Download Classical Papers

Classical Papers
Outline
• Central Dogma of
Molecular Biology
• Chromosomes in
Heredity
• What is a Gene?
CENTRAL DOGMA
OF MOLECULAR
BIOLOGY
Francis Crick, 1958
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
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
Classes of Information
Transfer
• Class I
–
–
–
–
DNA  DNA
DNA  RNA
RNA  Protein
RNA  RNA
(presumed to occur
because of existence
of RNA viruses)
Classes of Info Transfer
(cont’d)
• Class II
– RNA  DNA
– DNA  Protein
• Class III
– Protein  Protein
– Protein  RNA
– Protein  DNA
Classes of Info Transfer
(cont’d)
• Generally believed
that Class I almost
certainly existed,
Class II probably
rare or absent, and
Class III very
unlikely
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…
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”
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
Misunderstandings (cont’d)
PROTEIN
• It is NOT the same as
the sequence
hypothesis, a positive
statement saying that
the (overall) transfer
of nucleic acid to
protein existed
THE
CHROMOSOMES
IN HEREDITY
Walter Stanborough Sutton,
1903
Mendel in a Nutshell (1866)
• Characteristics
determined by
discrete units of
inheritance
• Law of independent
assortment
• Law of segregation
(allelomorphs,
inheritance,
dominance)
The State of Genetics, c. 1900
• “Chromosomes are the
physical basis of
inheritance” seems
reasonable
• How to test hypothesis?
?
Sea Urchin Chromosomes
• 1902 – Theodore
Boveri shows
through
experimentation with
sea urchins that
complete set of
chromosomes
necessary for
normal development
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
Chromosomal Basis of
Inheritance
• Published paper in
1902 on study of
grasshopper
chromosomes
• Observed meiosis,
number of
chromosomes
halved after division
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
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
The Chromosomes in
Heredity, 1903
• Mendel’s results
could be explained
on the assumption
that genes are part
of the
chromosomes
Heredity (cont’d)
• “We have seen reason…to
believe that there is a
definite relation between
chromosomes and
allelomorphs…but 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.”
Connection with Mendelian
Principles
• “The association of
paternal and maternal
chromosomes in pairs
and their subsequent
separation during the
reduction division…may
constitute the physical
basis of the Mendelian
laws of heredity”
!
WHAT IS A GENE?
Milislav Demerec, 1933
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
Biology Experiments:
Back 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
Definition of Gene
• A minute organic
particle
• Capable of reproduction
• Located in a
chromosome
• Responsible for the
transmission of a
hereditary characteristic
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?
Capacity of Reproduction
• Each gene must
divide at every cell
division
• Little known about
nature of gene
reproduction
?
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
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
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
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
Example, chromosome map
• Gene of fruit-fly
located in the Xchromosome
• Arranged in
genetic
“charting” order
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
Example, lavender/rose
• Unstable genes
change to purple
• Change in color
gene occur at
definite stage for
lavender, any time
for rose
Mutation Experiments Today
• Maize (corn)
• Study plant
evolution, crop
domestication, crop
improvement
• DNA sequencing
allows
understanding and
selection of
desirable traits
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
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
Physical Picture of a Gene
Look familiar?
Physical Picture (cont’d)
• “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…)
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)