Genes code for proteins

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Genes code for proteins
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Archibald E. Garrod (1857-1936)

• In 1896, Archibald E. Garrod, a physician at St.
  Bartholomew's Hospital in London, followed up
  patients with alkaptonuria, a rare but rather
  harmless disorder known as black urine
  disease. When exposed to air, patients' urine
  turns distinctively dark.

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Alkaptonuria behaves as a simple recessive
character

• Garrod soon concluded that alkaptonuria is a
  congenital disorder, not the result of a
  bacterial infection as was commonly thought.
• Rare in the general population but frequent in
  children of first-cousin marriages,
• The incidence of alkaptonuria conformed to the
  pattern of simple recessive inheritance described
  by Gregor Mendel.

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1909 publish his results in bookInborn errors of
metabolism

• Garrod understood both the new science of
  biochemistry and the emerging discipline of
  genetics.
• He suspected that, due to a genetic defect,
  patients with alkaptonuria failed to breakdown of
  protein, resulting in the accumulation of a
  chemical that darkens urine..

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50 years laterAlkaptonuria in humans results
from a block in phenylalanine catabolism
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George Beadle (left) and Edward Tatum (right)
receiving their Nobel Prizes
"for their discovery that genes act by regulating
definite chemical events 1958 Nobel Prize in
Medicine or Physiology
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One gene-one metabolic block ? One gene-one
enzyme

• It was probably George W. Beadle who brought
  Garrod to the attention of geneticists with his
  generous references to Garrod in his 1958 Nobel
  lecture. He even suggested that it was Garrod
  who first proposed a direct relation between
  genes and enzymes.

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Following genes from generation to generation in
Neurospora crassa
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Beadle and Tatum's experimental techniques
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Srb and Horowitz experiment
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In the following experiment determine the order
of the compounds in the pathway

• A B C D E
• C B A D E
• E B D A C
• C B D A E
• B D A E C

d. is the correct answer
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In the following experiment determine the order
of the genes controlling the pathway

• C w B x D y A z E
• C y B z D w A x E
• C y B w D z A x E
• C z B y D w A x E
• C x B w D z A y E

b. is the correct answer
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Sickle cell anemia
Erythrocytes with
Hb A
Hb S

• Hereditary disease of simple recessive
  inheritance found mainly among people of African
  descent.
• Sickle cell anemia (with two abnormal alleles)
• Sicklemia (or sickle cell trait, which carrying
  one abnormal allele)

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The opening of molecular medicine

• Linus Pauling, an Americas leading physical
  chemist.
• Pauling had studied hemoglobin, discovering
  alpha-helix
• (Nobel price)
• He assigned the sickle cell anemia project to
  Harvey A. Itano in 1946 as a Ph.D thesis topic.
• By means of elecrophoresis, Itano finally found
  electrophoretic differences in mobility between
  normal and sickle cell Hb, indicating that they
  carried a different electrical charge.

Linus Pauling 1901-1994
Harvey Itano
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1957 Vernon Ingram

• Demonstrated that mutations produce amino acid
  changes
• A specific chemical difference between the
  globins of normal human and sickle-cell anemia
  hemoglobin.
• Nature, Vol.178, pp. 792-794, 1956

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Broke down peptide chains in small pieces and
analyzed them
descending chromatography
There is a difference in the amino-acid sequence
in one small part of one of the polypeptide
chains, which he named it No. 4 peptide.
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Then sequenced the poly peptide pieces
Hb A His-Val-Leu-Leu-Thr-Pro-Glu-Glu-Lys Hb S
His-Val-Leu-Leu-Thr-Pro-Val-Glu-Lys
Nature, Vol.180, pp.326-328, 1957
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The colinearity of gene structure and protein
structure by C. Yanofsky

• TrpA gene (tryptophan synthetase) of E. coli
• 16 mutants with different locations alterations
  of the A gene
• Constructed a genetic map based on recombination
  of mutants
• Sequenced the protein products of each mutant and
  compared genetic distance with location of the aa
  substitution.

Stanford Professor EmeritusCharles Yanofsky
PNAS, 51266, 1964
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• the colinearity between the DNA and protein
  encoded by the DNA.
• -- order of observed mutations in the E. coli
  tryptophan synthetase gene was the same as the
  corresponding amino acid changes in the protein.