Week 5 Flashcards
Why do We need allele classification
There are 1000 upon 1000 DNA sequence changes that can affect an organisms phenotype. Need to organise these changes.
5,000 to 30,000 genes in organisms which requires a system of organization with respect to the effect of DNA sequence changes.
Familiarity with allele classification simplifies disucssion of genetic analysis
Statement of allele classification components
Inheritance
Effect of DNA sequence has on the protein produced from the mutant allele.
The effect that the change in protein structure has on function
Functional Allele
A gene that will be able to express an active gene product, a protein or RNA.
Allele classification based on Inheritance (vocabulary)
Complete dominance; Haplosufficient
Recessive
Incomplete dominance; partial dominance (haploinsufficient)
Haplosufficient
Complete dominance
It is sufficient to have only one functional allele to result in the phenotype.
Determine dominance by looking at
The heterozygote
Haploinsufficient
Incomplete dominance; partial dominance.
One allele produces half the amount of protein, not enough to fully express the phenotype.
Haploinsufficiency is a property of
The functional allele in diploids.
Not a function of the inactive allele.
This nonfunctional allele uncovers the property of the functional allele.
Mutations in human Pax6 result in Aniridia
Lack of an iris when heterozygous.
Inherited as a dominant genetic condition.
Inactive allele has nothing to do with the phenotype.
That one functional copy provides enough pax6 for the eye to form but not enough activity present for it to make an iris
How do I know that the phenotype observed in a heterozygote is a property of the functional allele and not the mutant allele?
Check by adding another functional allele. If the phenotype does not occur and WT is reinstated then the inactive allele has nothing to do with the phenotype.
Allele classification based on DNA sequence changes in the coding region of a gene.
SNP
Silent
Missense
Nonsense
Indel
Frameshift
Insertion/deletion of AA
Silent
DNA sequence changes that do not change the sequence of the polypeptide produced,
No change in function the protein
Due to redundancy of the genetic code
Missense
Amino acid change in the polypeptide chain.
Can affect fucntion of protein and change the phenotype
Nonsense Allele
premature stop codon results in a truncated protien.
Frameshift
Shifts the reading frame over resulting in a change in the amino acid sequence.
Insertion Allele
insertions or deletions occuring in multiples of three.
upon translation of the messenger RNA there is an insertion or deletion of an Amino Acid
Insertion Allele
insertions or deletions occuring in multiples of three.
upon translation of the messenger RNA there is an insertion or deletion of an Amino Acid
Synonymous substitutions
Silent mutations because the protein sequence is not changed.
Nonsynonymous substitutions
Missense and nonsense mutations because the protein sequence is changed
Problem with WT
Not every gene is meant to be functional.
Some phenotypes are simply just variation.
Loss of function (lf)
Generally recessive; exception haploinsufficiency
DNA sequence changes that reduce the function of the protein or RNA encoded by the gene.
LF allele subclasses
Null alleles: coding and regulatory
Weak/hypomorphic alleles: coding and regulatory
Conditional alleles: temperature sensitive
Null alleles
Amorphic alleles.
DNA sequence changes that result in a complete inactive gene product.
Completet deletion of a gene such that there is not a single nucleotide left in the genome.
no product ever produced.
Null amorphic alleles in regulatpry sequences
the gene is never transcribed
Weak alleles: hypomorphic alleles
DNA sequence changes that result in an inactive gene product.
the gene product might have some activity, the small presence activity the phenotype produced is less severe, much weaker.
Type 1 weak alleles-hypomorphic alleles
Partially inactive gene product: multifunctional proteins with only 1 of 2 functions affected by the change.
1 inactive domain.
Weak alleles-hypomorphic alleles in regulatory sequence
Partial expression of a gene product
Regulatory mutant resulting in partial expression
this gene is not expressed in all cells that it is normally expressed in.
Conditional Alleles: temperature sensitive alleles
Active gene product at low temperature; change in DNA sequence results in a protein that is still active when a temperature is grown at lwo temperature
Inactive gene product at high temperature; change in sequence results in the protein being unable to fold
Gain of Function Alleles
Generally associated with mis-regulation of a gene product’s activity and are generally dominant.
Hypermorph
Neomorph
Dominant gain of function allele
If we have a diploid we will still see expression of the phenotype.
Loss of negative regulation Ras example
RAS is a GTP binding protein
RAS proteins exist in two states GTP and GDP binding, these two states are in a dynamic equilibrium.
Substituition and Pi elimination.
These two states have two activation states.
Environmental signals regulates the amount of RAS present by shifting the equilibrium.
Deletion of RAS genes, no ras present in the GTP bound state.
Cells don’t grow.
Hydrolysis of GTP is important to the regulation of cell growth. RAS has the ability to hydrolyze GTP
Gain of Function
DNA sequence change results in an AA change that leads to an inability toe hydrolyze GTP. Ras is stuck in an on state. The cells grow themselves to death.
gf allele in RAS is
Dominant to the WT allele in heterozygotes.
Antennapedia
In a functional allele antennapedia is only expressed. in the cells that give rise to the leg and not in the cells that give rise to the antenna.
When we have antenna and leg primordia that lack antennapedia expression due to being homozygous for an antennapedia loss of function allele both the cells of the antenna primordia the leg primordia adopt antenna.
Dominant Negative
The gene product works in a complex, either with itself or another protein and the activity of all the proteins in the complex is essential for the activity of the complex.
Any protein inactive is responsible for the inactivity of the whole complex.
Mutation should not affect the ability of the dimer to form.
Dominant Negative
The gene product works in a complex, either with itself or another protein and the activity of all the proteins in the complex is essential for the activity of the complex.
Any protein inactive is responsible for the inactivity of the whole complex.
Mutation should not affect the ability of the dimer to form.
A dominant negative allele ______ ______ to ______ ______ than a null allele when heterozygous
reduces
activity
greater
extent
Greater reduction in activity because these proteins assort into complexes independently of one another.
Regulation of cell number
A major reason that all humans look the way they do is the regulation of cell proliferation and cell death.
Cells divide and differentiate to give rise to an arm but to have seperate digits….
the cells between the digit had to die.
There are mechanisms that regulate balances ________/____-_______ and cell death/survival
proliferation; non-profileration
C. Genetics
Cancer arises due to genetic variation in somatic cells; it is a somatic condition.
Cancer is not inherited. You may inherit a greater susceptibility to the effects of somatic genetic variation.
The environment (mutagens, diet, smoking etc.) can influence the rate of somatic genetic variation
C Mutant Allele Classification
Dominant Acting Oncogenes
Recessive acting tumour suppressor genes
Functional allele in C genetics
Proto-oncogene
Oncogenes as gain-of-functions alleles (gf); cell
Loss of negative regulation Ras.
Ras can no longer hydrolyze GTP. Cells continaully divide
Receptor tyrosine kinases
oncogne/gain of function allele
ligand dependent growth
Mutation or deletion of the extracellular domain.
Autophosphorylation of intracellular domain occurs regardless of the presence of the ligand/GF present
Bcl-2
Gain of function allele
The protein mediates cell death and cell survival.
Chromosome translocation.
IgG heavy chain promoter is moved into the regulatory region of the Bcl2 gene.
Bcl2 is overproduced resulting in cell survival
Tumor suppressor genes as loss-of-function alleles (lf)
These are recessive.
Two hit model for spontaneous tumors
Inheritance of susceptibility
Two origins of mutant alleles
Retinoblastoma
RB binds to the E2F transcription factor = no growth
Inactive RB is phosphorylated and can’t bind to E2F = Growth
RB null loss-of-function the cell grows.
Heterozygous for the functional allele = no illness
Retinoblastoma; inherit a seemingly _______ susceptibility
dominant
Inherit a mutant copy and then develops a somatic hit; leads to disease
