Transcript Lecture 4 - University of California, Santa Cruz

Lecture 4
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 T is dominant to t. And t is recessive to T.
Now if the short phenotype is observed in the heterozygote, then t is
dominant and short is dominant to tall.
Dominant and recessive are operational definitions.
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Some genes make enzymes
Genes are responsible for the production of specific enzymes.
***** Remember enzymes catalyze biochemical reactions.
Substrate
--------->
product
EnzymeA
^
|
GeneA
Wild-type= phenotype observed most of the time in nature
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Incomplete dominanceNow 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 dominanceAlthough 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
F1:
F2:
x
Pure red
All Pink
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
F1:
All Pink
F2:
1/4Red
1/2Pink
x
Pure red
1/4White
Do not use C and c to denote the two alleles- Use C1 and C2
In practice incomplete dominance can lie anywhere on the
phenotypic scale
The phenotype of the heterozygous individual is the key towards
determining whether an allele behaves as a recessive, dominant,
or incomplete dominance
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The classic example of this is the colors of carnations.
R1R2
x
R1R2
R1 is the allele for red pigment. R2 is the allele for no pigment.
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Co-dominance:
The biochemical basis of co-dominance is understood for the blood
groups M and N
The surface of a red blood cell carries molecules known as antigens.
More than 20 different blood group systems are recognized. the best
known are the ABO system and the Rh system.
The MN blood group system is of little medical importance.
In this system there are two antigens, M and N.
The L gene in humans codes for a protein present on the surface of
the red blood cells.
There exist two allelic forms of this gene
LM and LN
These two alleles represent two different forms of the protein on the
cell surface.
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So with respect to the red blood cells, the genotype and phenotype
relationships are as follows:
Both proteins are being expressed in the heterozygote.
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.
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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. This is because each antibody
actually has two functional binding sites enabling extensive crosslinking to occur.
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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Genotype
Phenotype=
Phenotype=
Precipitation by
- LN
- LM
antigen on RBC surface
In this case, the heterozygote is expressing both proteins.
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Paternity issues:
Paternity issues:
The M and N blood typing can be used to disprove that an individual
was the biological father of a child. For example if the mother
expressed only the M antigen, she could be only of one genotypeLMLM.
If the child was of the genotype LMLN, we know the biological
father must possess at least one LN allele.
Mother's genotype
LMLM
x
Father's genotype
LMLN
or
LNLN
This technique only rules out potential fathers. It cannot prove
that an individual is the father.
As you will learn later in the course, DNA fingerprints can actually
be used to identify the individual father.
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Phenotypes
When examining a dominance relationship between two alleles, we
compare genotype to phenotype in a heterozygote.
Genotype
phenotype
Tt
tall? Short? In between?
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.
With regards to the M and N blood groups (by Immunoprecipitation)
the phenotype is different in the two individuals.
We have discussed
pea shape,
flower and eye color,
Morphology
as phenotypes.
These are all properties that are easily visualized.
However with specialized tools, microscopes and specific probes such
as antibodies we can detect less easily visualized phenotypes.
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Phenotypes
We have discussed
pea shape,
flower and eye color,
Morphology
as phenotypes.
These are all properties that are easily visualized.
However with specialized tools, microscopes and specific probes such
as antibodies we can detect less easily visualized phenotypes.This
indicates that the phenotype has subjective nature to it. It depends
on the way the observer chooses to define it. This in turn depends on
the individual's powers of observation and the tools available. For
example, shown below are a normal and a mutant Drosophila wing.
What is the difference?
Wild-type
Mutant
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Sickle cell anemia
Sickle cell anemia is a good example of the variance in dominance
relationships.
Sickle cell results from a mutation in the gene coding for globin.
Hemoglobin, major constituent of RBCs is globin+ heme.
HbA: an allele that codes for the normal globin protein
HbS: an allele that codes for an abnormal form of globin
We will examine the phenotype of the two homozygotes and the
heterozygote at three levels:
the individual,
the cell
the protein.
Normal O2 levels
(Sea level)
Low O2 levels
(High altitude)
Remember, the phenotype of the heterozygote is the key to
understanding whether a gene behaves as a dominant or recessive.
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Genes and their products
Genes and their products (primarily proteins) do not function in
isolation, they interact with the environment.
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
HbS/HbS
HBS/HbA
At this level the alleles HbA and HBs are incompletely dominant
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Phenotype at the level of the protein.
-
+
HbA/HbS
HbS/HbS
HbA/HbA
With respect to the proteins HbS and HbA are co-dominant
So the HbS allele is classified differently depending on the level the
phenotype is analyzed:
Individual
Cell
Protein
Recessive/
Dominant
incomplete
dominant
co-dominant
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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. It was
proposed and later proven that heterozygous HbA/HbS individuals
are more resistant to the mosquito born parasite than HbA/HbA
individuals. 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/HbS
HbS/HbS
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Lethal allelesMost 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
fly?
For example in Drosophila, Cy
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Curly
When a heterozygous Cy male is crossed to a heterozygous Cy
female, Cy to non-Cy progeny are produced in a _____ rather than
the Mendelian ______ ratio
+ = normal or wild type gene
cy= dominant Cy mutation
One explanation for the ___ rather than the expected ___ ratio
is that Cy behaves as a recessive lethal mutation and cy/cy
individuals die prior to reaching adulthood
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How would you test this hypothesis?
Take the progeny and perform a test cross with the homozygous
recessive parent
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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.
Unlike cy, most recessive lethal alleles do not have an additional
dominant visible phenotype.
For example let say a gene codes for an essential enzyme.
The expected genotypes and phenotypes are as follows:
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Lethal stocks
It is difficult to keep a stock that is a recessive lethal and has
no other phenotype. In each generation some of the lethal
alleles are eliminated
Gene A
·
·
enzyme
encodes an essential enzyme:
A = normal allele that encodes functional enzyme
a = mutant allele that encodes a non-functional
and is recessive lethal (lethal when homozygous)
Genetics helps solve this:
In order to maintain a lethal allele geneticists use "marker"
mutations such as cy
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Take a heterozygous fly for both the A gene and curly
P:
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Multiple alleles
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.
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
******
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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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
As of 1996, there exist over 150 alleles of the white gene
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3 alleles
How many genotypes are possible given three alleles at the white
gene?
With 3 alleles, there are six possible pair-wise combinations
In a given protein the number of potential alleles= (No of amino
acids in protein)19
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The C gene in rabbits
·
These represent different alleles of the c locus with the
following dominance relationship:
The dominance relationship is relative to alleles being tested
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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
C
--------------->
---> Cch
---> Ch
Recessive
---->c
The dominance relationship is relative to alleles being tested
CC
Ccch
Cch
cchcch
cchch
cchc
chch
chc
cc
Cc
full color
chinchila
Himalayan
albino
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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
An on RBC
Ab in blood
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The ABO gene has three alleles
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 genotypes
B blood type is due to two genotypes
AB blood type is due to a single genotype
O Blood type is due to a single genotype
Three alleles give you six genotypes but only four phenotypes
Each phenotype is determined by two alleles
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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:
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Multiple alleles at the human HLA loci
The HLA locus is the basis of tissue incompatibility in humans.
That is, when an organ transplant or tissue graft is required,
the success of the procedure depends on host donor
genotypes.
If the two are mismatched, graft rejection occurs. Whether
a tissue is rejected depends primarily on the genotypes at two
important loci known as the HLA loci:
HLA-A------------ 23 recognized alleles
HLA-B------------ 47 recognized alleles
The HLA and HLB genes code for proteins that are located on
the surface of the cells. For a successful transplant, the
donor and recipient must have matching alleles at the HLA-A
and HLA-B genes or risk graft rejection.
If the alleles are different however, graft rejection will occur
in some but not all of the transplant combinations
Why this multiple allele system evolved at the HLA locus in
unclear. It probably involved the tagging of the system as self
or non-self (foreign). Cancer cells often express foreign
antigens and are recognized by the immune system as foreign
and destroyed.
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Polymorphism
Polymorphism is the existence of two or more allelic forms of a
gene segregating in a population. Often these allelic forms have
different phenotypic consequences.
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