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BIO 184
Fall 2006
LECTURE 10
Lecture 10:
Molecular Basis for Dominance and Recessivity
Mendel showed that round seeds are dominant to wrinkled seeds in Pisum
sativum, the common garden pea. Molecular studies have shown that round
seeds contain more starch than wrinkled seeds, which explains the phenotype.
Interestingly, the seeds of heterozygotes (“Rr”) contain only about half the
amount of starch as those of “RR” plants, yet they appear round to the naked
eye.
I. Explanations for Recessive Alleles
The hallmark of a recessive allele (a) is that heterozygotes (Aa) are phenotypically
identical to homozygous dominant individuals (AA). Only homozygous recessives (aa)
(or hemizygous males if the disease is X-linked) have the mutant phenotype.
A. Non-Limiting Enzymes
Many genes code for enzymes. In most cases, these enzymes made in vast excess
in homozygotes for the normal allele. Thus, although heterozygotes only make half
as much, they still have enough functional enzyme to have a normal phenotype.
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BIO 184
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LECTURE 10
enzyme
(excess)
SUBSTRATE
PRODUCT
Many recessive genetic diseases fall into this category. Examples include Tay
Sachs Disease, PKU, galactosemia, ALD, and hemophilia.
PKU is an interesting example because it is one of the few severe genetic diseases
whose symptoms can be eliminated by early intervention.
PKU is caused by mutations in the gene coding for the enzyme phenylalanine
hydroxylase (PAH), located on chromosome 12. This enzyme breaks down excess
phenylalanine (an amino acid found in most the protein-rich foods we eat) into
tyrosine (another amino acid) inside liver cells. This reaction is the source of more
than 95% of all the tyrosine that normal individuals have in their cells. (We get the
rest from food.) When a person is homozygous for a mutation in PAH gene, he or
she fails to make PAH and cannot catalyze this reaction.
As a result, excess phenylalanine builds up in the liver cells and is eventually
excreted into the bloodstream, where it travels all over the body. Unfortunately,
excess phenylalanine is quickly converted to phenylpyruvic acid, which is toxic to
brain cells, particularly during the early years of development (before age 12).
Thus, if children do not get treated for their condition, they will suffer brain
damage and become developmentally delayed (mentally retarded due to abnormal
brain development).
The effects of PKU can be prevented, however, by placing a PKU infant on a special
diet very low in phenylalanine within the first few weeks of life. The child usually
then remains on the diet throughout the rest of his or her life.
In the United States and most developed nations, all newborn babies
are tested for their levels of PAH by means of a “heel prick” blood
test. This allows affected infants to be detected early enough to
prevent brain damage.
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BIO 184
Fall 2006
LECTURE 10
NORMAL METABOLISM OF PHENYLALANINE
Amino
acid pool
(food)
Amino
acid pool
(food)
PAH
PHE
TYR
Melanin
Other Metabolites
ABNORMAL METABOLISM OF PHENYLALANINE
Amino
acid pool
(food)
Amino
acid pool
(food)
Path
blocked
PHE
X
TYR
Melanin
Other Metabolites
Phenylpyruvic
Acid
BRAIN DAMAGE
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BIO 184
Fall 2006
LECTURE 10
B. Structural Proteins Present in Excess
In many cases, a gene codes for a structural protein. If a single “good” copy of the
gene is sufficient to produce enough protein for the body to function normally,
mutations in the gene are inherited in a recessive fashion.
An example is the DMD gene; female carriers have functional dystrophin in
approximately half their cells (remember X-inactivation) and yet have an
essentially normal phenotype. Can you think of another example we have discussed
at some length already in class?
II. Explanations for Dominant Alleles
When mutations are inherited in a dominant fashion, heterozygotes (Aa) show the
mutant phenotype. Only aa individuals are wild-type.
Dominant mutations are rarer than recessive ones. However, dominant mutations do
exist and researchers have found a variety of reasons for why they are dominant
over the normal form of the gene.
A. “Poisonous Alleles”
Sometimes proteins produced from mutant alleles interfere with the function of
their normal counterparts, either directly or indirectly. Such alleles are said to
have a dominant negative effect and are often called poisonous alleles.
One example is found in a severe form of anemia called “Blue Blood Disease.” It is
caused by mutations in either alpha or beta hemoglobin and all cases are inherited
through families as autosomal dominant alleles.
Adult hemoglobin is a tetramer consisting of 2  and 2  subunits. Each subunit
binds one molecule of oxygen and one of iron.


= ferrous iron
= oxygen


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BIO 184
Fall 2006
LECTURE 10
In order for hemoglobin to bind oxygen, the iron bound by the subunits must be in
the ferrous (reduced Fe++) state; however, iron spontaneously becomes oxidized to
the ferric form (Fe+++) under physiological conditions. Ferric
hemoglobin is called methemoglobin.




= ferrous iron
= ferric
iron
An enzyme called methemoglobin reductase continually converts ferric iron to
ferrous iron, thereby turning methemoglobin into hemoglobin.
methemoglobin
reductase
Hemoglobin subunits bind oxygen cooperatively. Thus, if a hemoglobin molecule is to
bind oxygen efficiently, the iron in all of its subunits must be in the ferrous form.
Some missense mutations in the alpha or beta hemoglobin genes can prevent action
by methemoglobin reductase.
Mutant form of 
globin
methemoglobin
reductase
These mutations are inherited as autosomal dominants because every red blood cell
in heterozygotes has about half of its hemoglobin subunits in the ferric state.
Because of cooperative binding, this means that most of the hemoglobin molecules
carry a drastically reduced load of oxygen.
Individuals with these mutations are said to be “Blue-bloods” because of the
blue color of their blood, even upon exposure to oxygen.
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B. Rate-Limiting Enzymes and Feedback Loops
Disease genes that code for enzymes involved in rate-limiting reactions are often
inherited as dominants because in this case half the normal amount of enzyme is
NOT enough. The enzyme is produced in just-barely-sufficient quantities in normal
individuals (aa) so that the level of enzyme can limit the rate of a reaction.
An example can be found in acute intermittent porphyria, a severe but late-onset
illness caused by dominant mutations in the enzyme coding for uroporphyrinogen
synthase.
Uroporphyrinogen synthase is a crucial enzyme in the heme pathway, and it
catalyzes a rate-limiting step. The heme pathway also has a feedback mechanism
that tells the cell to make more heme precursors when heme is at low levels. Thus,
the pathway is driven by lack of its own by-product.
Uroporphyrinogen synthase
HEME
HEME PRECURSORS
If heme levels are low, more
heme precursors are made.
In heterozygotes (Aa), only about half the amount of heme is made as in
normal individuals (aa), leading to an overproduction of heme precursors.
Low Uroporphyrinogen
synthase levels
HEME PRECURSORS
HEME
Chronically low heme levels, so more heme precursors are made. However, they
build up because they can’t be converted to heme fast enough.
The precursors build up because there is not enough enzyme to catalyze additional
heme, and the cycle begins again. This leads to episodes of “crisis” characterized
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LECTURE 10
by colic, partial paralysis, and mental confusion as the body struggles to purge
itself of the build-up of toxic heme precursors.
C. Haploid Insufficiency of Structural Proteins
Sometimes cells with half the normal amount of a structural protein cannot
function properly - i.e. a haploid (1n) level of the gene coding for the protein is
insufficient; 2 copies (2n) are needed. This situation is called haploid insufficiency
of a structural protein.
One example is familial hypercholesterolemia, an autosomal dominant disorder
caused by mutations in a cell surface receptor protein that helps the liver control
the levels of LDL cholesterol in the body.
Liver cells are responsible for regulating the levels of cholesterol in the
bloodstream. Cholesterol is an important component of cell membranes and a
certain level of blood serum cholesterol is necessary to provide membranes with
the cholesterol they need. However, overly high levels of blood serum cholesterol
can block arteries and cause heart and blood vessel disease.
The liver senses the level of blood serum cholesterol via cell surface receptor
proteins called LDL receptors. These receptors are manufactured by the liver cells
and sit in the liver cell membranes.
LIVER
CELL
BLOODSTREAM
LDL
receptor
cholesterol
droplet
The LDL receptors “capture” the cholesterol from the bloodstream and transport
it into the liver cell via endocytosis. Thus, if serum cholesterol levels are low, the
intracellular levels of cholesterol also sink and the liver responds by synthesizing
additional cholesterol for export.
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BIO 184
Fall 2006
LECTURE 10
If serum cholesterol levels are high, the cells respond by producing more LDL
receptors in order to capture the excess cholesterol. The excess cholesterol is
then stored inside the liver cell.
In persons with familial hypercholesterolemia, defects in the LDL receptor result
in the build-up of cholesterol in the bloodstream, both because excess cholesterol
is not removed, and because the liver continues to make cholesterol even when
there is already an overabundance in the bloodstream.
Half the normal number of functioning LDL receptors is not enough for liver cells
to accomplish their task,and heterozygotes (Aa) have high serum cholesterol levels
and a high risk of early-onset atherosclerosis. Homozygotes for the defective
allele (AA) are severely affected and usually die of heart attacks or strokes as
young children.
III. Dominance and Recessivity May be Relative
A. Recessive Alleles that Also Show Dominance
When a disease allele is deemed recessive, what is usually meant is that there is no
clinically relevant phenotype in heterozygotes - i.e. heterozygotes are not sick.
However, there may be subtle manifestations of heterozygosity that normally do
not present themselves clinically.
1. BIOCHEMICAL OR CELLULAR MANIFESTATION

Tay Sachs carriers are phenotypically normal but when their blood is
examined biochemically, it is found to contain only half the normal amount
of hexosaminidase A; this fact formed the basis for early testing for
carriers.

The blood of sickle cell heterozygotes has some sickled cells, but not
enough to cause the disease phenotype. One might also say that sickle
cell is a dominant allele that protects an individual from malaria!
2. MANIFESTATION IN RESPONSE TO CONDITIONS

Sickle cell carriers are phenotypically normal but some will show
manifestations of the disease under conditions of low oxygen pressure
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LECTURE 10
(high altitude flying, mountain climbing above 12,000 feet, extreme
exertion, etc.)
3. MANIFESTATION AT THE MOLECULAR LEVEL

Ultimately, at the sequence level, all alleles are co-dominant! The notion
of recessivity thus applies only at the phenotypic level, never at the
molecular level.
B. Dominant Alleles that Are Really Incompletely Dominant
When a disease allele is deemed dominant, what is usually meant is that
heterozygotes and homozygotes for the disease allele are both sick. The
implication is that heterozygotes and homozygotes are phenotypically
indistinguishable. However, this is not always the case. Homozygotes for dominant
disease alleles are rare because heterozygotes are generally rare to begin with and
some may be too ill to mate. However, there are 2 ways that AA homozygotes
commonly arise:
1. Inbreeding - Increases the likelihood of matings between heterozygotes for
the same dominant disease allele.
2. Assortive Mating - The “misery loves company syndrome” - Two affected
individuals mate because they share a common “enemy” and/or meet due to support
groups, etc.
From studies of such matings, researchers have found that AA individuals are
often much more profoundly affected than Aa individuals.

The allele for polydactyly can be fatal among AA children, causing
developmental defects much more serious than extra digits.

Achondroplasia (short limb dwarfism) is much more severe among the AA
children of heterozygous dwarves.

On the other hand, the Huntington’s Disease allele is completely
dominant because Aa and AA individuals are equally affected with
symptoms and the mean age of disease onset is the same. This is probably
because the Huntington allele is a poisonous product, interfering with the
activity of any normal proteins present.
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