Website for class notes: https:www'cvm'tamu'edubimsjunior'shtml

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Website for class noteshttps//www.cvm.tamu.edu/
bims/junior.shtml
Dr. Natalie Halbert nhalbert_at_cvm.tamu.edu 862-4774
Tutorial by Ahmed Elhameky Tuesdays 300-500 VMR
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Gene Expression Phenotypes

• From Chapter 11
• Human Genetics Concepts and Applications, 6th
  edition
• by Ricki Lewis

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Replication, transcription, RNA processing,
translation, protein processing, protein
modification.. WHY SHOULD YOU CARE?
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Lactose Intolerance

• Lactose is metabolized by the enzyme lactase
• splits lactose into 2 sugars, glucose and
  galactose
• Lactose intolerance can range from 0 to 100 in
  human populations
• Autosomal dominant trait
• Most land mammals and human adults are
  lactose intolerant!

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Lactose Absorption in Various Populations
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Galactosemia is caused by an enzyme deficiency

• 1 in 57,000 births
• Lack of enzyme galactose-1-phosphate uridyl
  transferase
• Inability to break down galactose completely
• Example of a multiple allele system
• Can lead to mental retardation and death if
  untreated

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Hemoglobin structure function

• Hemoglobin (Hb) is protein in red blood cells
  that transports oxygen from lungs to tissues
• Each red blood cell contains millions of Hb
  proteins
• Hb comprised of 4 polypeptide chains 2 alpha and
  2 beta type
• Each polypeptide chain has hydrophobic pocket
  for heme group
• Critical function of Hb mutations that alter
  function can cause serious illness, widespread
  organ tissue damage, death

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Human beta-globin gene

• Small gene (1,700 bp including promoter)
• 2 introns account for 60 of gene length
• 8 alpha-helices coil and fold around heme group
  (tertiary structure)
• Heme protoporphyrin ring structure surrounding
  iron
• Hemoglobin as O2 CO2 carrier
• Hydrophobic heme pocket has affinity for O2
  molecules
• Arginine residues near carboxyl end of
  alpha-globin chains bind CO2
• Binding of O2 and CO2 in 2 different parts of
  protein.
• 
  but cannot be
  simultaneous!
• CO2 binding alters conformation decreased
  affinity for O2
• Release of CO2 in lungs increases affinity for O2

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Beta-globin chain variants with single amino acid
substitutions
Substitutions at the same amino acid position can
result in drastically different phenotypes!
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Sickle cell anemia

• First illness understood at the molecular level
• 6th amino acid substitution Glu -gt Val
• Hb A Glutamic acid (normal)
• Acidic, hydrophilic amino acid
• Hb S Valine
• Nonpolar, hydrophobic amino acid
• Inherited as an autosomal recessive trait.
• Affects 1/500 African Americans
• 1/12 African Americans are heterozygous carriers

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Single base change in hemoglobin gene causes
sickle cell anemia
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Sickle cell anemia phenotype

• HbS molecules attach to each other to form long
  chains when deoxygenated
• HbS fibers have reduced oxygen affinity, causing
  sickle shape of red blood cells
• Sickle shaped RBC do not readily pass though
  capillaries cause clots
• Lack of oxygen accumulation of CO2 widespread
  tissue damage, anemia, joint pain

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The cascade of phenotypes in sickle cell anemia
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How is HbS allele maintained?

• In heterozygotes recessive homozygotes, mutant
  hemoglobin makes RBC resistant to infection by
  Plasmodium falciparum
• P. falciparum causes malaria
• gt 2 million people die from malaria each year
• gt300 million people infected with malaria
  worldwide
• HbS/HbS at disadvantage due to sickle cell anemia
• HbA/HbA homozygotes are more susceptible to
  malaria
• HbA/HbS heterozygotes have some effects of sickle
  cell anemia, but are resistant to malaria
• HbS allele maintained in population due to
  heterozygote advantage (overdominance)

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Mutations in different sites of a gene can cause
distinct phenotypes ß-thalassemia

• Caused by excess of alpha hemoglobin compared to
  beta hemoglobin
• leads to iron release and aggregation of excess
  alpha subunits RBC destroyed
• expansion of bone marrow causes skeletal
  deformities iron overloading causes cirrhosis of
  the liver endocrine disfunction, diabetes and
  cardiac failure
• Ultimately, patients with severe ß-thalassemia
  suffer early death
• Two forms
• reduction of ß-globin synthesis (ß-thalassemia)
  - mild
• absence of ß-globin (ß0-thalassemia) - severe
• gt30 different mutations in ß-globin gene can
  cause ß-thalassemia
• Nearly half of known mutations disrupt intron
  removal

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Human ß-globin gene
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Exon 1
Intron 1
Exon 2
Intron 2
Exon 3
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AAGGTGAACGTGGATGAAGTTGGTGGTGAGGCCCTGGGCAGGTTGGTATC
AAGGGTTACAAAG
AAGGTGAACGTGGATGAAGTTGGTGGTGAGGCCCTGGGCAGATTGGTATC
AAGGGTTACAAAG
1
2
3

• normal intron splice site not functional due to
  mutation
• intron still removed, but incorrectly at one of
  cryptic splice sites
• cryptic splice sites only functional when
  cleavage cannot occur at normal splice site
• Intron 1 within reading frame for translation
  (phase 2 junction) cryptic sites out
• of frame, resulting in frameshift mutations
• Splicing at cryptic site 1 or 2 codons deleted
  from mRNA
• Splicing at cryptic site 3 new codons inserted
  into mRNA

Mutant ß-globin gene fails to produce any
functional ß-globin ß0-thalassemia
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Human ß-globin gene
Exon 1
Intron 1
Exon 2
Intron 2
Exon 3
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3 UTR
CTGCCTAATAAAAAA
AAUAAA polyadenylation signal
CTGCCTAAAAAAAAA

• T-gtA mutation disrupts proper polyadenylation
• Why would this mutation cause ß-thalassemia
  (mild form)?

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Pharmacogenetics

• A relatively new area of genetics that studies
  the genetic variations that underlie drug or
  chemical responses.
• Drug resistance
• Toxic sensitivity to low drug doses
• Development of cancer after prolonged exposure
• Unusual reaction to drug combination
• Example
• Phenylthiocarbamide (PTC) tasting in humans.
• TT and Tt tasters
• tt non-tasters 30 in U.S. Caucasians
  vs. 10 in blacks
• Phenotype is affected by modifying genes

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PTC/PROP

• Some food plants contain a PTC-like compound,
  PROP
• Kale, cabbage, broccoli, Brussels sprouts
• Capsaicin has a more intense taste to PTC/PROP
  tasters
• Sucrose and artificial sweeteners are more
  intense to tasters
• Tasters tend to dislike black coffee, dark beer,
  anchovies and strong cheeses.

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Genetics of smell

• 100-1,000 membrane proteins involved in detection
  of smell on surface of cells in nose and sinuses
• Some people cannot smell the odor released by
  skunks!

2/3 of the people tested could smell the pink
verbena but not the red verbena
1/3 of the people tested could smell the red
verbena but not the pink verbena
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Ecogenetics

• The study of genetic variation leading to
  different responses to environmental chemicals.
• Drugs
• Pesticides
• Foods
• Toxins
• Remember, we are all
• genetically unique.