Week 5

Question 1

Why do We need allele classification

Answer 1

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

Question 2

Statement of allele classification components

Answer 2

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

Question 3

Functional Allele

Answer 3

A gene that will be able to express an active gene product, a protein or RNA.

Question 4

Allele classification based on Inheritance (vocabulary)

Answer 4

Complete dominance; Haplosufficient

Recessive

Incomplete dominance; partial dominance (haploinsufficient)

Question 5

Haplosufficient

Answer 5

Complete dominance

It is sufficient to have only one functional allele to result in the phenotype.

Question 6

Determine dominance by looking at

Answer 6

The heterozygote

Question 7

Haploinsufficient

Answer 7

Incomplete dominance; partial dominance.

One allele produces half the amount of protein, not enough to fully express the phenotype.

Question 8

Haploinsufficiency is a property of

Answer 8

The functional allele in diploids.

Not a function of the inactive allele.

This nonfunctional allele uncovers the property of the functional allele.

Question 9

Mutations in human Pax6 result in Aniridia

Answer 9

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

Question 10

How do I know that the phenotype observed in a heterozygote is a property of the functional allele and not the mutant allele?

Answer 10

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.

Question 11

Allele classification based on DNA sequence changes in the coding region of a gene.

Answer 11

SNP
Silent
Missense
Nonsense

Indel
Frameshift
Insertion/deletion of AA

Question 12

Silent

Answer 12

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

Question 13

Missense

Answer 13

Amino acid change in the polypeptide chain.

Can affect fucntion of protein and change the phenotype

Question 14

Nonsense Allele

Answer 14

premature stop codon results in a truncated protien.

Question 15

Frameshift

Answer 15

Shifts the reading frame over resulting in a change in the amino acid sequence.

Question 16

Insertion Allele

Answer 16

insertions or deletions occuring in multiples of three.

upon translation of the messenger RNA there is an insertion or deletion of an Amino Acid

Question 16

Insertion Allele

Answer 16

insertions or deletions occuring in multiples of three.

upon translation of the messenger RNA there is an insertion or deletion of an Amino Acid

Question 17

Synonymous substitutions

Answer 17

Silent mutations because the protein sequence is not changed.

Question 18

Nonsynonymous substitutions

Answer 18

Missense and nonsense mutations because the protein sequence is changed

Question 19

Problem with WT

Answer 19

Not every gene is meant to be functional.

Some phenotypes are simply just variation.

Question 20

Loss of function (lf)

Answer 20

Generally recessive; exception haploinsufficiency

DNA sequence changes that reduce the function of the protein or RNA encoded by the gene.

Question 21

LF allele subclasses

Answer 21

Null alleles: coding and regulatory

Weak/hypomorphic alleles: coding and regulatory

Conditional alleles: temperature sensitive

Question 22

Null alleles

Answer 22

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.

Question 23

Null amorphic alleles in regulatpry sequences

Answer 23

the gene is never transcribed

Question 24

Weak alleles: hypomorphic alleles

Answer 24

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.

Question 25

Type 1 weak alleles-hypomorphic alleles

Answer 25

Partially inactive gene product: multifunctional proteins with only 1 of 2 functions affected by the change.

1 inactive domain.

Question 26

Weak alleles-hypomorphic alleles in regulatory sequence

Answer 26

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.

Question 27

Conditional Alleles: temperature sensitive alleles

Answer 27

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

Question 28

Gain of Function Alleles

Answer 28

Generally associated with mis-regulation of a gene product’s activity and are generally dominant.

Hypermorph
Neomorph

Question 29

Dominant gain of function allele

Answer 29

If we have a diploid we will still see expression of the phenotype.

Question 30

Loss of negative regulation Ras example

Answer 30

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.

Question 31

gf allele in RAS is

Answer 31

Dominant to the WT allele in heterozygotes.

Question 32

Antennapedia

Answer 32

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.

Question 33

Dominant Negative

Answer 33

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.

Question 34

Dominant Negative

Answer 34

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.

Question 35

A dominant negative allele ______ ______ to ______ ______ than a null allele when heterozygous

Answer 35

reduces
activity
greater
extent

Greater reduction in activity because these proteins assort into complexes independently of one another.

Question 36

Regulation of cell number

Answer 36

A major reason that all humans look the way they do is the regulation of cell proliferation and cell death.

Question 37

Cells divide and differentiate to give rise to an arm but to have seperate digits….

Answer 37

the cells between the digit had to die.

Question 38

There are mechanisms that regulate balances ________/____-_______ and cell death/survival

Answer 38

proliferation; non-profileration

Question 39

C. Genetics

Answer 39

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

Question 40

C Mutant Allele Classification

Answer 40

Dominant Acting Oncogenes

Recessive acting tumour suppressor genes

Question 41

Functional allele in C genetics

Answer 41

Proto-oncogene

Question 42

Oncogenes as gain-of-functions alleles (gf); cell

Answer 42

Loss of negative regulation Ras.

Ras can no longer hydrolyze GTP. Cells continaully divide

Question 43

Receptor tyrosine kinases

Answer 43

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

Question 44

Bcl-2

Answer 44

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

Question 45

Tumor suppressor genes as loss-of-function alleles (lf)

Answer 45

These are recessive.

Two hit model for spontaneous tumors

Inheritance of susceptibility

Two origins of mutant alleles

Question 46

Retinoblastoma

Answer 46

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

Question 47

Retinoblastoma; inherit a seemingly _______ susceptibility

Answer 47

dominant

Inherit a mutant copy and then develops a somatic hit; leads to disease