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Genetics > Week 8 Lecture Content > Flashcards

Week 8 Lecture Content Flashcards

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1
Q

How frequent is a point mutation

A

Rare per replication but common in populations
1. Phenotype level: 10^-6 to 10^-8 / individual
2. DNA sequence level: 10^-9 per base per replication - consistent across all species due to intrinsic DNA replication process

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2
Q

Do beneficial mutations happen more often?

A

No it happens randomly

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3
Q

The Fluctuation Test of Luria and Delbruck

A
  • Set up 3 different cultures and introduced T1 phage into them
  • If random, the number of phage-resistant cells fluctuates substantially among populations as a result of random timing of mutation
  • If adaptive, all populations will carry approximately the same proportion of phage resistant cells
  • Found that proportions vary - random
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4
Q

In multicellular organisms, does the same mutation in different cell types have the same effects?

A

No, the same mutation in different cells can have very different effects
- Germ-line mutations: can be passed form one generation to the next
- Somatic mutations: not genetically impact the next generation

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5
Q

How are point mutations classified?

A
  • Coding sequence mutations
  • Regulatory mutations
    Can also be classified as transition or transversion mutations
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6
Q

Coding sequence mutations

A
  • Synonymous: no AA change
  • Missense: changes on AA
  • Nonsense: Creates a stop codon and terminates translation
  • Frameshift: wrong sequence of AA
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7
Q

Regulatory Mutations

A
  • Promoter: Changes timing or amount of transcription
  • Polyadenylation: alters sequence of mRNA
  • Splice site: Improperly retains an intron or excludes an exon
  • DNA replication mutation: increases number of short repeats of DNA
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8
Q

Transition vs transversion mutations

A

Transition: A and G or T and C
Transversion: A to T or C and G to T or C

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9
Q

Forward mutation

A

A wild-type allele to a mutant allele

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10
Q

Reverse Mutation (reversion)

A

Mutant alleles to wild-type of near wildtype allele
- True reversion: another mutation restores wild-type DNA sequence
- Intragenic Reversion: second mutation elsewhere in the same gene restores gene function
-Second-site reversion (suppressor mutation): mutation in a different gene that compensates for the original mutation, restoring the organism to wild type

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11
Q

How are mutations generated?

A
  1. Changes in the chemical structure of a nucleotide base
  2. Errors in DNA replication: 1 x 10^-9 per base per replication
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12
Q

Strand slippage

A

The DNA polymerase temporarily dissociates and then reattaches to resume replication
- Leads to an altered number of repeat elements

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13
Q

Why is nucleotide repeat changes significant

A

many human disorders caused by repeated expansions
- Wild-type alleles have a certain number of DNA trinucleotide repeats
- Increases in the number of repeats beyond a certain threshold causes the disorders

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14
Q

What are the mechanisms of point mutations?

A
  1. Mispaired nucleotide during replication: Non-complementary base pairing can occur (incorporated error)
  2. Spontaneous nucleotide base changes
  3. Caused by chemical and or ionizing radiation
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15
Q

Depurination

A

The loss of a purine - apurinic site
- if not repaired, DNA polymerase will put an adenine into the site during replication
- type of spontaneous nucleotide base change

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16
Q

Base modification

A

Eg. Deamination
The loss of an amino group from nucleotide base
- Deamination of methylated cytosine produces thymine
- replication will produce mutant and wild-type sister chromatids

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17
Q

Mutagens

A
  • Physical agents
  • Chemicals agents
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18
Q

Modes of action of chemical mutagens

A
  1. Nucleotide base analogs
  2. Deaminating agents
  3. Alkylating agents
  4. Oxidizing agents
  5. Hydroxylating agents
  6. Intercalating agents
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19
Q

Radiation-induced DNA damage

A
  • Higher energy radiation - more DNA damage (short wavelength)
  • UV -> photoproducts: aberrant structures with additional bonds involving nucleotideWs
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20
Q

What kind of mutagenic event occurs as a result of an oxidizing agent

A

transversion mutation

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21
Q

How do we know if a chemical is a mutagen

A

The ames test

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22
Q

Ames test

A
  1. S9 extract is added to mutant strains of his- S. typhimurium
    2.his-1 is a base substitution mutant, his-2 is a frameshift mutant
  2. the S9-bacterial mixture from each strain is spread on one experimental plate and one control plate
  3. A paper disk is put on each plate. the test compound is added to the experimental plate disks
  4. The presence of a significant number of revertant colonies indicates the test compound induces base-substitution
  5. The control plates determine the rate of spontaneous his- to his+ reversion
  6. An insignificant number revertant colonies indicates the test compound does not induce frameshift mutations
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23
Q

Mutagenicity of Aflatoxin B determined by the Ames test

A

Used Ames test and found increased reversion with base-pair substitution bacteria
- means Aflatoxin B1 is a mutagen and causes base substitution, not insertion or deletion

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24
Q

What types of DNA damage repair systems are there?

A

Direct repair mechanisms

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25
Q

Photoreactive repair

A

Repair of UV-induced photoproducts catalyzed by photolyase activated by visible light

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26
Q

Base excisions repair

A

Removal of an incorrect or damage DNA base and repair by synthesis of a new strand segment
1. DNA N-glycosylase recognizes a base-pair mismatch
2. Removes the incorrect nucleotide creating an apyrimidinic site
3. AP endonuclease generates a single-stranded nick on 5’ side of the AP site
4. DNA polymerase removes and replaces several nucleotides of the nicked strand by nick translation

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27
Q

Nucleotide excision repair

A

removal of a strand segment containing DNA damage and replacement by new DNA synthesis

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28
Q

Mismatch repair

A

Removal of a DNA base-pair mismatch by excision of a segment of the newly synthesized strand followed by resynthesis of the excised segment

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29
Q

Hoe does the repair system know which base to remove in a mismatch base pair

A

Mismatch repair enzymes distinguish between the original, correct nucleotide and the new mismatch nucleotide through presence of methylation on original strand
1. MutH binds to hemimethylated DNA
2. MutS bings to a base-pair mismatch and attracts MutL and the complex contacts MutH
3. MutH cleaves the unmethylated DNA strand, generating a single-strand gap
4. The gap is filled by DNA polymerase activity to repair the mismated

30
Q

How are large damages repaired

A

Translesion DNA synthesis by translesion DNA polymerase, which is error prone with no proofreading ability

31
Q

How are double-strand breaks repaied

A

Nonhomologous end joining or synthesis-dependent strand annealing

32
Q

Double strand bearks

A
  • Chromosome instability - cell death
  • Uncontrolled cell growth -cancer and chromosome structural mutations
33
Q

Nonhomologous End joining

A
  1. X-ray or oxidative damage produces double-strand break in DNA
  2. Ku80-Ku70-PKcs protein complex binds DNA ends
  3. Ends are trimmed, resulting in a loss of nucleotides
  4. DNA ligase ligates blunt ends to reform an intact duplex
34
Q

Synthesis-dependent Strand annealing

A
  1. One chromatid undergoes a double-stranded break
  2. Nuclease digest a portion of the broken strands. Rad51 binds the undamaged chromatid
  3. Strand invasion of the sister chromatid creates a D loop. a replication fork assembles on the D loop
  4. New strand synthesis takes place using the available intact strands as templates
  5. Partial strand excision occurs; duplexes reform, and strands are ligated
35
Q

Key molecule involved in repair to prevent breast and ovarian cancer

A

BRCA1

36
Q

Key molecule involved in repair to prevent tumor suppressor

A

p53

37
Q

How do transposable genetic elements move and create mutations in genomes?

A
  1. Cut and paste
  2. Copy and paste
38
Q

Transposable genetic elements (TGE)

A

DNA sequences that can move within the genome through transposition
- Can vary in length, sequence composition and copy number

39
Q

What are features of transposable elements

A
  1. Terminal inverted repeats on its ends
  2. The inserted transposable element is bracketed by flanking direct repeats
40
Q

How do DNA elements transpose?

A
  1. Staggered cuts cleave the DNA strands of the target sequence
  2. Single-stranded ends result from staggered cuts of the target sequence
  3. The transposable element is inserted into the target sequence
  4. the gaps are filled by DNA polymerase
41
Q

Categories of transposed elements

A
  1. DNA transposons: transpose as DNA sequence
  2. Retrotransposons: are composed of DNA but transpose through an RNA intermediate
42
Q

Processes of DNA transposons

A
  1. Replicative: copy and paste
  2. Non-replicative: cut and paste
43
Q

Process of retrotransposons

A

DNA to RNA to reversed transcribed into DNA then inserts into the new location

44
Q

Insertional inactivation

A

If inserted into wild-type allele, can inactivate gene

45
Q

Which type of transposon is more rare

A

DNA trasnposons

46
Q

Transposable element Alu and cancers

A
  • Insertion increases expression of gene
  • Increases speed of cell cycle
  • Leads to many cancer types
47
Q

Forward genetics

A

Start with phenotypic difference to identify its genetic basis

48
Q

Reverse genetics

A

Manipulate specific genetic change to identify its phenotypic effect

49
Q

What is a common approach to identifying genes controlling phenotypic differences

A

Genetic cross and linkage mapping

50
Q

Types of phenotypic variations

A
  • Natural phenotypic variations
  • Artificial random mutagenesis
51
Q

Choosing an organism for fundamental questions

A

Select a model organism with features such as;
- Progress through its whole life cycle in a laboratory
- have a short generation time
- produce a reasonable number of progeny
- amenable to crossing and sexual reproduction
- amenable to genetic manipulations
Eg: E. coli, B. subtilis, baker’s yeast, fruit fly, zebra fish, mice

52
Q

Choosing an organism for applied questions

A

Organism-specific and the organism is already selected for you
- Natural phenotypic variations
- Artificially introduced phenotypic variations through random mutagenesis

53
Q

Choosing a mutagen

A

CHEMICAL
- Ethyl methanesulfonate
- mostly SNP
- usually loss-of-function, rarely hypermorphic
RADIATION
- Fast-neutron, X-ray, gamma-ray
- rearrangements (deletions, inversions, translocations)
- usually Loss-of-function, but can be gain-of-function
INSERTIONAL
- Transfer DNA, transposons
- Insertions
- Usually loss-of function

54
Q

How to investigate the effect of mutagenesis in diploids

A
  1. Mutagenize sperm cells
  2. Mate with wild-type female
  3. Identify dominant mutations in F1 individuals
    - If F1 progeny shows 1:1 phenotype ratio then dominant
    - To check if recessive, intercross F1 individuals
55
Q

What are the differences between mutations in haploid vs diploid organisms?

A
  • Haploid: both recessive and dominant mutations can be identified directly
  • mutations that cause lethality cannot be obtained in haploids but can be in diploids
56
Q

How do you identify if a mutation is lethal in haploid

A

conditional mutant alleles

57
Q

How to identify interacting genes

A

use a genetic modifier screen to identify a second gene that can modify the phenotype of the first mutation

58
Q

Enhancer screen

A

Identifies second-site mutant allele that enhances the mutant phenotype

59
Q

Suppressor screen

A

Identifies second-site mutation that suppress the effect of the first mutation

60
Q

Synthetic Lethality

A

Combination of two viable mutations results in an inviable double mutant

61
Q

Between-pathway gene interactions

A

Two pathways both preform the same essential function
- mutation of either alone may be inconsequential
- mutation of both will result in loss of the essential function

62
Q

Within-pathway gene interactions

A
  • Partial loss of function mutations alone reduce functions
  • if both components are mutated the pathway may become nonfunctional
63
Q

How to locate the mutated gene in the genome?

A
  • Through genetic crosses and/or pedigree analyses
  • Often involved multiple iterations
  • can only identify to an approximate chromosomal location
  • Genome-wide association analyses
64
Q

How to identify the mutant genes?

A
  1. Construct DNA library
  2. Transformation and complementation
65
Q

Genomic Library

A

Collections of cloned DNA fragments representing the ENTIRE genome of an organism

66
Q

Complementary DNA libraries

A

Collections of cloned DNA fragments representing all mRNA produced by an organism

67
Q

Complementation

A

Introduce a wild-type gene to the mutant and revert the mutant phenotype to wild type

68
Q

What are 6 common reverse genetics technologies?

A
  • Knockouts by homologous recombination
  • CRISPR
  • Random T-DNA
  • Transposon insertions
  • TILLING
  • RNAi
69
Q

Homologous recombination with circular DNA

A
  • Single crossover results in integration of introduced DNA without replacement of target gene
  • Double crossover results in replacement of target gene
70
Q

Homologous recombination with linear DNA molecule

A
  • Single crossover results in integration of introduced DNA and loss of chromosomes distal to integration site
  • Double crossover results in replacement of target gene

Genetics (18 decks)

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