Mutations Flashcards

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1
Q

Two main sources of genetic variation:

A

Mutations and Recombination

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2
Q

Mutations as sources of genetic variation

A
  • Permanent alteration to DNA sequence
  • Mutations create new alleles in population
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3
Q

Recombination as sources of genetic variation.

A

Independent assortment of chromosomes and genetic crossing over between chromatids of homologous chromosomes during meiosis > 8 million possible combinations

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4
Q

Why without mutations would evolution not be possible?

A

Without mutations, evolution would not be possible: mutations provide the “raw material” upon which the mechanisms of natural selection can act; by way of this process, those mutations that furnish individual organisms with characteristics better adapted to changing environmental conditions are passed on to offspring at an increased rate, thereby influencing the future of the species.

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5
Q

Silent mutation

A

base substitution results in the generation of a codon for the same aa (redundancy of genetic code) (wobble effect)

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6
Q

Missense mutation

A

base substitution results in a codon that specifies a different amino acid and this leads to a different polypeptide sequence;

-> can be conservative (Val -> Ala) or nonconservative

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7
Q

Nonsense Mutation

A

base substitution results in the generation of a stop codon (UAA, UGA, UAG)

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8
Q

Examples of the effect of a point mutation - missense?

A

K-Ras proto-oncogene is activated by missense mutation
The most frequent K-Ras mutation in human cancers is K-RasG12V

A consequence of missense mutation:
GGC -> GTC resulting in a change of Gly to Val at position 12

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9
Q

K-Ras mutations are observed in what % of all cancers?

A

K-Ras mutations are observed in 17%–25% of all cancers;
most frequently in pancreatic (80% - 90%),
Lung (~30%)
Colorectal (30% - 40%) cancers

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10
Q

Examples of the effect of a point mutation - missense? SSA

A

Sickle Cell Anaemia:
HbSS mutant protein is a result of missense mutation
GAG -> GTG in the β-globin gene
A consequence of which is glutamate (E/Glu) being substituted by valine (V/Val) at position 6 (E6V substitution)

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11
Q

POINT MUTATION INSERTION effect?

A

Insertion or deletion of just one base pair can lead to a frameshift mutation (change in the reading frame) resulting in a change of amino acid sequence and sometimes in premature termination of translation (truncated protein).

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12
Q

Example of a Point Deletion: Cystic Fibrosis:

A

CF is caused by a mutation in the gene CFTR encoding for cystic fibrosis transmembrane conductance regulator (CFTR) protein

The most common mutation, ΔF508, is a deletion of three nucleotides that results in a loss of the amino acid phenylalanine (Phe/F) at position 508 on the protein

More than 1500 other mutations are associated with CF

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13
Q

Where can mutations also occur ? - In promoter or enhancer* sequences of a gene - TERT

A

Mutation effect in the promotor region:

Activation of TERT oncogene by mutation

TERT gene promoter mutations generate de novo consensus binding motif for ETS/TCF transcription factors resulting in increased expression of TERT gene

TERT gene promoter mutations are observed in ~ 30% of primary melanomas

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14
Q

Where can mutations also occur ? - In splice donor and acceptor sites - β-thalassemia

A

β-thalassemia
Abnormal processing of the β-globin primary RNA transcript in humans with the β-thalassemia.
The disease (severe anaemia due to aberrant haemoglobin synthesis) is caused by splice-site mutations found in the genomes of affected patients.

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15
Q

Where can mutations also occur ? - In splice donor and acceptor sites - PKU

A

Phenylketonuria (PKU)
A single base mutation (GT-to-AT) that corresponds to a change from 5’-GU to 5’-AU in the splice donor site of Intron 12 that makes the site unrecognizable by the splicing enzymes.

This results in Exon 12 being excised along with Introns 11 & 1
Individuals with this mutation have a 156bp deletion in the mRNA, corresponding precisely to the length of Exon 12 that leads to a truncated PAH (phenylalanine hydroxylase) protein that is unstable with almost zero PAH activity.

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16
Q

Where can mutations also occur ? besides splice sites and promoters regions?

A

In termination Signals
In Ribosome Binding Sites

17
Q

Causes of Mutations:

A

1.Errors in DNA Replication
2. Chemical Damage to DNA
3. Radiation

18
Q

Errors in DNA Replication as a cause of mutation:

A

DNA replication machinery errors rate:
1 in 1010 nucleotides of DNA synthesized

->this high fidelity is due to intrinsic base selectivity and proofreading exonuclease activity of DNA polymerase and post-replication mismatch repair.

However, errors do occur including rare tautomeric forms with altered base-pairing and DNA strand slippage during replication.

19
Q

Chemical Damage to DNA

A

Many chemical mutagens both man-made and environmental, are capable of damaging DNA.

Many chemotherapeutic drugs and intercalating agent drugs function by damaging DNA.

20
Q

Radiation

A

Ionizing and UV radiation can interact with compounds in the cell generating free radicals which cause chemical damage to DNA.

21
Q

Tautomeric shift

A

Tautomeric shifts that modify the pairing of nucleotides can result in base substitutions and, as a result -> mutations.

22
Q

Slippage during DNA replication

A

Replication slippage or slipped-strand mispairing involves the misalignment of DNA strands during the replication of repeated DNA sequences

23
Q

What does Slippage during DNA replication cause?

A

can lead to genetic rearrangements

Incorrectly paired nucleotides become permanent mutations after the next cell division: this is because once such mistakes are established, the cell no longer recognizes them as errors

24
Q

Chemical mutagens definition

A

A mutagen is a physical or chemical agent that permanently changes DNA and thus increases the frequency of mutations above the natural background level

25
Q

Examples of Chemical Mutagens

A

TSNAs (tobacco-specific nitrosamines) and
PAHs (polycyclic aromatic hydrocarbons
-> carcinogens that are found in tobacco products including cigarettes, snuff, e-cigarette liquid, and smokeless tobacco
TSNAs and PAHs cause bulky DNA adducts (adduct is a piece of DNA covalently bond to a chemical) that if not repaired can lead to mutations -> ultimately cancer)

26
Q

Chemical mutagens - What are Alkylating agents

A

Alkylating agents work by
-> adding an alkyl group to the guanine base of the DNA molecule.

Alkylating agents induce cross-linking between strands of DNA and the loss of a basic component (purine) or the breaking of the nucleic acid

27
Q

Examples of Alkylating agents ?

A

Alkylating agents - first anticancer drugs used, and, despite their hazards, they remain a cornerstone of anticancer therapy

Examples: nitrogen mustards (chlorambucil and cyclophosphamide), cisplatin, nitrosoureas (carmustine, lomustine, and semustine), alkylsulfonates (busulfan), ethyleneimines (thiotepa), and triazines (dacarbazine)

28
Q

What is Ionizing radiation (alpha, beta, gamma, neutrons and X-rays) and how does it affect DNA structure? primary and secondary effects

A

Directly affects DNA structure by inducing DNA breaks,
->particularly double strand breaks (DSBs)

Secondary effects are
-> the generation of reactive oxygen species (ROS) that oxidize proteins and lipids

->This also induced several types of DNA damage, generation of a basic sites, single strand breaks (SSBs) and DSBs

29
Q
  1. UV radiation and how does it affect DNA structure?
A

The major type of damage induced by UV light is the formation of pyrimidine dimers in which adjacent pyrimidines on the same strand of DNA are joined by the formation of a cyclobutene ring.

The formation of such dimers distorts the structure of the DNA chain and blocks transcription or replication past the site of damage.

UV-induced thymine dimers can be repaired by photoreactivation, in which energy from visible light is used to split the bonds forming the cyclobutane ring

30
Q

Types of DNA damage:

A

Types of DNA damage:
Double strand break -> e.g. Xray, chemo
Chemical bond between neighbouring nucleotides e.g. UV light
Chemical modification of a nucleotide e.g. ROS, chemo agents
Chemical linkage of 2 strands e.g. ROS, chemo, cellular and environmental chemicals

31
Q

DNA REPAIR - Base excision repair - BER

A

BER corrects small base lesions that do not significantly distort the DNA helix structure, such as DNA damage from oxidation, deamination and alkylation.

Example: uracil (U) has been formed by deamination of cytosine (C) and is therefore opposite a guanine (G).

  • The bond between uracil and the deoxyribose is cleaved by a DNA glycosylase, leaving a sugar with no base attached in the DNA (an AP site)
  • This site is recognized by AP endonuclease, which cleaves the DNA chain
  • The remaining deoxyribose is removed by deoxyribose phosphodiesterase
  • The resulting gap is then filled by DNA polymerase and sealed by ligase, leading to incorporation of the correct base (C) opposite the G
32
Q

DNA REPAIR - Nucleotide-excision repair (NER)

A

NER Recognize a wide variety of damaged bases that distort the DNA molecule,
-> including UV-induced pyrimidine dimers and bulky groups added to DNA bases as a result of the reaction of many carcinogens with DNA.

Example: NER repair of thymine dimers
Damaged DNA is recognized and then cleaved on both sides of a thymine dimer by 3′ and 5′ nucleases

Unwinding by a helicase results in excision of an oligonucleotide containing the damaged bases

The resulting gap is then filled by DNA polymerase and sealed by ligase

33
Q

Mismatch repair (MMR)

A

Recognizes mismatched bases that are incorporated during DNA replication

mismatched bases -> removed by the proofreading activity of DNA polymerase

The ones that are missed are subject to later correction by the mismatch repair system, which scans newly replicated DNA.

if a mismatch is found, the enzymes of this repair system are able to identify and excise the mismatched base specifically from the newly replicated DNA strand, allowing the error to be corrected and the original sequence restored

Mutations in mismatch repair genes (MutS and MutL) are responsible for a common type of inherited colon cancer (hereditary nonpolyposis colorectal cancer, or HNPCC)

34
Q

Homologous recombination (HR) and non-homologous end joining (NHEJ) repair

A

Provide a mechanism for the accurate repair of DNA double-strand breaks
-> protecting cells from chromosomal aberrations