Evolutionary and Population Genetics > Mutation > Flashcards

Mutation Flashcards

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1
Q

What is a mutation?

A

A stable, heritable alteration to the genetic material

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2
Q

What is a mutagen?

A

Any chemical capable of inducing heritable changes to the genetic material

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3
Q

What type of mutations are passed on?

A

Germline mutations

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4
Q

What is the background mutation rate caused by?

A

Spontaneous mutation

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5
Q

What is induced mutation?

A

Mutations caused by external agent or mutagen, such as radiation or noxious chemicals that increase mutation rate above background rate

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6
Q

What do somatic mutations have an impact on? 2

A
  1. Ageing
  2. Cancer (activation of oncogenes or inactivation of tumour supressor genes)
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7
Q

How many inherited defects are there in humans?

A

Over 3000

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8
Q

List 4 recessive diseases

A
  1. CF
  2. Thalassemia
  3. Tay Sachs disease
  4. Sickle cell Anemia
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9
Q

What happens in CF?

A

Breakdown in iron channels in the lung and pancrease lead to defects in functioning of the lung and excretion of enzymes by the pancrease

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10
Q

What does Thalassemia provide?

A

Malaria resistance

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11
Q

Where does the mutation for Albinism normally occur?

A

Early on in the Melanin chemical pathway in the tyrosinase causing no melanin to be produced

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12
Q

Name two dominant disorders

A
  1. Huntington’s
  2. Polycsytic kidney disease
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13
Q

Name 2 x-linked disorders

A
  1. DMD
  2. Haemophilia A
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14
Q

List 5 inherited cancer predispositions

A
  1. Li-Fraumeni (p53)
  2. BRCA 1 & 2
  3. HNPCC (mismatch repair system)
  4. Xerogerma pigmentosum (excision repair system)
  5. Retinoblastoma (pRb)

Functionally recessive but inherited in a dominant fashion

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15
Q

What is a complex disorder?

A

Many genes acting together. Recessive or dominant affect. Low penetrance

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16
Q

What are polymorphisms?

A

Fixed mutation at a frequency of >2%

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17
Q

What are Copy Number Variations (CNVs)?

A

Large portions of DNA that different from person to person (can be repetitive DNA)

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18
Q

List 4 systems that mutations can derive from

A
  1. Replication - rate of error incorporation
  2. Recombination - gene conversion
  3. Repair - efficacy of repair
  4. Metabolism - oxygen species can be mutagenic
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19
Q

What are gross mutations?

A

Chromosomal in scope - deletions, inversion and translocations

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20
Q

Non-Disjunction mutations

A

Errors in chromosomal segregation - one daughter cell ends up with too many or not enough chromosomes

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21
Q

5 disorders caused by Non-Disjunction trisomy

A
  1. Edwards’ Syndrome
  2. Down’s Syndrome
  3. Patau’s Syndrome
  4. Klinefelter’s Syndrome
  5. Triple X
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22
Q

2 disorders caused by Non-Disjunction deletions

A
  1. Turner’s Syndrome
  2. Cri du Chat
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23
Q

What is an important gene deleted in Cri du Chat?

A

TERT (telomerase reverse transcription) which is important for telomere function

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24
Q

When does Non-Disjunction occur most?

A

During Meiosis I

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25
When do most T18 happen?
MII
26
When do most T16 happen?
MI
27
Deletion mutation
Loss of a piece of DNA from a chromosome, making a smaller chromosome
28
Duplication mutation
DNA is copied and inserted into another chromosome
29
Inversion mutation
A piece of DNA is cut out, turned back to front and reinserted into another chromosome. DNA could be moved to part of a chromosome that has less activity
30
Insertion mutation
Part of a chromosome removed from one chromosome and inserted into another (original chromosome is now smaller)
31
Translocation mutation
Swapping event between chromosomes, no loss of DNA
32
What is a Philadelphia Chromosome?
Part of chromosome 9 and 22 is swapped. This fuses the ABL gene (a kinase causing growth proliferation) to the break point cluster which has a powerful promoter and drives expression of ABL causes cell to become tumorigenic
33
Chromothripsis
Chromosome shatters and is randomly reassembled causing inversions, deletions, duplication etc (new chromosome has little resemblance to old) - involves 1 chromosome
34
Chromoplexy
Inter and intra - chromosomal rearrangements ( lesser number of events than chromothripsis) can be duplication and deletions
35
3 Effects of gross mutations
1. Gene dosage ( number of copy of a gene in genome) Reduction to Hemizygosity and polyploidy/trisomy 2. Fusion genes - changing gene expression 3. Disruption of other genes
36
Transposable elements
Small common sequences of DNA that are capable of making a copy of themselves and moving that somewhere else causing mutation
37
What are copia and gypsy?
Two families of TEs responsible for almost 50% of mutations with phenotypic effect in Drosophila
38
What percent of the human genome do LINEs, SINEs, SVA and Alu repeats make?
50%
39
What are base substitutions?
Micro-type mutations affecting a single base
40
Silent mutations
No change in AA
41
Missense mutation
Change to AA
42
Nonsense mutation
A codon that codes for an AA, changes to a codon that codes for a stop codon. most serious
43
Frameshift mutations
the insertion or deletion of nucleotide bases in numbers that are not multiples of three. Can alter protein structure and cause translation to stop prematurely
44
Transitions (how many possibilites)
Pyrimidine exchanges for another (T<>C) Purine exchanges for another (A<>G) 4 possibilities
45
Transversions (how many possibilities)
Pyrimidine changes to a purine or vice versa 8 possibilities
46
Ratio of transitions to transversions
2:1
47
Conclusions of the fluctuation test
Single cultures give similar numbers and different culture fluctuate significantly Mutations are present in population before being subjected to selective pressure
48
Adaptive mutation : SOS response in E.coli
. induced by stress (DNA damage) . induction of mutator/error prone repair phenotype .extensive damage causes arrest of polymerase III . UmuD'2C (mucAB - pol V) and DinB polymerases (pol IV) . Cells revert to normal phenotype assume they survive and threat passes
49
Environmental stress mutation
Stress induced activity of DinB through RpoS (sigma factor) DinB causes 50% of mutation in starving cells, both frameshift and SNP Ciprofloxin (antibiotic) inhibits DNA gyrase Sublethal doses induces stress related mutation (DinB, SOS etc) promoting higher mutation rates and can lead to antibiotic resistance
50
Mutator phenotypes associated with increased virulence in HIV
Sloppy RT polymerase introducing errors 3-TC resistant RT has lower mutation rate
51
Lytic RNA viruses mutation rates
1. Poliovirus - 0.8 2. Vesicular stomatitis virus - 3.5 3. Influenza A ~ 1.0 4. Bacteriophage Qb - 6.5
52
Mutation rate of retroviruses compared to Lytic RNA viruses
10 fold lower
53
Mutation rate in DNA- based organisms with small genomes
0.0034
54
Human mutation rate
1.2x10-8
55
How much higher is the paternal mutation rate compared to the maternal?
~4 (3.3)
56
What type of mutations are more seen in maternal line
Non-Disjunction
57
What type of mutations are more seen in the paternal line?
SNPs, INDELs
58
What might be a reason for higher rates of mutation in sperm?
High methylation
59
Germline mutation rates at CpG and non-CpG sites
1.2x10-8
60
Mutations in human somatic cells compared to germline cells
Mutations occur 4 to 25 times more in somatic cells
61
2 types of background mutation causes by spontaneous breakage of the glycosydic bond inn aqueous environment
1. Acid and temperature dependent (proton attacks glycosyl bond causing hydrolysis) 2. Addition of chemical (alkyl) group to pu & py rings labilise the bond (results in apurinic or apyrimidinnic site which is detected by AP endonuclease and repaired)
62
Mutation in 5me-Cytosine
If NH2 group is lost it will look like thymine and commonly escaped repair
63
What does deamination of cytosine create?
Uracil
64
What does deamination of Adenine create?
Hypoxanthine
65
oxo8dG:C (oxidative mutation of guanine)
Exists in normal anti form presenting 3H bonding opportunities Anti can swing around on its glycosidic bond and looks like thymine so an adenine is added
66
lactam =
keto
67
lactim =
enol
68
What does thymine (keto) bond with?
Adenine (amino)
69
What does cytosine (amino) bond with?
Guanine (keto)
70
What does thymine (enol) bond with?
Guanine (keto)
71
what does cytosie (imino) bond with?
Adenine (amino)
72
What does Thymine in its normal keto form have?
Double O bond
73
What does Thymine in its enol form have?
OH group which is no longer able to bond with the NH2 group of adenine
74
What does 5-BU in keto form behave like?
Thymine
75
What does 5-BU in its enol form behave like?
Cytosine
76
Tautomeric shift
Spontaneous isomerisation of a nitrogen base to an alternative hydrogen-bonding form, possibly resulting in a mutation
77
What percent of oxygen we breath turns into oxygen radicals?
Up to 1%
78
What does oxidation cause damage to?
Bases, ribose ad phosphodiester bonds
79
What does oxidation do to bases?
OH addition to double bonds
80
What does oxidation do to ribose?
Strand breakage ad base release
81
What does oxidation do to phosphodiester bonds?
If two bonds are broken near each other, it can cause a breakage in the chromosome and loss of parts of the chromosome
82
What are double strand breaks caused by?
Oxidative mutagens, radiation, enzyme activity
83
What is the only way to fix double stranded breaks without damage?
Using recombination repair which is only available when there is two copies of the chromosome near by - usually after S phase or in G2 phase
84
What kind of source of mutation is oxidative damage?
Endogenous
85
What are intercalating agents and what do they cause?
Exogenous mutagens that are flat molecules that slow between neighbour base pairs increasing separation. They cause frameshift and InDel mutations and confuse DNAP as its replicating DNA
86
Name 5 intercalating agents
1. 5-aminoacridine 2. acridine yellow 3. ethidium bromide 4. ICR-191 - bias for C/G strings 5. TNF-one - bias for CG strings
87
What structural components do intercalating agents have?
3 benzene rings tied together - can fit between two strands of the DNA helix
88
Use of Ehitidium bromide
Used as a marker in DNA gel as it fluoresces when exposed to UV light
89
What does the deamination of guanine form?
Xanthine - Nitrous acid attacks NH2 group replacing it with O
90
What does the oxidation of guanine form?
oxo8dG
91
Alkylating agents
Introduce bulky substituents to DNA causing mispairing during replication as hydrogen bonding characteristics are changed.
92
What does EMS donate to bases?
C2H5
93
What does EMS do?
Can cause mispairing - reacts with T&G Attacks oxygen molecule at C6 of G
94
Crosslinking reagents
Covalently crosslink bases on separate strands and prevent separation of strands
95
Name 2 crosslink reagets
1. Mitomycin-C (antibiotic that prevents DNA replication) 2. Psoralens - activated by light used to treat psoriasis
96
List 3 radiation mutagens
1. Ionizing radiation - causes damage through oxidative processes 2. UV - thymidine dimer formation 3. Radon gas
97
Radiation sources
1. Natural sources (300mRem) 2. Artificial sources (60mRem) Normal annual dose = 500mRem
98
List 2 structural causes of mutation
1. Rearrangment of DNA due to homologous recombination during meoisis 2. Recombination between tandemly repeated genes
99
3 effects of recombination between tandemly repeated genes
1. Loss of copies on one chromosome (haploinsufficiency) 2. Increase on other chromosome 3. Recombinant hybrid genes (C-B' gene)
100
alpha-thalassemia - alpha globin gene deletion
1. Unequal crossing over between repetitive segments in cluster. Leads to instability and deletions resulting in chromosomes with either 1 thalassemia or 3 copies of genes
101
Beta-thalassemia - beta-globin
Similar process to alpha - mostly caused by genome rearrangements and deletions
102
What causes growth hormone deficiency?
Recessive condition resulting from deletion of GH1 part of a GH cluster. Repeated segments flank GH1
103
Glucocorticoid-remediable Aldosteronism
Autosomal dominant disorder - increase in aldosterone secretion produced by ACTH is no longer transient Aldosterone causes the tubules of the kidneys to retain sodium and water. Increases fluid in the body and drives up blood pressure
104
Repetitive sequences engage in recombinant events that causes... such as
Deletions and duplication Charcot-Marie-Tooth type 1A syndrome - increased dosage of PMP22 gene HNPP - reduced dosage of PMP22 gene
105
DNA inversion + example
Part of chromosome breaks off and reattaches in the reverse direction Haemophilia A
106
DNA inversion + example
Part of chromosome breaks off and reattaches in the reverse direction Haemophilia A
107
3 examples of simple tandem repeats STR
1. Microsatellites - TGFbeta 2. Single nucleotide strings 3. Triple repeat sites - Fragile X and Huntingtons
108
What are the most common chromosomal abnormality in cancer?
t(14;18) tanslocation
109
What does t(14;18) cause?
Leads to promoter exchange and overexpression of BCL2 - anti-apoptotic protein
110
Mutation tests
Ames test
111
Ames test
Looking at reversion of his- mutations in Salmonella to prototrophy Bacteria mutated to enhance mutagenic potential - activated UmuD'2C (pKM101)
112
How many more times susceptible is internucleosomal than nucleosome bound DNA?
3.5 times
113
Carcinogen in salted/pickled food?
N-nitroso cpds
114
Naturally occurring toxic agents 4
Aflatoxin-B Psoralens (parsnips, parsley, celery) Solinins (potatoes) Hydrazinobensoate (mushrooms
115
Carcinogens by cooking smoked, barbecued and roasted foods 6
1. Nitrosamines 2. Hetereocyclic amines 3. Polycyclic hydrocarbons (charred meat) 4. Furans (sugar) 5. Ep-, hydroper-oxides (fats) 5. Polyacrylamide (chips)
116
Coffee contains 40ppm carcinogens, what are they? 5
1. Caffeic acid 2. Catechol 3. Furfural 4. Hydroquinone 5. Hydrogen peroxide
117
Mutation and cancer progression line
DNa lesions > Mitogenesis > mutagens/errors >or equal to cancer
118
Almost all cancers have which mutated effector molecules? 4
1. pRB 2. p53 3. p16 4. p21
119
What kind of mutations are seen in p53?
Normally missense, truncation very rare
Evolutionary and Population Genetics
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