

A

UNDERSTAND THE DIAGRAM AND THE PROCESS ON SLIDE 29

66
Q

DNA Repair: Non-Homologous End-Joining (NHEJ) = 4

A

1 * Double strand break (DSB) repair

2 * Multiple rounds of resection and addition possible

3 * The process is error-prone around the repair junction

4 * NHEJ can also repair DSB without loss/change

67
Q

DNA Repair: Non-Homologous End-Joining (NHEJ) DIAGRAM

A

UNDERSTAND THE DIAGRAM AND THE PROCESS ON SLIDE 30

68
Q

LIST THE WAYS OF DNA REPAIR = 6

A

1.Non-Homologous End-Joining (NHEJ)

2.Homologous Recombination (HR)

  1. Slippage

4.Mismatch Repair (MMR)

  1. Nucleotide Excision Repair (NER)
  2. Base Excision Repair (BER)
69
Q

DNA Repair = 3

GENERALLY SPEAKING

A

1 * Not every change is repaired before it is replicated

2 * Not every detected change is successfully repaired

3 * The repair genes themselves can be mutated, leading to pathology

70
Q

Type of DNA repair = Base excision repair (BER)

…Mechanism..Genes..Disorders..

A

Base excision repair (BER)

  • Removal of abnormal bases
  • MYH
  • Colorectal cancer
71
Q

Type of DNA repair = Nucleotide excision repair (NER)

…Mechanism..Genes..Disorders..

A

Nucleotide excision repair (NER)

  • Removal of thymine dimers and large chemical adducts
  • XP genes
  • Xeroderma pigmentosum
72
Q

Type of DNA repair = Post-replication repair

…Mechanism..Genes..Disorders..

A

Post-replication repair

  • removal of double-strand breaks by homologous recombination or non-homologous end-joining
  • NBS, BLM, BRCA1/2
  • Nijmegen breakage syndrome
  • bloom syndrome
  • breast cancer
73
Q

Type of DNA repair = MISMATCH REPAIR (MMR)

…Mechanism..Genes..Disorders..

A

MISMATCH REPAIR (MMR)

  • Corrects mismatched bases caused by mistakes in DNA replication
  • MSH and MLH genes
  • Colorectal cancer (HNPCC)
74
Q

HNPCC

A

hereditary non-polyposis colorectal cancer

75
Q

Classifying mutations..

ORIGIN:

SPONTANEOUS AND INDUCED

A

SPONTANEOUS: Occurs in absence of known mutagen

INDUCED: occurs in presence of known mutagen

76
Q

Classifying mutations..

CELL TYPE:
SOMATIC VS GERMLINE

A

SOMATIC - occurs in non-reproductive cells

GERMLINE: occurs in reproductive cells

77
Q

Classifying Mutations… EXPRESSION

CONDITIONAL VS UNCONDITIONAL

A

CONDITIONAL: Expressed only under restrictive conditions (such as high temperature)

UNCONDITIONAL : expressed under permissive conditions as well as restrictive conditions

78
Q

Classifying Mutations…
EFFECT ON FUNCTION =4

A
  1. LOSS OF FUNCTION (KNOCKOUT, NULL) - eliminates normal function
  2. HYPOMORPHIC (LEAKY) - reduces normal function
  3. HYPERMORPHIC - increases normal function
  4. GAIN OF FUNCTION (ECTOPIC EXPRESSION): expressed ar incorrect time in or in appropriate cell types.
79
Q

Classifying Mutations…

MOLECULAR CHANGE = 5

A
  1. NUCLEOTIDE SUBSTITUTION = one base pair in duplex DNA replaced with a different base pair
  2. TRANSITION = pyrimidine (T OR C) to pyrimidine, or purine ( A or G) to purine
  3. TRANSVERSION: pyrimidine (T or C) to purine or purine (A or g) TO PYRIMIDINE
  4. INSERTION: One or more extra nucleotides present
  5. DELETION: One or more missing nucleotides
80
Q

Classifying Mutations… EFFECT ON TRANSLATION = 4

A
  1. SYNONYMOUS (SILENT) = no change in amino acid encoded
  2. MISSENSE (NONSYNONYMOUS) = chnage in amino acid encoded
  3. NONSENSE (TERMINATION) = Creates translational termination codon (UAA, UAG or UGA)
  4. FRAMESHIFT = Shifts triplet reading of codons out of correct phase
81
Q

Effects of mutations…

germline, somatic, transition, transversion

A

1 * Germline mutations
- Present in either (or both) the sperm and egg that made the individual, therefore present in every cell the individual has

2 * Somatic mutations
- Arise after fertilization, during cell replication/division/differentiation/migration, therefore only present in a subset of the individual’s cells

3 * Transition:
- purine-purine or pyrimidine-pyrimidine substitution

4 * Transversion:
- purine-pyrimidine substitution or vice versa

82
Q

Effects of mutations: DIAGRAM

A

LOOK AND UNDERSTAND DIAGRAM IN SLIDE 33

83
Q

Effects of mutations…TYPES OF MUTATIONS AND WHAT DO THEY DO…6

A

1 * Missense mutation:
- causes one amino acid to replace another

2 * Nonsense mutation:
- creates a STOP codon at the site of the mutation

3 * Neutral mutation:
- changes the amino acid content of the protein, but has no functional consequences

4 * Silent (synonymous) mutation:
- does not change the amino acid content of
the protein

5 * Frameshift mutation:
- A mutation that shifts the ribosome’s reading frame, by
inserting or deleting nucleotides in the mRNA

6 * Splice mutation
- A mutation that affects the pattern of RNA splicing, thereby changing the content of the mRNA

84
Q

Effects of mutations

..LOSS OF FUNCTION VS GAIN OF FUNCTION…2

A

1 * Loss-of-function mutations impair the function of the protein
– Multiple ways to do this (reduced expression, function removed)

2 * Gain-of-function mutations cause a protein to perform more of its function
– Over expression or expression at incorrect time/location

85
Q
  • Effects can vary and are often subtle but are dependent on CONTEXT; 7
A

1 * Junk DNA (often no effect)

2 * Promoter regions (level of mRNA)

3 * UTRs (tissue distribution, mRNA stability)

4 * Coding regions (Synonymous and non synonymous)

5 * Splice sites (altered splicing)

6 * Introns (splicing enhancers/silencers)

7 * Premature stop codons (truncated proteins)

86
Q

“Silent” mutations may not be all they appear….

A

“Silent” mutations may not be all they appear and may change the splicing of the mRNA (intronic mutations may also)

87
Q

How do mutations cause disease?

A

IMPORTANT TO LEARN THE DIAGRAM = SLIDE 36

1PATH3305 Medical Genetics (20 decks)

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