Classical Papers

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Classical Papers

• Chihiro Fukami
• October 6, 2005

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Outline

• Central Dogma of Molecular Biology
• Chromosomes in Heredity
• What is a Gene?

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CENTRAL DOGMA OF MOLECULAR BIOLOGY

• Francis Crick, 1958

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Francis Crick (1916 2004)

• one of the co-discoverers (w/ James Watson) of
  the double helix structure of the DNA molecule in
  1953
• awarded the 1962 Nobel Prize for Physiology or
  Medicine

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Origins of Term

• Put forward at a time when molecular genetics was
  not well understood
• Principle problem formulation of general rules
  for information transfer from one polymer to
  another

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Classes of Information Transfer

• Class I
• DNA ? DNA
• DNA ? RNA
• RNA ? Protein
• RNA ? RNA (presumed to occur because of existence
  of RNA viruses)

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Classes of Info Transfer (contd)

• Class II
• RNA ? DNA
• DNA ? Protein
• Class III
• Protein ? Protein
• Protein ? RNA
• Protein ? DNA

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Classes of Info Transfer (contd)

• Generally believed that Class I almost certainly
  existed, Class II probably rare or absent, and
  Class III very unlikely

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Conclusions?

• No overwhelming structural reasons why Class II
  should not be impossible
• Good general reasons against all transfers in
  Class III
• Conservative claim about transfer of
  information leads to

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Central Dogma of Molecular Biology

• Central dogma Once information has passed into
  protein, it cannot get out again
• About class II, I decided to remain discreetly
  silent

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Misunderstandings about CD

• CD says nothing about what the machinery of
  transfer is made of, and nothing about errors
  (assumed that accuracy of transfer is high)
• CD says nothing about control mechanisms (i.e.
  rate of processes)
• Intended to apply only to present-day organisms

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Misunderstandings (contd)

• It is NOT the same as the sequence hypothesis, a
  positive statement saying that the (overall)
  transfer of nucleic acid to protein existed

PROTEIN
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THE CHROMOSOMES IN HEREDITY

• Walter Stanborough Sutton, 1903

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Mendel in a Nutshell (1866)

• Characteristics determined by discrete units of
  inheritance
• Law of independent assortment
• Law of segregation (allelomorphs, inheritance,
  dominance)

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The State of Genetics, c. 1900

• Chromosomes are the physical basis of
  inheritance seems reasonable
• How to test hypothesis?

?
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Sea Urchin Chromosomes

• 1902 Theodore Boveri shows through
  experimentation with sea urchins that complete
  set of chromosomes necessary for normal
  development

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W.S. Sutton (1877 1916)

• Worked under C.E. McClung at U of Kansas
  (grasshoppers!)
• Moved to Columbia, where he wrote his two famous
  papers

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Chromosomal Basis of Inheritance

• Published paper in 1902 on study of grasshopper
  chromosomes
• Observed meiosis, number of chromosomes halved
  after division

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Grasshopper Chromosomes

• Found 23 chromosomes in grasshopper spermatogonia
• One accessory chromosome and 11 pairs
• Fertilization of ovum (11) and sperm (11)
  restores diploid number of 22

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Pertinent Cytological Data

• Chromosomes exist in homologous pairs (one set
  from father, other from mother?)
• As a result of meiosis, every gamete receives one
  chromosome of each pair
• Distribution of members of each pair during
  meiosis is independent from each other

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The Chromosomes in Heredity, 1903

• Mendels results could be explained on the
  assumption that genes are part of the chromosomes

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Heredity (contd)

• We have seen reasonto believe that there is a
  definite relation between chromosomes and
  allelomorphsbut we have not inquired whether an
  entire chromosome or only a part of one is to be
  regarded as the basis of a single allelomorph.

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Connection with Mendelian Principles

• The association of paternal and maternal
  chromosomes in pairs and their subsequent
  separation during the reduction divisionmay
  constitute the physical basis of the Mendelian
  laws of heredity

!
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WHAT IS A GENE?

• Milislav Demerec, 1933

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Biology c. 1933

• 1928 - First antibiotic, penicillin, discovered
  by Alexander Fleming
• 1929 - Phoebus Levene discovers the sugar
  deoxyribose in nucleic acids
• 1933 - Tadeus Reichstein artificially synthesizes
  vitamin C first vitamin synthesis

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Biology ExperimentsBack in the Day

• Our present information about genes is largely
  obtained by indirect, genetic methods
• X-ray technology (discovered in 1895) used to
  observe effects of photoelectrons on genes

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Definition of Gene

• A minute organic particle
• Capable of reproduction
• Located in a chromosome
• Responsible for the transmission of a hereditary
  characteristic

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Size of the Gene

• Found by dividing the volume by the number of
  estimated genes
• Estimates range from 10 70 millimicrons
• An ultramicroscopic particle?
• Single/multiple molecules?

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Capacity of Reproduction

• Each gene must divide at every cell division
• Little known about nature of gene reproduction

?
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Location of Genes

• Genes are located in chromosomes
• Arranged in a linear order
• Definite order retained with great regularity,
  each gene has permanent locus on gene string
• Gene may attain several forms, allelomorphs

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Studies of fruit-flies

• Studied more intensively than any other species
• Genes arranged in a definite order in the
  chromosomes
• Relative positions of over 200 genes determined

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Fruit-fly chromosomes

• Fruit fly has 4 pairs of chromosomes
• For the gene located in the white locus of fruit
  fly, at least 11 different allelomorphs known,
  all of which affect eye color

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Transmission of Hereditary Characteristics

• No single gene is solely responsible for
  appearance of any one character
• Final effect produced through interaction of the
  whole complement of genes
• Some genes have greater influence than others on
  expression of certain characteristics

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Example, chromosome map

• Gene of fruit-fly located in the X-chromosome
• Arranged in genetic charting order

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Stability of the Gene

• Mutations occur in different frequency in
  different gene
• No sharp division between stable and unstable
  genes
• Rate of change in various genes may depend on
  tissue or stage of development

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Example, lavender/rose

• Unstable genes change to purple
• Change in color gene occur at definite stage for
  lavender, any time for rose

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Mutation Experiments Today

• Maize (corn)
• Study plant evolution, crop domestication, crop
  improvement
• DNA sequencing allows understanding and selection
  of desirable traits

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Nature of Gene Changes

• Evidence suggests changes in genes are chemical
  processes
• End product of changes is always the same
• Change is not always a random process, favored by
  or limited to certain tissues
• Several genetic factors known to stimulate rate
  of change in certain unstable genes

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Importance of Genes

• Whole complement of genes necessary for organism
  to live, and for cell to function properly
• In other words, primary function of gene is to
  regulate life process of cell

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Physical Picture of a Gene
Look familiar?
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Physical Picture (contd)

• Genes are not larger than a particle containing
  a few complex organic molecules
• Molecular groups constituting this molecule
  (whatever these groups may be) would be arranged
  in chains and side chains. (hmm)

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The Big Picture
Dominant and Recessive Factors in Crossbreeding
(1858)
Chromosomes Heredity (1902)
Genes Heredity (1933)
Double Helix Structure of DNA (1953)
Central Dogma (1958)