inherited traits that have major effects on health nutrition and gene expression jan 23, 2014
TRANSCRIPT
INHERITED TRAITS THATHAVE MAJOR EFFECTS
ON HEALTH
Nutrition and Gene Expression
Jan 23, 2014
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 moleculerequires 2 alpha chains, andtwo beta chains.
The gene for the beta chainis on Chromosome 11,near location: “11p15.5”
Gene for thebeta chain.
M-11 P-11
Topic: Normal Hb,Sickle trait,and Sickle Cell Disorder
M is the chromosomefrom the mother,and P is the chromosomefrom the father.
Paternal and maternal: same DNA sequence, twofunctional globin proteins are made, with commonamino acid sequence
Paternal and maternal: the variation in the paternalgene leads to beta-globin S production, butbeta-globin from the maternal gene is standard.This USUALLY does not cause problems, since thecell 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.
P M
Recessivemutation
Homozygousmutation
FROM EACH PARENT, YOU CAN GET THE COMMONOR THE VARIANT GENE FOR BETA-CHAIN OF Hb.
What is the mutation that accompanies sickle trait and sickle disease?
At position 6 of the BETA-CHAIN, there is a substitution ofVALINE for GLUTAMIC ACID. The new protein is called Beta-Globin-S.
A cell can make Beta-globin-normal from one chromosome, andBeta-Globin-S from the other chromosome. Hemoglobin molecules will be assembled from random mixturesof the two kinds of chains.
Change in the DNAfrom GAG to GTG:The result is theVALINE in thepeptide chain.
2d-alpha-chain
2d beta-chain
Each Hb molecule gets 2 beta chains. If all the Hb moleculesin the cell contain beta-globin-S, the Hb in that cell cansickle under low oxygen conditions.
The boy only gets ONE copyof the X chromosome!
WHAT ABOUT THE EFFECTIN BOYS OF MUTATIONSON THE X-CHROMOSOME?
They don’t have “spare copy” toprovide a good backup gene, andthose 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 SELECTIONAGAINST 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.
Dystrophin gene, at Xp21.
X-linked (Duchenne’s) muscular dystrophy is causedby a mutation in the Dystrophin gene (at Xp21) whichcodes 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. Functioningcontractile cells in the heart (myocytes) are graduallyreplaced by fibroblasts (a form of scar tissue).
Milder defects in Dystrophin protein are compatiblewith survival, accompanied by muscle weakness.
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.
With no (or very little) Factor VIII made, blood coagulationis defective, and hemorrhage can occur. WHY ARE FEMALECARRIERS PROTECTED FROM THE DISORDER?
Xq28
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 photoreceptorsare ALSO near Xq28! There are about 1000 genes on theX-chromosome, so addresses are just approximate.
A GOOD TEST FOR COLOR VISION IS AVAILABLE AT:
http://colorvisiontesting.com/ishihara.htm#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.
CARRIERSAFFECTED
Paternal and maternal: same DNA sequence, twofunctional globin proteins are made, with commonamino acid sequence
Paternal and maternal: the variation in the paternalgene leads to beta-globin S production, butbeta-globin from the maternal gene is standard.This USUALLY does not cause problems, since thecell 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.
P M
Recessivemutation
Homozygousmutation
Sickle-cell disease: AUTOSOMAL RECESSIVEIf one gene is OK, it largely blocks the harmfuleffects of the other gene.
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.
AFFECTEDAFFECTED
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.