Transcript Gene needed for health

INHERITED TRAITS WITH HEALTH
EFFECTS:
RECESSIVE AND DOMINANT
Nutrition and Gene Expression
Jan 29, 2015
These lectures are about the possibility
that a child may get ONE good copy
of a gene, or and another copy that does
not function. The defective copy may
also (rarely) cause problems.
A RECESSIVE trait is when the one good copy
basically does the job with no problems.
The first example is sickle cell disorder.
Each hemoglobin molecule
requires 2 alpha chains, and
two beta chains.
The gene for the beta chain
is on Chromosome 11,
near location: “11p15.5”
Topic: Normal Hb,
Sickle trait,
and
Sickle Cell Disorder
M-11
P-11
Gene for the
beta chain.
M is the chromosome
from the mother,
and P is the chromosome
from the father.
PM
FROM EACH PARENT, YOU CAN GET THE COMMON
OR THE VARIANT GENE FOR BETA-CHAIN OF Hb.
Paternal and maternal: same DNA sequence, two
functional globin proteins are made, with common
amino acid sequence
Recessive
mutation
Homozygous
mutation
Paternal and maternal: the variation in the paternal
gene leads to beta-globin S production, but
beta-globin from the maternal gene is standard.
This USUALLY does not cause problems, since the
cell has a lot of normal beta-globin
Paternal and maternal: the beta-globin made
from BOTH chromosomes is B-globin S.
This can result in sickle cell disease.
What is the mutation that accompanies sickle trait and sickle disease?
At position 6 of the BETA-CHAIN, there is a substitution, with
VALINE instead of GLUTAMIC ACID. The new protein is called
Beta-Globin-S.
A cell can make Beta-globin-normal from one chromosome, and
Beta-Globin-S from the other chromosome.
Hemoglobin molecules will be assembled from random mixtures
of the two kinds of chains.
Change in the DNA
from GAG to GTG:
The result is the
VALINE in the
peptide chain.
2d beta-chain
2d-alpha-chain
Each Hb molecule gets 2 beta chains. If all the Hb molecules
in the cell contain beta-globin-S, the Hb in that cell can
sickle under low oxygen conditions.
MUTATIONS ON THE X-CHROMOSOME:
An important problem in genetics.
It has VERY significant effects on males,
because they only have one X-chromosome
(there is no backup copy).
The boy only gets ONE copy
of the X chromosome!
WHAT ABOUT THE EFFECT
IN BOYS OF MUTATIONS
ON THE X-CHROMOSOME?
They don’t have “spare copy” to
provide a good backup gene, and
those mutations can be serious.
These are called “X-linked traits”,
and can lead to major disorders.
THE GENES ON THE X-CHROMOSOME CAN BE
RANKED BY THE SEVERITY OF MUTATIONS:
• Essential for embryonic development:
mutation causes loss of the fetus
• Needed for survival to adulthood:
child will be born, but may be critically ill
• Important for health: child may survive,
but may have lifelong illness and disability
• Mutation causes secondary loss of function,
but can usually be tolerated
• Harmless mutation (for example, the code
still generates the same amino acid).
TYPE OF MUTATION:
Gene is essential for embryonic development:
mutation causes loss of the fetus.
Several genes on the X-chromosome have
been identified that are essential for development,
and effect the skin, CNS and skeleton.
THERE WILL BE SUBSTANTIAL NATURAL SELECTION
AGAINST THESE MUTATIONS. Why?
TYPE OF MUTATION:
Gene is needed for survival to adulthood: child will
be born, but may be critically ill, with limited survival.
X-linked (Duchenne’s) muscular dystrophy is caused
by a mutation in the Dystrophin gene (at Xp21) which
codes for a very large protein (3500 amino acids).
This protein is needed for the cytoskeleton in
striated muscle cells, including heart muscle.
Boy children become handicapped by age 5, and then
death from heart failure occurs by age 30. Functioning
contractile cells in the heart (myocytes) are gradually
replaced by fibroblasts (a form of scar tissue).
Milder defects in Dystrophin protein are compatible
with survival, accompanied by muscle weakness.
Dystrophin gene, at Xp21.
TYPE OF MUTATION:
Gene needed for health: child will survive, but may have lifelong illness
The gene for Factor VIII is at Xq28.
There are several mutations possible.
The male offspring can inherit a mutant
version of the gene.
Xq28
With no (or very little) Factor VIII made, blood coagulation
is defective, and hemorrhage can occur. WHY ARE FEMALE
CARRIERS PROTECTED FROM THE DISORDER?
TYPE OF MUTATION:
Mutation in the gene causes secondary loss of function,
but can the mutation be tolerated
The genes for the pigments in the red and green photoreceptors
are ALSO near Xq28! There are about 1000 genes on the
X-chromosome, so addresses are just approximate.
A GOOD TEST FOR COLOR VISION IS
AVAILABLE AT:
http://colorvisiontesting.com/ishihara.h
tm#plate%20with%2010%20answer
Since only 5% of our genes are on the X-chromosome
(and <1% on the Y-chromosome), most of the interest
in mutations focuses on chromosomes 1-22,
which are called AUTOSOMES.
Disorders on these chromosomes are called
AUTOSOMAL DISORDERS, and are of two types:
- Autosomal recessive
- Autosomal dominant
- Autosomal recessive:
The working copy of the gene maintains
normal functions (commonly happens).
The defective copy has minimal impact.
- Autosomal dominant:
The mutant gene makes a protein,
that interferes with the protein
from the working gene.
- NEED TO WORK ON THIS DEFINITION
- Recessive:
a gene that is only strongly expressed if it
is present on both alleles
- Dominant:
a gene that can be expressed if it only
present on one allele
AFFECTED
CARRIERS
PM
Sickle-cell disease: AUTOSOMAL RECESSIVE
If one gene is OK, it largely blocks the harmful
effects of the other gene.
Paternal and maternal: same DNA sequence, two
functional globin proteins are made, with common
amino acid sequence
Recessive
mutation
Homozygous
mutation
Paternal and maternal: the variation in the paternal
gene leads to beta-globin S production, but
beta-globin from the maternal gene is standard.
This USUALLY does not cause problems, since the
cell has a lot of normal beta-globin
Paternal and maternal: the beta-globin made
from BOTH chromosomes is B-globin S.
This can result in sickle cell disease.
Some important autosomal recessive traits in nutrition.
-Phenylketonuria (PKU): both genes are defective that make the
enzyme phenylalanine hydroxylase. Phenylalanine accumulates
and is converted to the harmful product phenylpyrvuvate
-Hereditary galactosemia: galactose accumulates, along with
galactose-1-phosphate.
BOTH CAN BE MANAGED BY SPECIAL DIETS.
HOMEWORK ASSIGNMENT: Look up the biochemistry of these
disorders, and sketch the abnormal molecular pathway that results
from the enzymatic defect.
AFFECTED
AFFECTED
AUTOSOMAL DOMINANCE AND DISEASE:
The protein made from the mutant gene actually BLOCKS
the function of the protein from the normal gene.
These mutations are much less common than RECESSIVE mutations.
Autosomal dominant mutations lead to MARFAN syndrome.
People with this syndrome make a large amount of
defective FIBRILLIN, which leads to problems with
connective tissue.
In nutrition, autosomal dominant mutations have been
more difficult to identify. Polycystic kidney disease (PKD)
is caused by a defective protein (PDK1, on chromosome 16) that
leads to the formation of CYSTS within the kidney. The
mechanism of cyst formation is still not well-defined.
Low-salt diets are of some benefit.
NEXT WEEK, WE WILL DISCUSS IN DETAIL THE KINDS OF
MUTATIONS THAT CAN OCCUR, WHICH CAN LEAD TO
DEFECTIVE GENE FUNCTION.
The key principle is that:
“DNA REPLICATION IS NOT ALWAYS PERFECT”.
When DNA is replicated to provide chromosomes to ova
and sperm, MISTAKES CAN BE MADE and THE WRONG
BASE CAN BE INCORPORATED IN THE DNA.
There are >100 enzymes that function to maintain proper
DNA replication, but mistakes still happen (not very often!,
and that can lead to harmful mutations.
RECESSIVE TRAITS AND HEALTH
There are LOTS of recessive traits, covered in basic biology
texts, that are completely OK (red hair, blue eyes, etc).
This web document lists some of them (you will
have to research the genetics of each trait):
http://employees.csbsju.edu/ssaupe/biol115/genetics_single_gene.htm
IN THIS CLASS, WE WILL FOCUS ON RECESSIVE TRAITS
WITH HEALTH IMPACTS, ESPECIALLY GENES THAT
ARE CRITICAL FOR HEALTHY NUTRITION.