Lecture 9

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Questions and Answers

Which of these is a possible cause of a spontaneous mutation?

Exposure to radiation

Errors during DNA replication (correct)

Cellular stress response

Introduction of foreign DNA

Which type of mutation can be inherited by offspring?

Mutations in differentiated cells

Mutations in somatic cells after birth

Somatic mutations

Germline mutations (correct)

What can result from errors in DNA transcription?

Changes in DNA polymerase activity

Alternative splicing (correct)

Tautomerization of bases

Oxidative deamination of bases

Which of the following is not a mechanism of spontaneous base modification in DNA?

DNA polymerase proofreading (C) Signup and view all the answers

What is a characteristic of a nitrogenous base in its tautomeric form?

It differs by the position of protons and double bonds, and can spontaneously transition between forms (A) Signup and view all the answers

Why is replication not a completely error-free process?

The requirement for infinite accuracy in replication would demand an infinite amount of energy, which is not possible. (D) Signup and view all the answers

What is the primary difference between somatic and germline mutations?

Somatic mutations occur in the body and are not passed to offspring, while germline mutations arise in reproductive cells and can be. (C) Signup and view all the answers

A mutation arises during spermatogenesis. This is best classified as which type of mutation?

A germline mutation (B) Signup and view all the answers

What is the defining characteristic of a de novo mutation?

It arises in the offspring but was not present in the parents. (D) Signup and view all the answers

Which of the following best describes the role of mutations in evolution?

Mutations introduce variability in genetic information, which is the basis of evolution. (D) Signup and view all the answers

Which mutation type causes the premature creation of a STOP codon?

Nonsense mutation (B) Signup and view all the answers

What is a potential consequence of oxidative deamination of adenine?

It converts to hypoxanthine. (B) Signup and view all the answers

Which process involves the exchange of genetic material between two chromosomes?

Translocation (A) Signup and view all the answers

What type of mutation can lead to a shift in the reading frame of DNA?

Frameshift mutation (A) Signup and view all the answers

What is the primary mechanism used for repairing double-stranded DNA breaks in mammalian cells?

Non-homologous end joining (C) Signup and view all the answers

Which mutation occurs when one base is replaced by another but produces no change in the amino acid sequence?

Silent mutation (A) Signup and view all the answers

What effect does the 8-oxoguanine nucleotide have when formed from guanine?

It pairs with adenine. (A) Signup and view all the answers

Which form of structural chromosomal aberration leads to a loss of genetic material?

Deletion (B) Signup and view all the answers

What distinguishes a reciprocal translocation from a non-reciprocal translocation?

It attaches fragments from different chromosomes without exchange. (D) Signup and view all the answers

During which stage does MMR repair mismatched nucleotides?

Recognition of damage (B) Signup and view all the answers

What does oxidative deamination primarily convert cytosine into?

Uracil (D) Signup and view all the answers

What type of mutation is caused by replication slippage?

Expansion (B) Signup and view all the answers

In the context of nucleotide excision repair, what is the role of helicases?

Unwinding DNA strands (B) Signup and view all the answers

Which statement correctly characterizes missense mutations?

They can be conservative or non-conservative. (C) Signup and view all the answers

Which of the following scenarios is LEAST likely to result in a de novo mutation?

Inheritance of a mutation from a parent (D) Signup and view all the answers

During DNA replication, a guanine base shifts into its enol form. What is the MOST likely consequence of this tautomeric shift?

Formation of a bond with a non-traditional base pairing partner (B) Signup and view all the answers

If a mutation occurs due to an error in transcription, where would this error MOST likely originate?

Regulatory sequences in the DNA (C) Signup and view all the answers

A biological sample shows an unusually high rate of depurination and depyrimidination. Which of the following is the MOST direct consequence that needs to be addressed?

Loss of nitrogenous bases from DNA (C) Signup and view all the answers

The frequency of a rare tautomeric form of a nitrogenous base in DNA is approximately 1 in 10,000. What is the MOST significant implication of this in terms of DNA replication fidelity?

The potential for non-standard base pairing, leading to mutations (A) Signup and view all the answers

If a mutation occurs in a somatic cell, which outcome is the most likely?

It may initiate the formation of cancer in the affected individual. (A) Signup and view all the answers

What is the key difference between a mutation and a variation within a population?

Mutations are sudden, unintended changes, while variations are naturally occurring differences. (B) Signup and view all the answers

A de novo mutation is best described as a mutation:

That arises spontaneously in an organism but was not inherited from the parents. (D) Signup and view all the answers

Which of the following best explains why replication is not 100% accurate?

Achieving infinite accuracy would require an unsustainable level of energy expenditure. (C) Signup and view all the answers

A mutation that arises during the process of oogenesis would be classified as:

Germline and heritable. (A) Signup and view all the answers

What is the primary consequence of a cytosine base undergoing oxidative deamination?

The formation of uracil, which pairs with adenine causing a mutation. (D) Signup and view all the answers

Which type of mutation involves a change in the order of nucleotides within a DNA strand?

Inversion (C) Signup and view all the answers

What is the direct result of a pericentric inversion in a chromosome?

A break in two places on both arms and a flip of segment which includes the centromere (D) Signup and view all the answers

What is the primary mechanism by which Robertsonian translocations occur?

Breaks in the centromeric region of two acrocentric chromosomes, fusion of long arms, and loss of short arms (C) Signup and view all the answers

A mutation that causes a change in the nucleotide sequence but does not modify the resulting amino acid in the protein is referred to as:

A silent mutation (A) Signup and view all the answers

What best describes the immediate consequence of a frameshift mutation within the coding region of a gene?

Alteration of all codons downstream of the mutation, potentially resulting in a changed protein (C) Signup and view all the answers

Which of the following is a key characteristic of non-homologous end joining (NHEJ) in DNA repair?

Formation of a multi-nucleotide deletion around the site of the DNA break (B) Signup and view all the answers

What is the function of DNA glycosylase in base excision repair?

To remove a damaged nitrogenous base via breakage of the N-glycosidic bond (B) Signup and view all the answers

In the context of nucleotide excision repair, what role do XPA and XPC proteins primarily have?

To recognize the location of DNA damage (C) Signup and view all the answers

What crucial event occurs during homologous recombination (HR) that allows for error-free DNA repair?

The use of the sister chromatid as a template (B) Signup and view all the answers

A cell experiences a mutation which results in the formation of a uracil base. Which DNA repair mechanism would most likely fix that?

Base excision repair (D) Signup and view all the answers

What is the key difference between tandem and inverted duplication?

The gene order in a duplicated fragment is in the reverse order in an inverted duplication but the same in a tandem duplication (B) Signup and view all the answers

The Philadelphia chromosome is formed from a translocation between chromosomes 9 and 22, resulting in the formation of:

The Bcr-Abl fusion gene, which turns proto-oncogene into oncogene. (A) Signup and view all the answers

Which of these best describes the outcome of a nondisjunction event during meiosis?

Presence of an abnormal number of sex chromosomes. (D) Signup and view all the answers

What is the role of DNA ligase in DNA repair?

To seal breaks in the sugar-phosphate backbone of a DNA strand (B) Signup and view all the answers

A rare enol tautomer of thymine is incorporated during DNA replication. Which of the following is the MOST likely immediate consequence of this event during the subsequent replication round?

Incorrect incorporation of a guanine base opposite the enol-thymine. (D) Signup and view all the answers

Which cellular process involving DNA is MOST susceptible to errors resulting from the spontaneous formation of rare tautomeric structures?

DNA replication through regions with high GC content. (C) Signup and view all the answers

A somatic cell experiences a spontaneous de novo mutation. Which of the following is the MOST probable scenario involving the transmission of this specific mutation?

The mutation is unlikely to be transmitted to offspring, but could affect the somatic cell lineage it originally arose in. (C) Signup and view all the answers

A research study identifies a novel mutation arising from transcription errors in a eukaryotic cell. Which of the following cellular components is MOST likely to be directly affected by this error?

Regulatory promoter regions in the DNA. (D) Signup and view all the answers

During DNA replication, a guanine base undergoes oxidative deamination. What is the MOST direct consequence in terms of base pairing during the subsequent replication cycle if the change is not repaired?

A pairing with adenine instead of cytosine. (D) Signup and view all the answers

In the context of mutagenesis, how do de novo mutations most significantly differ from other categories of mutations?

They are not present in the parental genome and appear spontaneously in the offspring's genome. (D) Signup and view all the answers

Considering the evolutionary implications of mutations, how does the inevitable variability in genetic information primarily influence the course of evolution?

It provides the raw material for natural selection through heritable changes. (A) Signup and view all the answers

During the cell division process, what is the main distinction between the impact of a somatic mutation and a germline mutation on subsequent generations?

Germline mutations can be inherited by offspring, while somatic mutations are not. (B) Signup and view all the answers

What role does the constant potential for errors during DNA replication ultimately play in the biology of organisms, according to the provided details?

It establishes the foundation for mutations, which introduces diversity and drives evolution. (B) Signup and view all the answers

Considering the differences between somatic and germline mutations, which scenario would MOST likely result in a heritable genetic disease?

A single nucleotide change within the DNA of a developing sperm cell during spermatogenesis. (D) Signup and view all the answers

Which of the following describes a consequence of a frameshift mutation?

The amino acid sequence following the mutation's site will be altered, which impacts the protein structure. (C) Signup and view all the answers

A mutation occurs involving a substitution at the third position of a codon. This change results in the same amino acid being coded for; however, a sequence variation is detected in population analysis. How is this variation best described?

A single nucleotide polymorphism (SNP) (A) Signup and view all the answers

A cell undergoing meiosis experiences a break in the centromeric region of two acrocentric chromosomes, followed by the fusion of their long arms. What specific chromosomal aberration has occurred?

A Robertsonian translocation (D) Signup and view all the answers

During DNA replication, a hypoxanthine base is found to be pairing with a cytosine base on the newly synthesized strand. What mechanism resulted in this situation?

The oxidative deamination of adenine (A) Signup and view all the answers

Which scenario represents a situation that creates a non-conservative missense mutation?

A change in a codon that codes for a different amino acid that alters the protein function. (D) Signup and view all the answers

A double-stranded DNA break is recognized by the Ku70/Ku80 protein complex. Considering the described repair mechanism, what will be the MOST DIRECT outcome of this action?

The initiation of non-homologous end joining (NHEJ) to directly connect the damaged ends. (B) Signup and view all the answers

A circular chromosome structure is observed in a karyotype analysis. This was the result of a chromosome having terminal parts removed by breaks, and then the remaining parts attaching to form a circle. What type of chromosomal aberration is this?

Ring chromosome (B) Signup and view all the answers

A genetic analysis reveals the presence of the Bcr-Abl fusion gene. What is the mechanism that likely led to this specific genetic outcome?

A reciprocal translocation between chromosomes 9 and 22 (A) Signup and view all the answers

Following exposure to a mutagen, a cell initiates nucleotide excision repair. What distinguishes this repair mechanism from base excision repair?

Nucleotide excision repair uses nucleases to remove a larger segment, while base excision removes single bases. (C) Signup and view all the answers

During DNA repair, a segment of DNA containing a damaged nucleotide is excised, and a polymerase synthesizes a complementary strand. What step follows this synthesis?

The new strand is joined to the existing DNA by a DNA ligase. (C) Signup and view all the answers

A cell has initiated homologous recombination (HR) to repair a double-strand break. What step is critical for this repair, distinguishing it from non-homologous end joining (NHEJ)?

Using a sister chromatid as a template to accurately restore the damaged DNA sequence. (C) Signup and view all the answers

A cell is found to have a segment of its DNA where a chromosomal fragment has been inserted into another location, and the order of genes within the inserted fragment is reversed. Which specific type of structural aberration has occurred?

An inverted duplication (C) Signup and view all the answers

A segment of DNA is found with an 8-oxoguanine paired with adenine. Which of these outcomes is most likely to result from this modified base?

The formation of an 8-oxoguanine:A base pair instead of a G:C base pair in the daughter strand. (C) Signup and view all the answers

What is the key role of DNA glycosylases during base excision repair?

To remove a damaged nitrogenous base by cleaving its N-glycosidic bond. (C) Signup and view all the answers

A chromosome undergoes two breaks, and the segment between the breaks rotates 180 degrees before rejoining. The centromere is not included in the inverted segment. Which structural aberration does this scenario describe?

A paracentric inversion (C) Signup and view all the answers

Study Notes

DNA Damage and Repair

DNA replication cannot be perfectly accurate, as infinite precision requires infinite energy.
Errors during DNA replication, without proofreading, result in 1 mistake per 10⁵ nucleotides copied.
With proofreading, but without mismatch repair, errors decrease to 1 mistake per 10⁷ nucleotides copied.
With mismatch repair, the error rate further reduces to 1 mistake per 10⁹ nucleotides copied.
The Philadelphia chromosome is formed by translocation between chromosomes 9 and 22 [t(9;22)(q34;q11)], resulting in the formation of the Bcr-Abl fusion gene.
The Abl gene is a proto-oncogene, and when combined with the Bcr gene it becomes an oncogene.
The new protein, BCR-ABL, blocks DNA repair, impairs cells' ability to undergo apoptosis, and is created de novo in somatic cells.
The Philadelphia chromosome occurs in 95% of chronic myeloid leukaemias, 25-30% of adults and about 6% in children with acute lymphoblastic leukaemias, and in less than 1% of acute myeloid leukaemias.

Mutation

Mutation is a sudden, unintended change in a DNA nucleotide sequence.
This arises due to the influence of mutagenic factors – both internal and external.
Mutations alter genetic information in somatic and germ cells, which are passed onto daughter cells.
Somatic mutations occur in body cells, not inherited, and may cause cancer.
Germline mutations arise during gametogenesis or embryo development, may be inherited, leading to genetic diseases.
De novo mutations occur in an organism but not its parents. They can arise spontaneously or from induced factors, affecting somatic and germline cells, and sometimes the embryo itself.

Spontaneous Mutations

Spontaneous mutations can emerge from errors during DNA replication and transcription.
Replication errors are linked to modifications or loss of nitrogenous bases in DNA, accompanied by DNA polymerase slippage.
Transcription errors are tied to changes in promoter or regulatory sequences, alongside alternative splicing.

Base Modifications

Spontaneous base modifications in DNA can stem from various sources, including tautomerization, oxidative deamination, oxidation, methylation, and depurination/depyrimidination.

Base Tautomerization

Nitrogen bases exist in tautomeric forms, structural isomers differing in proton and double bond positions.
Examples include the keto/enol forms of thymine/uracil/guanine and amino/imine forms of adenine/cytosine.
Rare tautomeric forms can contribute to incorrect base pairings, resulting in mutations.

Oxidative Deamination

Oxidative deamination replaces an amino group (-NH₂) with an oxygen atom (-O-).
This leads to conversions: adenine to hypoxanthine, guanine to xanthine, and cytosine to uracil.
These conversions can cause mutations by altering correct base pairings.

Oxidation

Guanine reacting with reactive oxygen species (ROS) forms 8-oxoguanine (8-oxoG).
8-oxoG pairs with adenine rather than guanine, leading to G:C to 8-oxoG:A mutations, a common spontaneous DNA damage.

Depurination and Depyrimidination

Depurination removes purine bases from a nucleotide, while depyrimidination removes pyrimidines.
A hydroxyl group (-OH) takes the place of the removed base, causing significant DNA damage.
Depurination is more common than depyrimidination.

Replication Slippage

DNA polymerase can make errors due to "slippage errors," leading to fragments of DNA being duplicated.
Expansion/contraction typically involves trinucleotide repeats, with duplication lengths of two, three, four, or occasionally five nucleotides.
This mostly affects the lagging strand.

Transcriptional Mutations

Mutations in promoter, enhancer, or silencer sequences can affect gene transcription levels impacting mRNA production and protein levels.
Either decreasing or increasing gene transcription levels in this way, can have drastic effects on the levels of proteins in a cell.

Splicing Mutations

During post-transcriptional processing, mutations in splicing, including exon skipping, exon shuffling, and intron retention can alter the nucleotide sequence in mature mRNA and therefore the amino acid sequence in proteins.

Mutagenic Factors

Physical mutagens include ionizing radiation (e.g., alpha, beta, gamma rays, X-rays), and non-ionizing radiation (e.g., ultraviolet radiation).
Chemical mutagens are categorized as base analogs, chemicals, or intercalators, which exert their effects by altering the structure and properties of DNA.
Biological mutagens include viruses and bacteria.

Cell Response to Mutation

Cells can repair damage, die (apoptosis), or pass on mutations to daughter cells. This encompasses partial DNA repair or complete restoration to the original DNA structure, or the complete deletion of a cell to prevent further damage.

Influence of Mutations on Phenotype

Mutations can be beneficial, inert, adverse, or lethal, impacting the organism's traits (phenotype).

Mutation Types

Point mutations are alterations to the DNA's molecular level.
These can include substitution, insertion, deletion, inversion, and duplication of nucleotides within the DNA sequence.
Chromosomal mutations affect chromosome structure or numbers.
These could involve deletions, insertions, inversions, duplications, translocations (reciprocal or non-reciprocal), Robertsonian translocations, centric division, isochromosomes, ring chromosomes, and dicentric chromosomes.
Beyond chromosomal, mutations can occur in mitochondria or chloroplasts.

Point Mutations

These modify the specific nucleotide sequence, sometimes leading to incorrect and dysfunctional proteins.

Types of Point Mutations

Includes substitutions (transition or transversion), insertions, deletions, inversions and duplication.

Effects of Point Mutations

Silent mutations have no impact on the encoded amino acid.
Nonsense mutations premature create a STOP codon.
Missense mutations change the encoded amino acid, potentially affecting protein function (conservative or non-conservative).
Frameshift mutations alter the reading frame, affecting all subsequent codons.

Silent Mutations

Nucleotide changes in the third codon position often do not alter the amino acid encoded, or cause no change in the protein encoded.
These are often considered polymorphisms rather than mutations when occurring in more than 1% of a population (SNP).

Nonsense Mutations

Produce premature STOP codons, shortening the protein and leading to dysfunction.

Missense Mutations

Altering the encoded amino acid could lead to conservative or non-conservative changes impacting a protein's function.

Frameshift Mutations

Insertion or deletion of one or more nucleotides that are not evenly divisible by 3 causes a shift in the reading frame, drastically alters the amino acid sequence, and creates a dysfunctional protein.

DNA Repair

Cells have mechanisms to protect their genome from altered structure.
DNA damage responses typically occur in three stages - Recognition, Repair, and Restoration.
Stage I: damaged DNA is recognized and removed via enzymes called nucleases, which cut phosphodiester bonds connecting DNA nucleotides in the damaged strand.
Stage II: A DNA polymerase will utilize the undamaged DNA strand as a template to synthesize a copy of the complementary strand.
Stage III: the breaks in the sugar-phosphate backbone of the repaired DNA strand are then joined together to complete the repair process using another DNA enzyme, DNA ligase.

DNA Repair Systems

Direct repair involves repairing mismatched nucleotides.
Excision repair manages damage to single-stranded DNA (base excision repair or nucleotide excision repair).
Double-stranded DNA breaks repair utilizing two distinct mechanisms (nonhomologous end joining and homologous recombination).

Direct Repair

Involves removing alkyl groups from specific DNA bases without breaking the DNA strand's continuity. Methyltransferase enzymes achieve this removal of potentially harmful alkyl groups.

MMR-type Repair

Corrects mismatched nucleotides using specific proteins (MutS, MutL, MutH).

Base Excision Repair

Specialized enzymes, DNA glycosylases remove damaged nitrogenous bases creating AP sites.

Nucleotide Excision Repair

Repairing larger DNA damage using complex proteins (XPA, XPC, XPG, XPF).

Double Strand DNA Break Repair

Non-homologous end joining (NHEJ) and homologous recombination (HR) repair double-stranded breaks in DNA accurately, though NHEJ may introduce errors.

NHEJ Repair

Ku proteins recognize broken ends, and other proteins like Artemis and endonuclease remove damaged parts.
The ends are then joined by the XRCC4-ligase complex, resulting in possible nucleotide deletions.

HR Repair

Initiated immediately after replication. ATM kinase identifies the break and triggers cell-cycle arrest. A single strand is then formed.
A homologous, undamaged DNA strand from the sister chromatid is used as a template to repair the damaged site.

Chromosomal Aberrations

These are structural or numerical mutations large enough to be observed under a microscope.
Structural aberrations involve changes in chromosome structure (deletions, insertions, inversions, duplications, translocations).
Numerical aberrations involve changes in the number of chromosomes (aneuploidy and polyploidy).
Causes of aneuploidy - Nondisjunction (failure of chromosome separation during meiosis or mitosis) is a common cause.

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Description

This quiz explores the mechanisms of DNA damage and repair, focusing on the precision of DNA replication. It covers the types of mutations, their causes, and the differences between somatic and germline mutations. Test your understanding of how these processes impact genetic information.