Genetics Quiz: Recessive Mutations and Phenotypes

Lecture Title and Details

• Fundamental Topics in Biology 2X: Molecular Biology II: Mutations II
• Lecture 3
• Prof Joe Gray
• September 25th, 2024

Aims and Objectives

• Students should be able to outline how recessive mutations affect phenotype, with examples.
• Explain, with examples, why most mutations are recessive.
• Explain with examples, why some mutations are dominant.
• Understand the importance of dominance/recessivity for hypotheses about mechanisms and interventions/therapies in molecular biology and genetics.

What's in a Genome Sequence?

• A large expanse of DNA base pairs are shown.

Recessive Versus Dominant: Heterozygote Behavior

• Wild-type (B/B) organism behaves as wild-type.
• Homozygous mutant (b/b) organism behaves as mutant.
• Heterozygote (b/B) organism always behaves as mutant.

Recessive vs Dominant: Why and WIIFM?

• Trivial/Myopic view: Focuses on pea scientists and history of science.
• Operational: Key to inheritance patterns (Mendel), probability, Punnett Squares, probability. Affects natural selection and spread of mutations.
• Profound: Understands the root cause, showing how a mutation affects the gene, what the gene does, and suggests therapy/intervention strategies impacting populations.

Recessive Mutations: Albinism Pathway Mutations

• Four biochemical conditions related to Albinism: Albinism, Alkaptonuria, Cretinism, Phenylketonuria.
• Do these conditions share similarities or underlying patterns?

Recessive Mutations: Albinism ... background

• Four genes involved in converting Tyrosine to Melanin: OCA1, OCA2, OCA3, and OCA4.
• OCA1 mutations cause severe albinism (tyrosinase enzyme).
• OCA2 mutations cause mild albinism (P protein, tyrosinase helper).
• OCA3 and OCA4 mutations cause weak albinism (tyrosine-related gene and SLC45A2 protein, tyrosinase helper).
• Various related disorders to albinism exist.

Recessive Mutations: Albinism ...

• Gene encodes Tyrosinase: determines effect of a mutation on the gene/gene product (e.g., more or less activity).
• Substrate A: Tyrosine, Product B: Melanin.

Recessive Mutations: Albinism

• Genes encode Tyrosinase. Less or no tyrosinase activity leads to too much substrate (tyrosine) and too little product (melanin).
• Less melanin is linked to increased skin cancer risk.

Phenylketonuria

• Characterized by high phenylpyruvic acid levels, progressive brain dysfunction.
• Mutation in phenylalanine hydroxylase gene, manifesting as a recessive condition.
• Treatment includes a phenylpyruvic acid birth test, and a low phenylalanine diet.

Phenylketonuria

• Gene encodes Phenylalanine Hydroxylase. The effect of a mutation is determined:
• Question: Is the activity more/different than WT , or less/no activity( of Tyrosinase)..
• Substrate A: Phenylalanine , Product B / Tyrosine

Phenylketonuria (PKU)

• Gene encodes phenylalanine hydroxylase (enzyme).
• If a mutant version of the enzyme has less or no activity, then it results in too much substrate (phenylalanine) and too little product (tyrosine).

Recessive Mutations = Commonality (Effect on Gene)

• Albinism = pigmentation.
• Alkaptonuria = black urine.
• Cretinism = mental retardation.
• PKU = progressive brain dysfunction.
• Question: How does each mutation affect the gene or gene product?
• In all cases, the enzyme activity is lessened or absent; the gene product is less or absent.

Recessive Mutations = Commonality (Change Phenotype)

• Albinism = Pigmentation.
• Alkaptonuria = Black urine.
• Cretinism = Mental retardation.
• PKU = Progressive brain dysfunction.
• Question: How do mutations change the phenotype?
• Options: Too much substrate, or too little product.

Rule of Thumb 1

• To avoid confusion, think from the mutant allele's perspective.
• The mutant allele is recessive to the wild-type allele.
• The wild-type is the reference state.

Rule of Thumb 2

• Genes make gene products (usually proteins) affecting phenotype.
• Dominance/recessivity depends on how the gene products work together.

Rule of Thumb 3

• Most Recessive mutations are LOSS-of-FUNCTION mutations
• Corollary: Most Loss-of-function mutations are recessive.

Pause in Awe...

• Most recessive mutations are loss-of-function.
• One functioning allele in a diploid organism usually appears normal.
• The question of some genes needing more than one functioning copy to appear normal is raised.

Rule of Thumb 4

• Most dominant mutations are GAIN-of-FUNCTION mutations.

NOTE: Reality is rarely so simple…

• Dominant mutations likely aren't fully dominant (incomplete dominance).
• Having one mutant allele may be enough to alter phenotype.
• Having more than one mutant allele may result in a worse outcome.

Gain of function

• Most dominant mutations are gain-of-function.
• This can manifest in more activity, production of abnormal product, or completely new function.

Gain of normal function: Achondroplasia

• Most common form of dwarfism.
• Caused by missense mutations in the FGFR3 gene.
• FGFR3 normally inhibits limb growth, and mutations lead to the receptor being locked in an active state, inhibiting bone growth.

Strange facts about Achondroplasia

• Only 20% of individuals with achondroplasia have a parent with the condition.
• Identical point mutations are often causative.
• The mutated site is known as the most mutable single site in the human genome (regarding the most common form.)
• Two heterozygote parents may have normal and Achondroplasia offspring in a 1:2 ratio.

Gain of new/abnormal function: Huntington's

• Progressive neurodegenerative disease with an autosomal dominant inheritance pattern.
• Mutation in the HTT gene which has an unknown function, but likely involves cytoskeleton.
• Symptoms show up in the 30s or 50s.

Huntington's

• The CAG triplet repeats encode glutamine, and a larger than normal number of repeats leads to a neurotoxic protein.

Recessive vs Dominant: Checklist

• Operational: understanding Mendel's principles and inheritance patterns.
• Profound: understanding the root cause of a mutation's effects on gene function, and its potential implications for therapy and intervention.

Knowledge Matters: What Genes Actually Do

• Studying wingless mutant flies shows the difference between recessive and dominant mutations. Recessive mutation reduces production of wing-making proteins, whereas in dominant mutation prevents normal prevention of wing formation due to mutations.

Knowledge Matters: what genes do II

• Most recessive mutations result in loss-of-function.
• Most dominant mutations are gain-of-function.
• Recessive mutation: gene product required for wing development is lost.
• Dominant mutation: gene product that normally prevents wing development is mutated resulting in abnormal/extra formation of wing.

Knowledge Matters: affects treatment strategy

• How to treat recessive or dominant disease/condition?
• Gene therapy (Introduce WT allele or inactivate mutant allele)?
• Pharmacology (Develop agonist or antagonist)?

Recessive vs Dominant: Overall

• Operational: Understanding Mendel's principles and inheritance patterns; the impact of mutation in Punnett Squares to determine probability.
• Profound: Understanding the root cause of mutations (how mutations cause changes to the gene) impacting populations.

Finally...MOST mutations

• Most mutations affecting a gene are recessive, even before considering natural selection factors.

MOST mutations

• Most mutations (approximately 95%) affecting a gene are recessive, appearing in a phenotype only in homozygous forms.
• Random changes are more often damaging a gene, causing less function (recessive)

Puzzle

• Students are encouraged to ask questions about the material presented or their own misunderstandings.
• A key question example is: Should someone with PKU also be albino?

###References

• Campbell & Reece, Biology.
• Griffiths, Gelbart, and others, Modern Genetic Analysis.
• Griffiths et al. (2006) Intro. Genet. Anal., 8e, pp. 362-364.

Test your understanding of recessive mutations and their impact on gene function and phenotype. This quiz covers key concepts such as phenylketonuria, albinism, and the importance of mutant alleles. Explore how these mutations can lead to various outcomes, including conditions related to glutathione metabolism and mental retardation.