INHERITED TRAITS WITH HEALTHEFFECTS:

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 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, withVALINE instead of 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.

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 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.

- 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

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.