Allelic variation and pleiotropy of a single gene

are the mutations in haplosufficient genes dominant or recessive and why?

• they are recessive

haplosufficient means that with one copy of the wild type allele is sufficient to cary out the function of the gene → it looks wild type

• to be able to see the phenotype associated with the mutant, you must be homozygous for the mutant

describe the effect of dominant mutations

when you create a heterozygous what phenotype do you see?

having a single copy of the mutation produces a phenotype despite having a wild-type copy of the gene

What happens if a gene becomes hyper activated?

When a gene is hyper-activated, that’s a gain-of-function situation.
Gain-of-function mutations are typically dominant:

• One hyper-active copy is enough to change the phenotype

• The normal (wild-type) copy can’t “turn off” the overactive one

What are haploinsufficient genes?

For some genes you need both alleles to for the gene to carry out their function

there is a phenotype associated with the number of doses (homozygous recessive, heterozygous and homozygous dominant all have different phenotypes associated)

haploinsufficient mutations are often dominant

What is a dominant negative mutation?

occur when proteins form dimers

the mutation produces a mutant protein that interferes with the function of the normal protein causing a dominant loss of function

ie. P53 → it is a transcription factor which means it contains a DNA binding domain and in the case of the mutation the DNA binding domain becomes inactive due to a missense mutation. it forms a tetramer to bind the DNA but the mutation affects its ability to bind DNA but not to create a tetramer → P53 can still be expressed and form a tetramer complex but then the ones that are non functional can interfere with the wild-type

What is incomplete dominance?

• an allele doesn’t behave like a complete loss of function where you would see a 3:1 ratio in mendelian genetics

• the gene responsible for producing this pigment is NOT haplosufficient

• in this case having only one functional allele just doesn’t produce the pigment as much as it does when two functional copies are present

• phenotype is visible → homozygous recessive, heterozygous and homozygous dominant all have different phenotypes associated

• the incomplete dominance is between the mutant and wild-type

What is codominance?

• case where in the heterozygous you can clearly see the two alleles in the phenotype

• best example is blood type

  • the loss of function mutant i encodes a gene responsible for the production of glycosyltransferase → puts sugar group onto the sugar chain

  • type A has a specific sugar added and B has an extra galactose, whereas type O (I/i) doesn’t have the ability to add the last sugar

• Codominance arises in type AB because of the assy that we use to determine whether you’re type A or type B (you have one copy of each allele)

• if we put an antibody that can recognize the specific sugar added by the glycosyltransferase → if it recognizes it molecule it will coagulate

How do we classify dominance?

• often determined by the phenotype we characterize

• ie. phenotype = anemia

HbA/ HbA = no anemia

HbS/HbS = anemia

HbA/HbS = no anemia

as long as you have one functional copy you won’t have anemia

this shows dominance of HbA over HbS

• ie. phenotype = blood cell shape

HbA/HbA = normal shape

HbS/HbS = sickle shape

HbA/HbS = slight sickle shape

this shows incomplete dominance

Describe the codominance idea of HbS in blood

If you look at how it migrates on a gel:

• unaffected migrates faster (A)

• sickle cell anemia migrates slower (S)

• sickle cell trait (the heterozygous) you can see both the bands

HbA and HbS are codominant because both allele can be clearly discerned at the protein level

what is a recessive lethal gene?

homozygous mutations causing lethality in the animal, either recessive or dominant mutations

• really you just need two copies of the mutation → you don’t survive (doesn’t really have anything to do with just recessive, it can be dominant)

• ie. mouse coat

wild type - black coat

mutant - yellow coat (dominant)

but when you look at viability → yellow is recessive because its lethal

if you cross the yellow to normal → 1:1

if you cross yellow to yellow → 2:1

reason for this because yellow is the dominant allele and black is mutant

yellow mice are heterozygous and you can’t get homozygous (AA) because the dominant is lethal which is why you get the 2:1 ratio

the yellow allele is dominant over dark pigmentation, but recessive lethal, two copies of the dominant allele cause lethality

What are conditional alleles?

expression of a phenotype depends on certain conditions

ie. phenotype is influenced by temperature or arginine controls their growth

• stability of the protein may be affected because drosophila for example can’t control their body temperature like mammals so they can express the different phenotype at different temperatures

• auxotrophs: without arginine they lose the ability to synthesize certain substances required for their growth

• certain rabit type: at lower temperatures they produce black pigment in their extremities whereas at lower temperatures they don’t and this is become tyrosine kinase (protein responsible for this) is activated at a lower temperature

What is penetrance?

the percentage of individuals given allele who exhibit the phenotype of the allele

• everyone will carry the allele but only some will show the phenotype linked to the allele

• ie. BRCA2 → not everyone who carries the gene will show the phenotype because there are other factors like the environment that can have an affect

What is expressivity?

the degree to which a given allele is expressed at the phenotypic level → the intensity of the phenotype