DNA Replication and Mutation Rates
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Questions and Answers

What is the main consequence of CAG repeat expansion in the IT15 gene?

  • It enhances muscle strength.
  • It cures Huntington's disease.
  • It leads to neurodegeneration. (correct)
  • It prevents dementia.

    • Which of the following diseases is NOT caused by expanding trinucleotide repeats?

  • Huntington's Disease
  • Fragile X syndrome
  • Kennedy Disease
  • Type 1 Diabetes (correct)

    • What defines simple tandem repeats in the context of genetic sequences?

  • They are sequences repeated multiple times in succession. (correct)
  • They are only found in mitochondrial DNA.
  • They involve complex recombination processes.
  • They are short segments of RNA that transcribe protein.

    • What type of transposon exhibits an intermediate RNA stage during its insertion into the genome?

    <p>Retrotransposons</p> Signup and view all the answers

    Why is the sickle cell hemoglobin mutation considered beneficial in certain populations?

    <p>It offers protection against malaria.</p> Signup and view all the answers

    What role do Alu repeats play in the human genome?

    <p>They serve as recombination hotspots.</p> Signup and view all the answers

    What ethical issue is raised by genetic screening for Huntington's disease?

    <p>The psychological impact of knowing one's genetic fate.</p> Signup and view all the answers

    How many repeats in the CAG sequence of the Huntingtin gene indicates a risk for Huntington's disease?

    <p>36 or more repeats</p> Signup and view all the answers

    What type of mutation introduces a premature stop codon?

    <p>Nonsense Mutation</p> Signup and view all the answers

    Which of the following mutations is associated with Duchenne muscular dystrophy?

    <p>Nonsense mutations resulting in premature stop codons</p> Signup and view all the answers

    What is a characteristic of missense mutations?

    <p>They result in a change to the amino acid sequence</p> Signup and view all the answers

    Insertions and deletions can cause which type of mutation effect?

    <p>They can lead to frameshifts affecting protein function</p> Signup and view all the answers

    Which of the following represents a gain of function mutation?

    <p>A mutation leading to dwarfism like Achondroplasia</p> Signup and view all the answers

    Which of the following is true about indels?

    <p>Indels are responsible for 50% of Duchenne muscular dystrophy cases</p> Signup and view all the answers

    What is a common consequence of a missense mutation?

    <p>Alter the protein's amino acid sequence potentially affecting functionality</p> Signup and view all the answers

    What type of mutation is likely to have no effect on protein function?

    <p>Synonymous Mutation</p> Signup and view all the answers

    Which genetic disorder is chiefly caused by nonsense mutations?

    <p>Duchenne Muscular Dystrophy</p> Signup and view all the answers

    What is a mutation primarily defined as?

    <p>A hereditable change in DNA sequence</p> Signup and view all the answers

    Which of the following is a potential consequence of failed DNA repair mechanisms?

    <p>Development of cancer susceptibility</p> Signup and view all the answers

    Why is the mutation rate significant to organisms?

    <p>Too low a mutation rate can hinder adaptation, and too high can destabilize the genome</p> Signup and view all the answers

    Which type of mutation involves a change to a single nucleotide?

    <p>Point mutations</p> Signup and view all the answers

    What is the mutation rate of the human genome per base per generation?

    <p>2.5−8</p> Signup and view all the answers

    Which of the following is NOT considered a type of mutation?

    <p>Recombination events</p> Signup and view all the answers

    Which of the following statements about chromosomal mutations is correct?

    <p>Aneuploidy is a type of chromosomal mutation involving an abnormal number of chromosomes.</p> Signup and view all the answers

    What is the main cause of genetic variation in organisms?

    <p>Mutations and recombination</p> Signup and view all the answers

    Haploinsufficiency occurs when which of the following conditions is met?

    <p>One copy of a gene is deleted or inactivated</p> Signup and view all the answers

    What is the main advantage of having the sickle cell trait with one gene for Hb A and one for Hb S?

    <p>Greater chance of surviving malaria</p> Signup and view all the answers

    Why do loss of function mutants typically exhibit recessive traits?

    <p>Feedback loops often upregulate normal gene production</p> Signup and view all the answers

    In the context of gene products and quantitative signaling systems, what might a dosage effect indicate?

    <p>Gene products compete to determine cellular outcomes</p> Signup and view all the answers

    What is the significance of the combination of α and β globins in hemoglobin production?

    <p>They are needed in a specific ratio for effective function</p> Signup and view all the answers

    What accounts for approximately 75% of human genetic variation?

    <p>Single nucleotide changes</p> Signup and view all the answers

    How often do genetic differences between parental genomes typically occur?

    <p>Every 1000 bp</p> Signup and view all the answers

    What does the term heterozygote advantage refer to in the context of sickle cell traits?

    <p>Enhanced survival in malaria prevalence areas</p> Signup and view all the answers

    What percentage of changes in genetic variation represent structural changes primarily in copy number variation?

    <p>25%</p> Signup and view all the answers

    Which of the following best describes 'penetrance' in the context of genetic mutations?

    <p>The frequency at which a disease is manifested</p> Signup and view all the answers

    What is the approximate percentage of human DNA that encodes for proteins?

    <p>1.2%</p> Signup and view all the answers

    Which type of mutation typically does not change the encoded amino acid?

    <p>Silent mutation</p> Signup and view all the answers

    What happens to harmful mutations that reduce reproductive success over time?

    <p>They are gradually eliminated</p> Signup and view all the answers

    Which mechanism is considered the ultimate source of all genetic variation?

    <p>Mutation</p> Signup and view all the answers

    How do structural aberrations primarily affect genetic material?

    <p>They tend to affect protein sequence or not</p> Signup and view all the answers

    Transposable elements impact genetic variation by what means?

    <p>Allowing for mobile genetic changes</p> Signup and view all the answers

    What is a consequence of mutations having a mutation rate that is too low?

    <p>Organisms lose their ability to adapt to environmental changes.</p> Signup and view all the answers

    What differentiates genetic variation from mutations in terms of population frequency?

    <p>Genetic variation occurs at greater than 1% of the population.</p> Signup and view all the answers

    Which type of mutation refers specifically to a hereditable change in chromosome number?

    <p>Aneuploidy</p> Signup and view all the answers

    Which process is NOT a common way through which mutations can arise?

    <p>Hydrolysis of proteins leading to amino acid mutations.</p> Signup and view all the answers

    Which of these mutations is characterized by an insertion or deletion of a few nucleotides?

    <p>Indel mutation</p> Signup and view all the answers

    Which statement about mutations and genetic variation is true?

    <p>Mutations represent changes in DNA sequence, whereas genetic variation arises from positively selected mutations.</p> Signup and view all the answers

    What is a characteristic of DNA polymorphism?

    <p>It represents the variation in DNA sequences that can exist in more than 1% of the population.</p> Signup and view all the answers

    Which of the following best describes the significance of genetic variation in the context of evolution?

    <p>Genetic variation is essential for natural selection to occur.</p> Signup and view all the answers

    What health consequence can arise from genetic damage that is inaccurately repaired?

    <p>Neurological defects</p> Signup and view all the answers

    Which of the following best explains the relationship between gene recombination and genetic variation?

    <p>It enhances genetic diversity through crossover events.</p> Signup and view all the answers

    Study Notes

    DNA Replication Errors

    • Errors in DNA replication can lead to genetic damage that may not be repaired or is repaired incorrectly, resulting in changes to the DNA sequence.
    • Unrepaired genetic damage can have serious health consequences such as:
      • Cancer susceptibility
      • Progeria (accelerated aging)
      • Neurological defects
      • Immunodeficiency

    Mutations

    • Mutations are heritable changes in DNA sequence, chromosome number, form, or structure.
    • Most changes in DNA sequence occur due to errors in DNA replication.
    • The mutation rate is crucial:
      • Too low, organisms cannot adapt.
      • Too high, information cannot be retained.

    Mutation Rates

    • Mutation rates vary depending on the type of DNA and organism:
      • Transcription in vitro: 10-5 per base per generation.
      • DNA replication in vitro: 10-9 per base per generation.
      • Prokaryotic genome: 10-3 per base per generation.
      • Eukaryotic genome: 0.1-10 per base per generation.
      • Human genome: 2.5-8 per base per generation.
      • Mitochondrial genome: 3-5 per base per generation (highest!).

    Genetic Variation

    • All genetic changes originate from mutations.
    • Recombination (crossover events during meiosis) significantly contributes to genetic variation.

    Types of Mutations

    • Point Mutations: Changes to a single nucleotide (substitution), including missense and nonsense mutations, and insertions or deletions (indels).
    • Insertions and Deletions (Indels): Few nucleotides or several kb in size.
    • Chromosomal Mutations:
      • Polyploidy: Multiple sets of chromosomes.
      • Aneuploidy: Abnormal number of chromosomes (extra or missing).
      • Chromosome rearrangements: Parts of chromosomes moved to other chromosomes.

    Missense Mutations

    • A change in the nucleotide sequence that alters the amino acid sequence.
    • Includes point mutations and frameshifts.
    • May or may not affect protein function.
    • Can lead to:
      • Loss of function (e.g. Phenylketonuria (PAH), where multiple mutations in the gene cause the disease).
      • Gain of function (e.g. Achondroplasia, a form of dwarfism, usually caused by the same mutation).

    Nonsense Mutations

    • A change in the nucleotide sequence that results in a premature stop codon.
    • Usually leads to a non-functional protein.
    • Examples:
      • Mutations in the PAH gene.
      • Mutations in the BMPR2 gene.
      • Duchenne muscular dystrophy (often caused by mutations introducing a premature stop codon in the dystrophin gene).

    Insertions/Deletions (Indels)

    • Removal of one to several million nucleotides.
    • Account for 5-10% of all mutations.
    • Examples:
      • 50% of all Duchenne Muscular Dystrophy cases.
      • Majority of α-Thalassemias.
      • Associated with melanoma.

    Expanding Trinucleotide Repeats

    • Simple tandem repeats (same short sequences repeated many times) exist throughout the genome (e.g. CGG, CAG, CTG).
    • During replication, their copy number can increase.
    • Cause around 17 diseases, including:
      • Huntington's Disease
      • Fragile X syndrome
      • Kennedy Disease
      • Myotonic Dystrophy

    CAG Repeats in Huntington's Disease

    • CAG repeats encode a poly-glutamine region in several proteins.
    • In the IT15 gene encoding the Huntingtin protein, the region consists of 6-35 repeats.
    • 36 repeats or above cause Huntington's disease, a neurodegenerative disorder.

    Transposons

    • Sequences of DNA that can move around the genome.
    • Often regularly repeated throughout the genome and act as recombination hotspots.
    • Two main types:
      • Retrotransposons: "Copy and paste" system, with an intermediate RNA stage before insertion into the genome.
      • DNA transposons: "Cut and paste" the transposable element (TE).

    Alu Repeats

    • The most abundant mobile element in the human genome.
    • The LDL receptor has a high number of Alu repeats, potentially contributing to the large number of pathogenic deletions in this gene.
    • The LDL receptor removes "bad" cholesterol from the body (familial hypercholesterolemia (FH), atherosclerosis).

    Selective Pressure - Case: Malaria

    • Sickle Cell Hemoglobin (Hb S) mutation provides protection against malaria.
    • Individuals with sickle cell trait (one Hb A and one Hb S gene) have a higher chance of surviving malaria and don't suffer from adverse consequences of the Hb S gene.
    • Individuals with sickle cell disease (two Hb S genes) are susceptible to death from complications of the disease.
    • This illustrates heterozygote advantage.

    Haploinsufficiency

    • We inherit two copies of each gene (one from each parent).
    • Haploinsufficiency occurs when one copy is deleted or inactivated by a mutation, leaving only one functional copy.
    • Loss of function mutations tend to be recessive due to:
      • Feedback loops upregulating production of the normal gene in heterozygotes.
      • 50% of the gene product being sufficient.
    • Dosage effects can be seen when:
      • The gene product is part of a quantitative signaling system.
      • Gene products compete to determine a metabolic or developmental switch.

    Human Genetic Variation

    • Single nucleotide changes represent 75% of genetic variation.
    • Differences between parental genomes occur every 1000 base pairs, mostly in non-coding regions.
    • 25% of changes represent structural changes, mainly in copy number variation.
    • Genetic changes influence our risk of disease:
      • Rare high-risk variant with high penetrance.
      • Rare low-penetrance mutation/variation with moderate risk.
      • Common low-risk and low-penetrance variant.

    Functional Genetic Variation and Protein Polymorphism

    • Only 1.2% of our DNA encodes for proteins.
    • Most mutations have little effect as they are silent or in regulatory regions with no discernible effect.
    • Some mutations are harmful and are gradually eliminated from the population if they decrease reproductive success.
    • Some mutations are beneficial and become prevalent through positive selection.

    Summary and Take Home Points

    • A significant amount of genetic variation exists.
    • Mutations are the ultimate source of genetic variation, but recombination also plays a significant role.
    • Natural selection acts on genetic changes positively or negatively.
    • Different types of mutations exist, affecting protein sequence or not.
    • There's a spectrum of disease susceptibility variants.
    • Trinucleotide repeats and transposable elements contribute to genetic variation and disease.

    Genetic Variation and Mutations

    • Genetic variation: refers to differences in DNA sequences between individuals within a population.
    • Mutation: a change in the DNA sequence that typically affects fewer than 1% of the population.
    • DNA polymorphism: A genetic variation present in more than 1% of the population, often arising from a mutation that provided an evolutionary advantage.

    Mutation Causes

    • Strand breakage: Loss of nucleotides before end joining, which is error-prone.
    • Base loss: Glycosidic bonds are broken, leading to loss of a base.
    • Base change: Chemical modifications of bases can cause mispairing during replication.
    • DNA cross linking: UV light and chemical agents can cause DNA damage.
    • DNA replication error: Some errors are not corrected by DNA repair mechanisms.

    Consequences of DNA Repair Failure

    • Genetic damage: Unrepaired or inaccurately repaired DNA damage.
    • Health consequences:
      • Cancer susceptibility
      • Progeria (accelerated ageing)
      • Neurological defects
      • Immunodeficiency

    Mutations: Types

    • Point Mutation: Change to a single nucleotide, also called a Substitution.
      • Missense mutations: result in a change to the amino acid sequence.
      • Nonsense mutations: result in a premature stop codon, often leading to a non-functional protein.
    • Insertions and Deletions (Indels): Insertion or deletion of small to large stretches of nucleotides.
    • Chromosomal Mutations
      • Polyploidy: Possessing multiple sets of chromosomes.
      • Aneuploidy: Having an abnormal number of chromosomes, either extra or missing.
      • Chromosome rearrangements: Parts of chromosomes moved to different locations.

    Missense Mutations

    • Point mutations and frameshifts can cause missense mutations.
    • May or may not affect protein function.
    • Loss of function: Some mutations can result in non-functional proteins, leading to diseases like Phenylketonuria (PAH).
    • Gain of function: Mutations can lead to increased or altered protein function, as seen in achondroplasia (dwarfism).

    Nonsense Mutations

    • Point mutations and frameshifts can cause nonsense mutations.
    • Result in a premature stop codon.
    • Usually result in a non-functional protein.
    • Examples: Phenylketonuria (PAH), mutations in BMPR2 genes, Duchenne muscular dystrophy.

    Insertions and Deletions (Indels)

    • Removal of a small number of nucleotides to several million.
    • 5-10% of mutations are Indels.
    • Small Indels often cause frameshifts, leading to missense or nonsense mutations.
    • Major cause of Duchenne Muscular Dystrophy and Alpha-Thalassemia.
    • Associated with melanoma.

    Pulmonary Arterial Hypertension (PAH)

    • Caused by mutations in the BMPR2 gene.
    • BMPR2 gene encodes a receptor protein involved in blood vessel development.
    • Mutation positions are denoted by amino acid location and type of substitution (e.g., G182D indicates a change from Glycine to Aspartic acid at position 182).
    • Some PAH mutations are located in specific functional domains of the BMPR2 protein:
      • LB (Ligand binding)
      • TM (Transmembrane)
      • LR (Ligand recognition)
      • KD (Kinase domain)
      • CD (C-terminal domain)

    Expanding Trinucleotide Repeats

    • Repeated sections of DNA can increase in copy number during replication, causing diseases like Huntington’s disease, Fragile X syndrome, Kennedy disease, and Myotonic Dystrophy.
    • Number of repeats determines severity of symptoms.

    Huntington's Disease

    • Caused by expanding CAG repeats in the IT15 gene.
    • CAG repeats encode a polyglutamine region in the Huntingtin protein.
    • 36 or more repeats lead to neurodegenerative disease.
    • Raises ethical considerations about genetic screening.

    Transposons

    • ‘Jumping genes’ that can move within the genome.
    • Retrotransposons: Copy and paste mechanism, involves an RNA intermediate.
    • DNA transposons: Cut and paste mechanism, directly moves the transposable element.
    • Alu repeats: The most abundant mobile element in the human genome.
    • LDL receptor gene: Contains a large number of Alu repeats, potentially contributing to pathogenic deletions that cause Familial Hypercholesterolemia (FH).

    Selective Pressure and Genetic Variation: Case of Malaria

    • Sickle cell haemoglobin (HbS) mutation: Provides protection against malaria
    • Heterozygote advantage: Individuals with one sickle cell allele and one normal allele (HbA) have a protective advantage against malaria without suffering from sickle cell anemia.
    • Homozygotes: Individuals with two HbA alleles are susceptible to malaria. Individuals with two HbS alleles have sickle cell anemia, which can also be fatal.

    Haploinsufficiency

    • Diploid organisms have two copies of each gene.
    • Haploinsufficiency occurs when only one functioning copy of a gene is present, often due to deletion or inactivation of one copy.
    • One functional copy is insufficient for normal function.
    • Loss of function mutations can be recessive due to:
      • Upregulation of the normal gene
      • 50% gene product being sufficient.
    • Dosage effects can occur when:
      • Gene product is part of a quantitative signaling system.
      • Gene products compete for a specific function.
      • Genes products combine in fixed stoichiometry.

    Human Genetic Variation

    • Single nucleotide changes represent 75% of human genetic variation.
    • Differences between parental genomes occur every 1000 base pairs but are often in non-coding regions.

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