Lecture 6 Flashcards
What is the wild type allele?
The most commonly found allele in a population
If identical alleles are present on both homologous chromosomes, the organism/cell is said to be ______ for that allele
Homozygous
If one allele is wild type and the other allele is not (I.e mutant allele) the organism/cell is said to be _______ for that allele
Heterozygous
The known mutant alleles for a given gene plus its wild type allele are referred to as an ________ or _________
The known mutant alleles for a given gene plus its wild type allele are referred to as an allelic series or Multiple alleles
Define homozygotes
A cell/organism with identical alleles of a gene of interest
-Two copies of the same allele
Define Heterozygotes
A cell/organism with one wild type copy and one mutant allele of a gene of interest
If an individual has two mutant alleles that are different from each other, what is this referred to as?
- Hereroallelic - general term
or
-Transheterozygous (drosophila community)
or
-Compound heterozygotes (mice community)
Define Hemizygous
A situation where a cell/organism has only one copy of a gene/locus/chromosomal region
What are two examples of when a hemizygote might be observed?
Example 1: deletion - corresponding gene/locus/region is deleted on the homologous chromosome
Example 2: the gene/locus/region occurs naturally in one copy (true for most genes on X or Y chromosomes in an XY individual)
i.e. males are hemizygous for most genes found on sex chromosomes given that they have one X and one Y
Complex traits are typically _______ (involving multiple genes)
Complex traits are typically Polygenic (involving multiple genes)
-likely derived from multiple genes = exibit large variety of phenotypes
Simple traits may be linked to a single gene with multiple alleles. Single gene traits are called ______
Monogenic
What is complete dominance
Type of dominance in which the same phenotype is expressed in homozygotes (AA) and in heterozygotes (Aa); only the dominant allele is expressed in a heterozygote
What is haplosufficiency?
Simply that one functional copy is sufficient for a wild type phenotype
What is incomplete dominance?
Type of dominance in which the phenotype of the heterozygote falls in between the phenotypes of the two homozygotes = blending (i.e both alleles contribute to phenotype
Define codominance
Type of allelic interaction in which the heterozygote simultaneously expresses the phenotypes of both homozygotes
Eg Sickle Cell Anemia: point mutation in haemoglobin
Eg2: Blood type of AO X BO:
Offspring: AO | AB | BO | OO (AB is codominance)
Define Haploinsufficiency
One functional copy is NOT sufficient for a wild type phenotype
Give an example of a heterozygous advantage
Hb^S allele: identical to Hb^S except for a missense mutation that provides some protection against malaria
What three mechanisms explain how a mutated allele can be dominant:
- Haploinsufficiency: one wt copy is not sufficient to produce a wt phenotype
- Dominant Negative Effect
- Gain of Function Effect
What is The dominant-negative effect
the gene product from the mutant allele interferes with the gene product from the WT allele (muller’s morph: “antimorph”), thus blocking the wildtype function
What is the Gain of Function effect?
the mutant allele acquires a new property not present in the WT allele and this new property causes a phenotype (mullers morph - “hypermorph” and “neomorph”
Who came up with five classes of mutant alleles?
H.J. Muller
Muller’s Morphs
Muller’s name for a morph that results in a complete loss of function:
“Amorph”
(Modern day called “Null mutation”)
What causes an amorph (null mutation)?
Provide three examples
Any mutation abrogating the function of a gene:
- complete deletion of entire gene
- missense point mutation that abolishes all functions of the protein
- A nonsense point mutation yielding a truncated, non-functional protein
What is Hypomorph?
Muller’s term for an allele with partial loss of function.
The allele is still partially functional but not at the level of the wild type gene
Two examples that could cause a hypomorph:
- Mutation in the regulatory element may cause reduced expression of a gene
- Point mutation may reduce the activity of the gene product
What is porphyrias?
- Group of diseases affecting heme production (there are 8 genes that make heme)
- the heme biosynthetic pathways are amorphic or hypomorphic
- Having no heme at all is lethal = at least one allele must have some activity
- “vampire disease” - injection of blood (heme) or glucose can reduce symptoms and highly sensitive to sunlight
What is a hypermorph?
Muller’s term for a gene that is active at a level higher than the wild type gene (more protein = more activity)
What is an example of how a hypermorph is caused?
- A mutation in a regulatory element (usually non-coding DNA) may increase the expression of a gene resulting in more protein (or RNA)
or
- A mutation in the coding region may cause the protein to be hyperactive while the protein levels are comparable to the WT allele
What kind of change is seen in a hypermorph (qualitative or quantitative)?
Quantitative: no new property gained just a higher amount of activity
Hypermorph vs Neomorph?
Hypermorph: must have increased activity in an area where there was already activity
Neomorph: New activity in a new location (where no previous activity by the gene in question)
Myostatin was provided as an example of one of muller’s morphs. What is myostatin and which morph (consider context) is it an example of?
Hint:
Respect to the gene?
Respect to muscle growth?
Myostatin is a repressor of muscle growth = mutation means excessive muscle growth
Stop codon truncates myostatin activity
Respect to the gene this is an amorph = stops activity of myostatin
Respect to muscle growth this is a hypermorph
What is a neomorph?
Muller’s term for a mutation that creates “something new” (gain of function - qualitative)
Allele is active but has acquired a function that the WT gene does not have
Provide three examples of how a neomorph might arise
- A mutation affecting the active centre of an enzyme may alter its substrate specificity
- More commonly, a mutation int he regulatory region activates the gene in the wrong tissues or the wrong times (eg Burkitt lymphoma)
- Translocations with breakpoints in genes may create new hybrid genes
What is Burkitt lymphoma?
translocation of an oncogene next to a novel regulatory element
- MYC gene is under control of REGig regulatory region = activity in an area there shouldn’t be = rapid proliferation = cancer
What is an Antimorph?
Muller’s term for a “dominant negative”
-Allele is not only active but can override the function of the wildtype allele in a heterozygous setting (different from normal dominance because it isn’t the wild type function of the gene that is causing the dominance)_
What are muller’s five morphs
- Amorph
- Hypomorph
- Hypermorph
- Neomorph
- Antimorph
What are complementation tests?
A tool to categorize mutants
ie allows identification of mutation in different genes
Mutations that complement are mutant in different _____ ______ and are called ____ _____ mutations
Mutations that complement are mutant in different gene loci and are called Non-allelic mutations
Mutations that fail to complement (non-complementing) are mutant in the ______ and are called _____ mutations
Mutations that fail to complement (non-complementing) are mutant in the same gene and are called allelic mutations
Complementation tests are crucial for:
The identification of new mutants
How do you make a random mutation for genetic screen
Classic approach:
- feed a chemical that induces mutation (mutagen)
- EMS is a commonly used mutagen - ethylmethane sulfate (G-A transitions and T-C transitions)
What are the target nucleotides for EMS (mutagen)
G and T
How does EMS induce mutations
- EMS is an alkylating agent - adds ethyl group to normal nucleotides (via oxygen on nucleotide)
- Results in mispairing after replication - Point Mutation
How is a genetic screen done?
- mutagenize animals to isolate new mutants
- Typically thousands of progeny are examined
What is the most famous genetic screen? What was the outcome?
- Heidelberg Screen
- Isolated 600 mutants representing 120 genes
- Revolutionized our understanding of developmental processes
- (many of) The discovered genes are conserved between flies and humans (ie homologous)
After feeding EMS you have 20 different stocks. What are the two extreme possibilities?
Extreme 1: 20 mutations in 20 different genes
Extreme 2: 20 mutations in the same gene
What is the overall purpose of a complementation test?
Determine whether two mutations represent alleles of the same gene
Fail to complement: you can conclude that two mutations have hit ______
Fail to complement: you can conclude that two mutations have hit the same gene
What is true breeding?
Homozygous for a particular gene
Consider the case where you have isolated 4 true-breeding lines that have white petals. All you know is the phenotype (white) and that they are true-breeding. How would you determine if they complement (ie if they are on different genes)
- Purple: AABB or AaBb or AABb or AaBB
- White: aaBb or aaBB or AAbb or Aabb or aabb
- bold = true-breeding
Cross the two genes = if they complement, they will produce purple offspring
