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Questions and Answers
What is the typical behavior of a homozygous mutant (b/b) genotype in terms of phenotype?
What is the typical behavior of a homozygous mutant (b/b) genotype in terms of phenotype?
Which of the following statements explains why most mutations are considered recessive?
Which of the following statements explains why most mutations are considered recessive?
In the context of genetics, how does a heterozygote (b/B) typically behave phenotypically?
In the context of genetics, how does a heterozygote (b/B) typically behave phenotypically?
Which of the following conditions is an example of a recessive mutation?
Which of the following conditions is an example of a recessive mutation?
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What key role does understanding dominance and recessivity play in genetics?
What key role does understanding dominance and recessivity play in genetics?
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Which of the following best describes gain-of-function mutations?
Which of the following best describes gain-of-function mutations?
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Which statement about incomplete dominance is true?
Which statement about incomplete dominance is true?
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How do mutations affect natural selection?
How do mutations affect natural selection?
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What is the primary effect of recessive mutations on gene function?
What is the primary effect of recessive mutations on gene function?
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Which of the following represents a phenotype change due to a recessive mutation?
Which of the following represents a phenotype change due to a recessive mutation?
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In terms of dominance and recessivity, what describes the relationship between a recessive mutant allele and a wild-type allele?
In terms of dominance and recessivity, what describes the relationship between a recessive mutant allele and a wild-type allele?
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What is an example of a consequence of a loss-of-function mutation?
What is an example of a consequence of a loss-of-function mutation?
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What is meant by the term 'wild-type' in genetic discussions?
What is meant by the term 'wild-type' in genetic discussions?
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How can a mutation result in incomplete dominance?
How can a mutation result in incomplete dominance?
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What potential outcomes can arise from a recessive mutation regarding substrate and product levels?
What potential outcomes can arise from a recessive mutation regarding substrate and product levels?
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What principle should guide the understanding of a mutant allele’s impact?
What principle should guide the understanding of a mutant allele’s impact?
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What is typically affected by the gene products encoded by alleles?
What is typically affected by the gene products encoded by alleles?
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Which statement about recessive mutations is accurate?
Which statement about recessive mutations is accurate?
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What characterizes most dominant mutations?
What characterizes most dominant mutations?
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In which situation is a loss-of-function mutation likely to be recessive?
In which situation is a loss-of-function mutation likely to be recessive?
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What is an example of incomplete dominance?
What is an example of incomplete dominance?
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How do wild-type alleles generally behave in genetic contexts?
How do wild-type alleles generally behave in genetic contexts?
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When might a single functioning copy of a gene not be enough?
When might a single functioning copy of a gene not be enough?
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Which of the following best describes wild-type specimens in model organisms?
Which of the following best describes wild-type specimens in model organisms?
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Study Notes
Lecture Title
- Fundamental Topics in Biology 2X: Molecular Biology II: Mutations II
Aims and Objectives
- Students should be able to outline how recessive mutations affect phenotype, using examples
- Explain why most mutations are recessive, using examples
- Explain why some mutations are dominant, using examples
- Understand the importance of dominance/recessivity for hypotheses about mechanisms and interventions/therapies related to molecular biology and genetics
What's in a genome sequence?
- A long sequence of nucleotides (letters) provided (A, T, C, and G).
Recessive versus Dominant: All about the heterozygote
- Wild-type (B/B) behaves as wild-type always
- Homozygous mutant (b/b) behaves as mutant always
- Heterozygote (b/B): behaves as wild type always
Recessive vs Dominant: why? and WIIFM?
- Trivial/myopic view: Only important to specific scientists
- Conspiracy theory: Useless detail to torture and bore students
- Operational: Key to inheritance patterns (Mendel), basic Punnett Squares, probability, how natural selection works on mutations.
- Profound: The root cause (the why); how mutations affect genes and what the gene does, intervention strategies.
Recessive Mutations: Albinism Pathway Mutations
- Four conditions (biochemically related): Albinism, Alkaptonuria, Cretinism, Phenylketonuria
- Are there underlying patterns amongst these?
- Example from Griffiths et al. textbook, Chapter 6, figure 6.5 shows the pathway.
Recessive Mutations: Albinism .. background
- Conversion of Tyrosine to Melanin: four genes in humans:
- OCA1: Tyrosinase enzyme -- mutants have severe albinism
- OCA2: P Protein (tyrosinase helper) -- mutants have mild albinism
- OCA3: Tyrosine-related gene (very rare) -- mutants have weak albinism
- OCA4: SLC45A2 Protein (tyrosinase helper) -- mutants have mild albinism
- Hermansky-Pudlak Syndrome -- other albinism-like syndromes described.
Recessive Mutations: Albinis
- The gene encodes Tyrosinase
- The mutation affects the gene or its product (enzyme)
- More or less or no activity compared to wild-type enzyme.
Recessive Mutations: Albinism ..
- If the mutant version of Tyrosinase has less or no activity, this causes too much substrate (tyrosine) and too little product (melanin) leading to the phenotype.
Recessive Mutations: Albinism
- Less melanin makes people more prone to skin cancer
Phenylketonuria
- High Phenylpyruvic acid
- Progressive brain dysfunction
- Mutation in phenylalanine hydroxylase gene
- Recessive condition
- Treatment: Phenylpyruvic acid birth test, Low phenylalanine diet
- Example from Griffiths et al. (2005), Chapter 6, figure 6.15 displays the pathway
Phenylketonuria
- The gene encodes Phenylalanine Hydroxylase:
- What effect does the mutation have on the gene or gene product? (MORE/DIFFERENT/LESS/NO activity than wild-type Tyrosinase).
Phenylketonuria (PKU)
- If the mutant version of Phenylalanine Hydroxylase has less or no activity, it causes too much substrate (Phenylalanine) and too little product.
Recessive mutations = commonality
- Albinism: Pigmentation (black)
- Alkaptonuria: Urine (black)
- Cretinism: Mental Retardation
- PKU: Progressive brain dysfunction
Recessive mutations = commonality (change phenotype)
- Albinism: Pigmentation (black)
- Alkaptonuria: Urine (black)
- Cretinism: Mental Retardation
- PKU: Progressive brain dysfunction
- One result can be too much substrate or too little product as a result of the mutation
Rule of Thumb 1
- The mutant allele = recessive to wildtype, wild-type organisms are a reference for study.
Rule of Thumb 2
- Gene products (proteins) affect phenotype and have functions
- Dominance/recessivity is decided by how gene products function in heterozygotes
Rule of Thumb 3
- Most recessive mutations are loss-of-function
- Most loss-of-function mutations are recessive
Pause in awe...
- Most recessive mutations are loss-of-function
- One functioning allele is enough to be normal in diploid organisms
- There must be some genes where one functioning copy is not enough.
Rule of Thumb 4
- Most dominant mutations are gain-of-function
- Gain-of-function mutations can be complete or incomplete
NOTE: Reality is rarely so simple....
- Dominant mutations are rarely fully dominant (incomplete dominance)
- Having one mutant allele can cause a change or difference compared to normal (heterozygote)
- Two mutant alleles have a more obvious difference from normal (homozygote)
Gain of function
- More of a "normal" function (increased or extreme activity)
- Example: More active enzyme (RAS oncogene stuck in "on" state) or producing more protein
- New function unrelated to the normal gene's function
Gain of normal function
- Achondroplasia: Most common form of dwarfism
- Autosomal dominant (but see next slide)
- 99% of cases: One of two missense point mutations in FGFR3 (Fibroblast growth factor receptor 3)
- FGFR3 normally inhibits/slows limb growth, it is normally activated by FGF binding, and can be stuck in active state even when FGF is not bound --> inhibits bone growth
Strange facts about Achondroplasia
- Only 20% of cases have a parent with achondroplasia
- 80% are de novo mutations in a germline
Gain of new/abnormal function
- Huntington's: Progressive neurodegeneration
- Autosomal dominant mutation
- Rare -- affects 1 in 10,000 patients
- HTT gene, huntingtin -- unknown function (cytoskeleton)
- Symptoms: Onset 30-50s, limb control issues, mortality 10-15 years after symptoms begin
Huntington's
- CAG triplet encodes glutamine -- repeat near N-terminus
- Wild-type allele has <35 units
- Mutant allele has >37 units --> Longer polyglutamine repeat in the protein that is neurotoxic.
Recessive vs Dominant: checklist
- Operational: Key to inheritance patterns and probability
- Profound: Understanding the mutation's affect on the gene, what the gene does, to suggest potential therapies
Knowledge matters: what the genes actually do
- Consider wingless mutant flies
- Recessive and dominant wingless mutations
Knowledge matters: what genes do II
- Most recessive mutations are loss-of-function
- Most dominant mutations are gain-of-function
- Example: In a recessive mutation, the gene product might be required for wing construction; In dominant mutations, the gene product might normally act to prevent wing formation
Knowledge matters: affects treatment strategy
- Treating recessive vs. dominant diseases with different approaches
- Consider gene therapy (introducing a WT allele or inactivating the mutant allele) or pharmacology (developing agonists and antagonists).
Recessive vs Dominant: overall
- Operational: Key to inheritance patterns and probability, effects how natural selection acts on mutations, and how they spread through populations
- Profound: Tells something about how mutations affect genes, tells something bout what the gene does, suggests potential therapies
Finally...MOST mutations
- MOST mutations (95%) that affect a gene are recessive
- This is true even before natural selection
MOST mutations
- Most mutations (95%) affect a gene in a recessive manner
- Random change to a gene or applying a sledgehammer often damages gene function.
- Damaging the system often makes it work less efficiently.
- A few changes will make it work more efficiently or in different ways.
PUZZLE
- Questions posed throughout the lecture
- Questions for students to ponder, like whether people with PKU would also be albino.
References
- Various resources for causes and consequences of mutations
- References for mutations with the albinism pathway
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Description
This quiz covers the fundamental concepts of mutations in molecular biology, focusing on their effects on phenotypes. Students will explore why most mutations are recessive, examples of dominant mutations, and the significance of understanding dominance and recessivity in genetic research and therapies.
