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Lecture 5 Dominance relationships

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What is the biochemical explanation for dominance?

The genetic definition of dominance is when an allele expresses its phenotype in the heterozygous condition.

By saying A is dominant over a, we are saying AA and Aa have the same phenotype.

Conversely the genetic definition of recessive is when allele does not express its phenotype in the heterozygous condition.

For example a gene responsible for height in the pea plant has a dominant allele, T.

T/T= 6ft T/t= 6ft t/t=2ft

By definition 6ft is dominant to 2ft. And t is recessive to T.

Now if the short phenotype is observed in the heterozygote, then

T/T= 6ft T/t= 2ft t/t=2ft

short is dominant to tall.

Dominant and recessive are operational definitions.

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Genes are responsible for the production of specific proteins/enzymes.

***** Remember enzymes catalyze biochemical reactions.

Substrate ---------> product

EnzymeA ^ |

GeneA

Wild-type= phenotype observed most of the time in nature

Phenotype is a characteristic of the majority of individuals of a species under “natural” conditions

Some genes make enzymes

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For example here is the biochemical reaction responsible for producing the red pigment in flowers:

Substrate ---------> Pigment

(white) EnzymeA (Red) ^ |

GeneA

GeneA has two alleles:

A= which is normal and makes functional enzyme

a = which is mutant and produces nonfunctional enzyme

Genotype Enzyme amountPhenotype (pigment)

AA 2 enzyme units Red

Aa 1 enzyme unit Red

aa 0 enzyme unit white

So for genes that code for an enzyme,

Enzyme activity is often not limiting and so 1 unit of enzyme is sufficient for WT function

Dominant = functional enzyme

Recessive = nonfunctional enzyme

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Incomplete dominance-

Now lets look at something different:

Although straightforward dominance/recessive relationships are the rule, there are a number of variations on this pattern of inheritance of PHENOTYPES

One of these variations is called Incomplete dominance

Incomplete dominance is the occurrence of an intermediate phenotype in the heterozygote.

The heterozygote exhibits a phenotype intermediate between the two homozygotes

A good example of this is in four o'clock plants:

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Incomplete dominance-

Although straightforward dominance/recessive relationships are the rule, there are a number of variations on this pattern of inheritance.

One of these variations is called Incomplete dominance

Incomplete dominance is the occurrence of an intermediate phenotype in the heterozygote.

The heterozygote exhibits a phenotype intermediate between the two homozygotes

A good example of this is in four o'clock plants:

P: Pure white x Pure red

F1: All Pink

F2: 1/4Red 1/2Pink 1/4White

How are these results explained?

How do we relate genotype to phenotype

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The following explanation readily explains the phenotypic outcome:

P: Pure white x Pure red

F1: All Pink

F2: 1/4Red 1/2Pink 1/4White

Do not use C and c to denote the two alleles- Use C1 and C2

C1= white C2= red C1/C2= pink

In practice incomplete dominance can lie anywhere on the phenotypic scale

Height:

A1A1= 2ft A2A2= 6ft A1A2= 2ft -6ft

The phenotype of the heterozygous individual is the key towards determining whether an allele behaves as a recessive, dominant, or incomplete dominance

In incomplete dominance, Phenotype ratio= Genotype ratio

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Another classic example of this is the colors of carnations.

R1R2 x R1R2

R1 R2

R1 R1R1 R1R2

R2 R1R2 R2R2

R1 is the allele for red pigment. R2 is the allele for no pigment.

Thus, R1R1 offspring make a lot of red pigment and appear red.

R2R2 offspring make no red pigment and appear white.

R1R2 and R2R1 offspring make a little bit of red pigment and therefore appear pink.

In biological systems when substrate/product is reduced, it sometimes leads to incomplete (dominance) phenotypes.

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Co-dominance:

Another variation on the classical pattern of inheritance of phenotype is co-dominance

The surface of a red blood cell carries molecules known as antigens.

There are approximately 250 antigens on the surface of blood cells

More than 30 different blood group antigen systems are recognized.

A B O system

Rh+/Rh- system

Blood groups M and N

……..

The MN blood group system is of little medical importance.

In this system there are two antigens, M and N.

A gene in humans (called the L gene) codes for a protein present on the surface of the red blood cells.

There exist two allelic forms of this L gene

LM and LN

These two alleles represent two different forms of the protein on the cell surface.

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We are used to phenotypes as flower color, height, hair length, shape etc.

The blood group phenotype is at a much finer level- that of the cell and is harder to observe.

*****

Remember the phenotype chosen is what the geneticists happens to notice. In this respect it can be somewhat subjective and depend on how observant the geneticists happens to be.

Genotype Phenotype

LM LM

LN LN

LM LN

At the protein level most phenotypes are Codominant!!!

Both proteins are being expressed in the heterozygote.

So with respect to the red blood cells, the genotype and phenotype relationships are as follows:

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Question: How do you study these phenotypes?

To determine the phenotype of the LM and LN blood cells a very

specific set of antibodies is required. The anti- LM antibodies

specifically recognize the LM blood-cell surface proteins and the

anti LN antibodies specifically recognize the LN surface proteins.

In practice, specific recognition by each antibody results in precipitation of the red-blood cells.

The antibody allows us to determine if the cell surface

markers are LM or LN

So with the anti- LM and anti- LN antibodies, one can

determine which form of the L gene (LM or LN) is being expressed in each individual

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In this case, the heterozygote is expressing both proteins.

Therefore, with regards to expression of LM and LN protein on the RBC surface these alleles are co-dominant

P: LM LM x LN LN

F1: LM LN (self cross)

F2: LM LM: LM LN : LN LN

1 2 1

Once again phenotype ratios are the same as genotype ratios.

Co-dominant phenotype is different from incomplete phenotype

Genotype Assay Phenotype

Binding by

- LN - LM antigen on RBC surface

LM LM No Yes LM

LN LN Yes No LN

LN LM Yes Yes LM and LN

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Phenotypes

With respect to blood in a LN LM individual and a LM LM

individual

Looking at RBC by the naked eye- the heterozygote will be

like the homozygote.

We have discussed

pea shape,

flower and eye color,

Morphology

as phenotypes.

These are all properties that are easily visualized.

Wild-type Mutant

However with specialized tools, microscopes and specific

probes such as antibodies we can detect less easily visualized

phenotypes.

With regards to the M and N blood groups (by

Immunoprecipitation) the phenotype is different in the two

individuals.

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Sickle cell anemia

Sickle cell anemia is a good example of the variance in dominance relationships.

Sickle cell is an inherited disorder that results from a mutation in the gene coding for the protein globin.

Hemoglobin is a major constituent of the red blood cells and is involved in O2 transport.

HbA: an allele that codes for the normal beta globin protein

HbS: an allele that codes for an abnormal form of beta globin

We will examine the phenotype of the two homozygotes and the heterozygote at three levels:

the individual,

the cell

the protein.

Remember, the phenotype of the heterozygote is the key to understanding whether a gene behaves as a dominant or recessive.

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HbA/HbA

HbA/HbS

HbS/HbS

Normal O2 levels Sealevel

Normal

Normal

Anemic

Dominant Phenotype?

Low O2 levels High altitude

Normal

Anemic

Anemic

Dominant Phenotype?

Depending on the O2 levels, the HBS allele (and the HBA allele) behaves as a dominant or recessive allele.

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Genes and their products

What is the cellular phenotype with respect to these genotypes

The HBS allelic form of the protein causes the red blood cells to sickle.

Cell shape

HbA/HbA Normal shape

HbS/HbS Sickled

HBS/HbA Partially sickled ***

At this level the alleles HbA and HBs are incompletely dominant

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Phenotype at the level of the protein.

So the HbS allele is classified differently depending on the level the phenotype is analyzed:

Individual Cell Protein

Recessive &/or incomplete co-dominantDominant dominant

-

+ HbA

/HbA

HbS/H

bS

HbA

/HbS

HbS and HbA are co-dominant

With respect to the presence or absence of the proteins

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Fitness

Individuals homozygous for HbS/HbS often die in childhood.

Yet, the frequency of the HbS allele is quite high in some regions of the world. In parts of Africa frequencies of 20% to 40% are often found for the HbS allele.

It was found however that in areas in which there was a high HbS allelic frequency, that there was also a corresponding high frequency of mosquitoes infected with the protozoan parasite, plasmodium. This parasite causes Malaria in humans.

Heterozygous HbA/HbS individuals are more resistant to the mosquito born parasite. Consequently this allele in maintained in the population in spite of its deleterious consequences in the homozygous state.

This condition in which the heterozygote is more fit than either of the two homozygotes is known as a balanced polymorphism (over dominance, heterozygote advantage)

HbA/HbA HbA/HbSHbS/HbS

Malaria sensitive resistant dead

resistance

Pleiotropy

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Pleiotropy: One Gene Influences More Than One Trait

Alleles of the –globin gene influence the type of hemoglobin produced, red blood cell shape, susceptibility to anemia,

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Lethal alleles-

Most of the mutations that we have discussed do not affect the viability of the individual. For example the mutations that produce white eyes in Drosophila or wrinkled yellow cotyledons in the plant do not disrupt viability. This means that the mutated gene is specifically involved in determining eye color and is not involved in processes central to viability of the fly.What would be the genetic consequences if we isolated a mutation that disrupted an enzyme that was critical for the viability of the organism?

In a plant

RPN1/rpn1 x RPN1/rpn1

seeds produced

You Plant seeds

75% seeds produce plants25% seeds do not produce plants (lethal)

RPN1 is a essential enzyme (proteosome)

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For example in Drosophila, Cy

Cy+/Cy+ is normal wings

Cy+/Cy is curly wings

Cy/Cy is (curly wings)

WHEN YOU LOOK AT WING SHAPE- The Curly mutation is a dominant mutation that produces Cy wings in the heterozygous condition:

Flat wings (wild type) is recessive

In animals lethal mutations are difficult to follow

You detect them by a distortion in the normal segregation ratio

(flies are alive)

(flies are alive)

(flies are dead)

WHEN YOU LOOK AT LIFE, The curly mutation is recessive- recessive (lethal).

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Curly

When a heterozygous Cy male is crossed to a heterozygous Cy

female,

look at LIVE PROGENY

Cy to non-Cy progeny are produced in a 2:1 rather than the

Mendelian 3:1 ratio

+ = normal or wild type genecy= dominant Cy mutation

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Curly

When a heterozygous Cy male is crossed to a heterozygous Cy female, look at LIVE PROGENYCy to non-Cy progeny are produced in a 2:1___ rather than the Mendelian 3:1___ ratio

+ = normal or wild type genecy= dominant Cy mutation

The explanation for the _2:1__ rather than the expected _3:1__ ratio is that Cy behaves as a recessive lethal mutation and cy/cy individuals die prior to reaching adulthood. So you cannot score the wing phenotype.

cy/+ x cy/+

Live Flies Curly: Non curly2 : 1

cy/cy cy/+ +/+All Flies Lethal CurlyNormal

1 2 1

Phenotype of survival 3alive (75%) : 1 dead (25%)Phenotype of curly 2 curly (66%) : 1 not curly (33%)

Some Alleles are Lethal in Homozygous Form

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The Ay allele is a dominant coat color allele that is lethal when carried in homozygous form.

Cross a true-breeding black mouse with a mutant yellow: Now cross two yellow offspring (AAy). Result is 2 yellow: 1black

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How would you test this hypothesis?

Take the progeny of the previous cross and perform a test cross with the homozygous recessive parent

+/+ x +/+ all normal flies

cy/+ x +/+ 1:1 curly:normal

cy/cy x +/+ all curly (not found)

All curly flies from the previous cross only give a 1:1 ratio.

There are no cy/cy flies!!!

(+/+ wild-type fly)- Test cross

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Unlike cy, most recessive lethal alleles do not have an additional dominant visible phenotype.

Mutations in enzymes required for DNA replication are lethal. Cells lacking this enzyme cannot replicate their DNA and die.

Lets say a gene codes for an essential enzyme.

Gene A (normal enzyme)Gene a (mutant enzyme)

The expected genotypes and phenotypes are as follows:

genotype: A/A A/a a/A a/aphenotype: alive alive alive die

Phenotype of survival is 3:1

Lethal mutations arise in many different genes.

These mutations remain “silent” except in rare cases of homozygosity.

A mutation produces an allele that prevents production of a crucial molecule

Homozygous individuals would not make any of this molecule and would not survive.

Heterozygotes with one normal allele and one mutant allele would produce 50% of wild-type molecule which is sufficient to sustain normal cellular processes- life goes on.

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Multiple alleles of a single gene

We have described a gene as exiting in one of two states: normal or mutant.

Each of these states is called an allele of that gene.

Normal (wild-type) -----> Mutant

Red eye white eye

Smooth peas wrinkled peas

However it is possible and common for a gene to have more than two forms.

Many genes exist in three or more forms (we say there exists three or more alleles of that gene)

Such a gene is said to have multiple alleles

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It is important to remember that even though a given gene may have many forms, each individual possesses only two forms of that gene. Diploids contain two copies of each gene.

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Eye color in Drosophila

For example in Drosophila, many alleles exist for the white gene: 1) The normal (wild-type) allele W or w+ gives red eyes

2) white allele w has white eyes

3) white apricot wa gives apricot colored eyes

There are over 150 alleles of the white gene!

But in an individual fly there are only two alleles- e.g. W & wa or w & wa

How many genotypes are possible given three alleles at the white gene?

With 3 alleles, there are six possible pair-wise combinations

W+/W+ w/w W+/w wa/wa W+/wa wa/w

WT

Enz V+Precursor -----Brown pigment \

\ transporter W+ ------------------ --------- Red /

Precursor ----- Vermilion pigment /Enz B+

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The C gene in rabbits

· C- full color

· cch- chinchilla (light gray)

· ch- Himalayan (albino, black extremities) · c- albino

These represent different alleles of the c locus with the following dominance relationship:

Dominant ---------------> Recessive

C ---> Cch ---> Ch ---->c

The dominance relationship is relative to alleles being tested. You can only test TWO alleles at a time in a diploid (because there are only two alleles in any one individual)

CC Ccch Cch Cc full color

cchcch cchch cchc chinchila

chch chc Himalayan

cc albino

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The C enzyme is a tyrosinase involved in melanin production

Tyrosinase breaks down tyrosine

Wildtype produces dark brown rabbits

Ch allele has 20% of the activity of normal. Therefore Chinchilla is light brown

h is a Ts mutant (active at low temp). Therefore Himalayan rabbits have dark brown/black feet and ears (cold) but white body (hot).

C is albino. No enzyme made.

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ABO blood groups

The Human A,B,O blood group is the result of multiple allelism They were discovered in 1900 by Dr. Landsteiner.

The 4 blood types were defined on the basis of a clumping reaction. Serum (the liquid part of the blood-Ab) from one individual is mixed with red blood cells (erythrocytes) from another individual. If they belong to different groups they will clump. This reaction is similar to the M and N groups discussed earlier. The clumping is due to the presence of antibodies in the serum.

Blood group Genotype Ant on RBC Ab in bloodA IAIA A B

IAi

B IBIB B AIBi

AB IAIB AB --

O ii - A B

A B

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The ABO gene has three alleles

IA

IB

i

IA synthesizes an enzyme that adds sugar A to RBC surface

IB synthesizes an enzyme that adds sugar B to RBC surface

i does not produce an enzyme

A phenotype arises from two genotypesIAIA and IAi

B blood type is due to two genotypesIBIB and IBi

AB blood type is due to a single genotypeIAIB

O Blood type is due to a single genotypeii

Three alleles give you six genotypes but only four phenotypesEach phenotype is determined by two alleles

IA is dominant to i but is co-dominant to IB

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Blood transfusions

There is a reciprocal relationship between antigens in the RBC surface and antibodies present in the serum. If an individual has A antigens in their RBCs, they will have B antibodies in their sera.

The biological significance of this reciprocal relationship and the presence of the antibodies are not clear.

This relationship has important implications for blood transfusions:

BA

A

A

AB

B

B

O

BA A

A

B

B

AB

Can get blood from anybody

UNIVERSAL ACCEPTOR

Cannot get blood from anyone except O individuals but can donate RBC to anyoneUNIVERSAL DONOR

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Blood transfusions

If O individuals are transfused with A blood, the anti-A antibodies will react with the A cells resulting in clumping.· If O individuals are transfused with B or AB blood, clumping also occurs· O individuals can only receive O blood, but they can donate Red blood cells to A,B, AB, and O individuals- they are universal donors.· Since AB individuals have no antibodies they can receive RBC from A,B,AB, or O individuals. They are universal recipients· With respect to dominant relationships we say IA and IB are dominant to i and that IA and IB are co-dominant

BA

A

AB

B

A B

O

BA A

A

B

B

AB

Can get blood from anybody(Universal acceptor)

Cannot get blood from anyone except O individuals but can donate RBC to anyone (universal donor)

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