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Questions and Answers
What is a key factor that distinguishes mutations from genetic variation?
Which statement accurately describes both mutations and genetic variation?
How do DNA crosslinking and strand breakage generally result in mutations?
Which of the following processes can lead to base loss during DNA mutation?
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What is a primary consequence of base change in DNA?
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Which of the following factors contributes to the generation of genetic variation?
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What role do mutations play in the context of diseases?
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Which statement accurately describes DNA polymorphism?
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What is the result of having 36 or more CAG repeats in the IT15 gene?
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Which of the following diseases is NOT associated with expanding trinucleotide repeats?
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What type of repeats are CAG, CGG, and CTG considered?
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What mechanism do retrotransposons use to incorporate themselves into the genome?
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What ethical issue is raised by Huntington's Disease regarding genetic screening?
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What is the role of the LDL receptor in the human body?
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Which term describes the process where transposons can lead to mutations in genes?
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What is the outcome of having a sickle cell haemoglobin mutation in areas with malaria?
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What is a mutation?
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Which of the following health consequences can result from DNA repair failures?
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What is the mutation rate for the human genome?
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What typically causes changes in DNA sequence?
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Which type of mutation involves changes to a single nucleotide?
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What is the role of recombination in genetic variation?
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Which of the following is NOT a type of mutation?
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What is the genetic makeup of a child with sickle cell trait?
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What is the consequence of having a mutation rate that is too low?
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Which condition exemplifies the heterozygote advantage?
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What does haploinsufficiency imply about gene function?
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Why are loss of function mutants usually recessive?
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What percentage of genetic variation is attributed to single nucleotide changes?
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In thalassemia, what condition must be met for α and β globins to effectively produce hemoglobin?
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What can cause a dosage effect in gene products?
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How often do differences occur between parental genomes?
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What percentage of genetic changes primarily involve structural changes in copy number variation?
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Which of the following represents a rare high-risk genetic variant?
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What does the term 'penetrance' refer to in the context of genetics?
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What percentage of human DNA encodes for proteins?
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Which type of mutation typically does not alter the encoded amino acid?
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What role do beneficial mutations typically play in evolution?
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Which of the following is NOT a type of genetic mutation mentioned?
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What major mechanism besides mutation is highlighted as driving evolution and genetic variability?
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Study Notes
Genetic Variation and Disease
- Genetic variation is the difference in DNA sequences among individuals.
- Mutations are changes in the base sequence that occur in less than 1% of the population.
- Genetic variation occurs at greater than 1% and likely arose from mutations that were positively selected during evolution.
- Polymorphism is the term used to describe DNA variation that occurs at greater than 1%.
How Mutations Arise
- Mutations arise from various mechanisms including:
- Strand breakage: DNA breaks and nucleotides are lost during repair
- Base loss: The glycosidic bond between a base and sugar is broken
- Base change: Oxidation, deamination, or bulky DNA adducts can alter base pairing
- DNA crosslinking: UV light or chemicals like cis-platinum can cause crosslinks between bases
- DNA replication errors: Some errors in replication are not corrected
- DNA repair mechanisms failing leads to unrepaired or incorrectly repaired DNA damage, resulting in changes in DNA sequence.
Health Consequences of Unrepaired DNA Damage
- Cancer susceptibility
- Progeria (accelerated ageing)
- Neurological defects
- Immunodeficiency
Mutations
- A mutation is a heritable change in DNA sequence, chromosome number, form or structure.
- Mutations primarily arise from errors in DNA replication and occur at a rate influenced by factors such as the type of organism, the environment, and the specific gene.
- Mutation rate is crucial for evolution - too low prevents adaptation, too high hinders information retention.
Mutation Rates
- Different entities have varying mutation rates, from low in vitro rates to higher in vivo rates across prokaryotes and eukaryotes.
- Human genome mutation rate is estimated to be 2.5-8 per base per generation.
- Mitochondrial genome has the highest mutation rate at 3-5 per base per generation.
Causes of Genetic Variation
- All genetic changes initially arise from mutations.
- Recombination (crossover events during meiosis) plays a significant role in generating variation.
Types of Mutations
-
Point Mutations:
- Changes to a single nucleotide (substitution).
- Can be missense (change amino acid) or nonsense (creates a stop codon).
-
Insertions and Deletions (Indels):
- Few nucleotides to several kilobases inserted or deleted.
-
Chromosomal Mutations:
- Polyploidy: Multiple sets of chromosomes.
- Aneuploidy: Abnormal number of chromosomes (extra or missing).
- Chromosome rearrangements: Parts moved to other chromosomes.
-
Expanding Trinucleotide Repeats:
- Short tandem repeats (same sequences repeated) throughout the genome.
- Replication can increase copy number.
- Linked to diseases like Huntington’s Disease, Fragile X syndrome, Kennedy Disease, and Myotonic Dystrophy.
CAG Repeats in Huntington's Disease
- CAG repeats encode a polyglutamine region in proteins.
- In the IT15 gene (Huntington protein), 36 repeats or more lead to neurodegenerative disease - Huntington's Disease.
- Huntington's raises ethical issues around genetic screening.
Transposons
- Sequences of DNA that can move around the genome, acting as recombination hotspots.
- Retrotransposons: "Copy and paste" system with an RNA intermediate stage.
- DNA transposons: "Cut and paste" system directly moving the transposable element.
- Alu repeats: Most abundant mobile element in the human genome.
- Alu repeats are linked to deletions in the LDL receptor, contributing to familial hypercholesterolemia (FH) and atherosclerosis.
Selective Pressure: Case of Malaria
- Sickle cell hemoglobin (Hb S) mutation provides protection against malaria, but also causes sickle cell anemia.
-
Heterozygote advantage:
- Individuals with one Hb A and one Hb S gene (sickle cell trait) are more resistant to malaria.
- Shows how genetic variation can be advantageous in specific environments.
Haploinsufficiency
- We inherit two copies of each gene, one from each parent.
- Haploinsufficiency occurs when one copy is deleted or inactivated by mutation, leaving only one functional copy.
- Individuals with haploinsufficiency may not have enough of the gene product to function normally.
- Loss-of-function mutations are often recessive.
- Dosage effects can occur if the gene product is part of a quantitative signaling system or competes with other products to regulate a metabolic or developmental process.
Human Genetic Variation
- 75% of genetic variation comes from single nucleotide changes (SNPs).
- Differences between parental genomes occur every 1000 base pairs, but mostly in non-coding regions.
- 25% of changes are structural, mainly in copy number variation.
- Genetic changes influence disease susceptibility and risk.
- Susceptibility varies depending on variant rarity, penetrance, and risk level.
- Penetrance refers to how frequently a mutation is manifested as a disease.
Functional Genetic Variation and Protein Polymorphism
- Only 1.2% of human DNA codes for proteins.
- Most mutations have little effect, being silent mutations (don't change the amino acid) or in regulatory regions with no discernible effect.
- Some mutations are harmful and are eliminated if they reduce reproductive success.
- Beneficial mutations become prevalent through positive selection.
Summary and Key Takeaways
- A significant amount of genetic variation exists within the human population.
- Mutations are the primary source of genetic variation, but recombination also plays a crucial role in generating diversity.
- Natural selection acts on genetic changes, positively or negatively.
- Multiple types of mutations exist, including point mutations, insertions and deletions, and chromosomal aberrations.
- Mutations can either affect the protein sequence (missense/nonsense) or have no impact (silent).
- Genetic variations contribute to a spectrum of disease susceptibility.
- Important genetic features include trinucleotide repeats and transposable elements.
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Description
Explore the intricate dynamics of genetic variation and its link to disease. This quiz dives into mutations, polymorphisms, and the mechanisms that give rise to genetic changes. Test your knowledge on how these variations impact evolutionary processes and human health.
