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Copyright 2005 Pearson Education, Inc. publishing as Benjamin Cummings
PowerPoint Lectures forBio logy, Seventh Edit ion
Neil Campbell and Jane Reece
Lectures by Chris Romero
Chapter 16
The Molecular Basis of
Inheritance
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Overview: Lifes Operating Instructions
In 1953, James Watson and Francis Crickintroduced an elegant double-helical model for the
structure of deoxyribonucleic acid, or DNA
DNA, the substance of inheritance, is the mostcelebrated molecule of our time
Hereditary information is encoded in DNA and
reproduced in all cells of the body
This DNA program directs the development of
biochemical, anatomical, physiological, and (to
some extent) behavioral traits
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Concept 16.1: DNA is the genetic material
Early in the 20th century, the identification of themolecules of inheritance loomed as a major
challenge to biologists
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The Search for the Genetic Material: ScientificInquiry
When Morgans group showed that genes arelocated on chromosomes, the two components of
chromosomesDNA and proteinbecame
candidates for the genetic material
The key factor in determining the genetic material
was choosing appropriate experimental organisms
The role of DNA in heredity was first discovered bystudying bacteria and the viruses that infect them
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Evidence That DNA Can Transform Bacter ia
The discovery of the genetic role of DNA beganwith research by Frederick Griffith in 1928
Griffith worked with two strains of a bacterium, a
pathogenic S strain and a harmless R strain
When he mixed heat-killed remains of the
pathogenic strain with living cells of the harmless
strain, some living cells became pathogenic
He called this phenomenon transformation, nowdefined as a change in genotype and phenotypedue to assimilation of foreign DNA
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LE 16-2
Living S cells
(control)
Living R cells
(control)
Heat-killed
S cells (control)
Mixture of heat-killed
S cells and living
R cells
Mouse dies
Living S cells
are found in
blood sample
Mouse healthy Mouse healthy Mouse dies
RESULTS
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In 1944, Oswald Avery, Maclyn McCarty, andColin MacLeod announced that the transformingsubstance was DNA
Their conclusion was based on experimental
evidence that only DNA worked in transformingharmless bacteria into pathogenic bacteria
Many biologists remained skeptical, mainly
because little was known about DNA
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Evidence That Vi ral DNA Can Program Cells
More evidence for DNA as the genetic materialcame from studies of a virus that infects bacteria
Such viruses, called bacteriophages (or phages),
are widely used in molecular genetics research
Animation: Phage T2 Reproductive Cycle
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LE 16-3
Bacterialcell
Phage
head
Tail
Tail fiber
DNA
100nm
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In 1952, Alfred Hershey and Martha Chaseperformed experiments showing that DNA is the
genetic material of a phage known as T2
To determine the source of genetic material in thephage, they designed an experiment showing thatonly one of the two components of T2 (DNA orprotein) enters an E. colicell during infection
They concluded that the injected DNA of thephage provides the genetic information
Animation: Hershey-Chase Experiment
LE 16 4
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LE 16-4
Bacterial cell
Phage
DNA
Radioactive
protein
Emptyprotein shell
PhageDNA
Radioactivity
(phage protein)
in liquid
Batch 1:
Sulfur (35S)
RadioactiveDNA
Centrifuge
Pellet (bacterialcells and contents)
PelletRadioactivity
(phage DNA)
in pellet
Centrifuge
Batch 2:Phosphorus (32P)
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Additional Evidence That DNA I s the Genetic
Material
In 1947, Erwin Chargaff reported that DNAcomposition varies from one species to the next
This evidence of diversity made DNA a more
credible candidate for the genetic material
By the 1950s, it was already known that DNA is a
polymer of nucleotides, each consisting of a
nitrogenous base, a sugar, and a phosphate group
Animation: DNA and RNA Structure
LE 16 5
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LE 16-5Sugarphosphate
backbone
5 end
Nitrogenousbases
Thymine (T)
Adenine (A)
Cytosine (C)
DNA nucleotidePhosphate
3 endGuanine (G)
Sugar (deoxyribose)
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Building a Structural Model of DNA: Scientif ic I nquiry
After most biologists became convinced that DNAwas the genetic material, the challenge was to
determine how its structure accounts for its role
Maurice Wilkins and Rosalind Franklin were usinga technique called X-ray crystallography to study
molecular structure
Franklin produced a picture of the DNA moleculeusing this technique
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LE 16-6
Franklins X-ray diffraction
photograph of DNA
Rosalind Franklin
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Franklins X-ray crystallographic images of DNAenabled Watson to deduce that DNA was helical
The X-ray images also enabled Watson to deduce
the width of the helix and the spacing of thenitrogenous bases
The width suggested that the DNA molecule was
made up of two strands, forming a double helix
Animation: DNA Double Helix
LE 16 7
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LE 16-7
5 end
3 end
5 end
3 end
Space-filling modelPartial chemical structure
Hydrogen bond
Key features of DNA structure
0.34 nm
3.4 nm
1 nm
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Copyright 2005 Pearson Education, Inc. publishing as Benjamin Cummings
Watson and Crick built models of a double helix toconform to the X-rays and chemistry of DNA
Franklin had concluded that there were two
antiparallel sugar-phosphate backbones, with the
nitrogenous bases paired in the molecules interior
At first, Watson and Crick thought the bases
paired like with like (A with A, and so on), but such
pairings did not result in a uniform width
Instead, pairing a purine with a pyrimidine resulted
in a uniform width consistent with the X-ray
LE 16 UN298
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LE 16-UN298
Purine + purine: too wide
Pyrimidine + pyrimidine: too narrow
Purine + pyrimidine: width
consistent with X-ray data
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Watson and Crick reasoned that the pairing wasmore specific, dictated by the base structures
They determined that adenine paired only with
thymine, and guanine paired only with cytosine
LE 16-8
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LE 16-8
Adenine (A) Thymine (T)
Guanine (G) Cytosine (C)
Sugar
Sugar
Sugar
Sugar
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Concept 16.2: Many proteins work together inDNA replication and repair
The relationship between structure and function ismanifest in the double helix
Watson and Crick noted that the specific base
pairing suggested a possible copying mechanismfor genetic material
i i i i i S
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The Basic Principle: Base Pairing to a Template Strand
Since the two strands of DNA are complementary,each strand acts as a template for building a new
strand in replication
In DNA replication, the parent molecule unwinds,and two new daughter strands are built based on
base-pairing rules
Animation: DNA Replication Overview
LE 16-9 1
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LE 16 9_1
The parent molecule hastwo complementarystrands of DNA. Each baseis paired by hydrogenbonding with its specificpartner, A with T and G withC.
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LE 16 9_2
The parent molecule hastwo complementarystrands of DNA. Each baseis paired by hydrogenbonding with its specificpartner, A with T and G withC.
The first step in replicationis separation of the twoDNA strands.
LE 16-9 3
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LE 16 9_3
The parent molecule hastwo complementarystrands of DNA. Each baseis paired by hydrogenbonding with its specificpartner, A with T and Gwith C.
The first step in replicationis separation of the twoDNA strands.
Each parental strand nowserves as a template thatdetermines the order ofnucleotides along a new,complementary strand.
LE 16-9 4
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_
The parent molecule hastwo complementarystrands of DNA. Each baseis paired by hydrogenbonding with its specificpartner, A with T and Gwith C.
The first step in replicationis separation of the twoDNA strands.
Each parental strand nowserves as a template thatdetermines the order ofnucleotides along a new,complementary strand.
The nucleotides areconnected to form thesugar-phosphate back-bones of the new strands.Each daughter DNAmolecule consists of oneparental strand and onenew strand.
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Watson and Cricks semiconservative model ofreplication predicts that when a double helixreplicates, each daughter molecule will have oneold strand (derived or conserved from the parent
molecule) and one newly made strand Competing models were the conservative model
and the dispersive model
LE 16-10
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Conservative
model. The two
parental strands
reassociate after
acting as
templates for
new strands,thus restoring
the parental
double helix.
Semiconservative
model. The two
strands of the
parentalmolecule
separate, and
each functions as
a template for
synthesis of a
new, comple-
mentary strand.
Dispersive model.
Each strand ofbothdaughter
molecules
contains
a mixture of
old and newly
synthesized
DNA.
Parent cellFirstreplication
Secondreplication
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Experiments by Meselson and Stahl supported thesemiconservative model
They labeled the nucleotides of the old strands
with a heavy isotope of nitrogen, while any newnucleotides were labeled with a lighter isotope
The first replication produced a band of hybrid
DNA, eliminating the conservative model A second replication produced both light and
hybrid DNA, eliminating the dispersive model and
supporting the semiconservative model
LE 16-11
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Bacteria
cultured in
medium
containing15N
DNA sample
centrifuged
after 20 min
(after first
replication)
DNA sample
centrifuged
after 40 min
(after second
replication)
Bacteria
transferred to
medium
containing14N
Less
dense
More
dense
Conservative
model
First replication
Semiconservative
model
Second replication
Dispersive
model
DNA R li ti A Cl L k
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DNA Replication: A Closer Look
The copying of DNA is remarkable in its speedand accuracy
More than a dozen enzymes and other proteins
participate in DNA replication
Getting Started: Origins of Replication
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Getting Started: Origins of Replication
Replication begins at special sites called origins ofreplication, where the two DNA strands are
separated, opening up a replication bubble
A eukaryotic chromosome may have hundreds oreven thousands of origins of replication
Replication proceeds in both directions from each
origin, until the entire molecule is copied
At the end of each replication bubble is a
replication fork, a Y-shaped region where new
DNA strands are elongating
LE 16-12
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In eukaryotes, DNA replication begins at may sitesalong the giant DNA molecule of each chromosome.
Two daughter DNA molecules
Parental (template) strand
Daughter (new) strand0.25 m
Replication fork
Origin of replication
Bubble
In this micrograph, three replicationbubbles are visible along the DNAof a cultured Chinese hamster cell(TEM).
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Animation: Origins of Replication
Elongating a New DNA Strand
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Elongating a New DNA Strand
Enzymes called DNA polymerases catalyze theelongation of new DNA at a replication fork
Each nucleotide that is added to a growing DNAstrand is a nucleoside triphosphate
The rate of elongation is about 500 nucleotidesper second in bacteria and 50 per second inhuman cells
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Antiparal lel Elongation
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Antiparal lel Elongation
The antiparallel structure of the double helix (twostrands oriented in opposite directions) affects
replication
DNA polymerases add nucleotides only to the free3end of a growing strand; therefore, a new DNA
strand can elongate only in the 5to3direction
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Along one template strand of DNA, called theleading strand, DNA polymerase can synthesize a
complementary strand continuously, moving
toward the replication fork
To elongate the other new strand, called the
lagging strand, DNA polymerase must work in the
direction away from the replication fork
The lagging strand is synthesized as a series of
segments called Okazaki fragments, which are
joined together by DNA ligase
LE 16-143
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Parental DNA
5
3
Leading strand
3
5
3
5
Okazaki
fragments
Lagging strand
DNA pol III
Template
strand
Leading strand
Lagging strand
DNA ligaseTemplate
strand
Overall direction of replication
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Animation: Leading Strand
Priming DNA Synthesis
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Priming DNA Synthesis
DNA polymerases cannot initiate synthesis of a
polynucleotide; they can only add nucleotides to
the 3 end
The initial nucleotide strand is a short one called
an RNA or DNA primer
An enzyme called primase can start an RNA chain
from scratch
Only one primer is needed to synthesize the
leading strand, but for the lagging strand each
Okazaki fragment must be primed separately
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LE 16-15_2Primase joins RNA
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53
nucleotides into a primer.
Template
strand
5 3
Overall direction of replication
RNA primer3
5
35
DNA pol III addsDNA nucleotides tothe primer, formingan Okazaki fragment.
LE 16-15_3Primase joins RNA
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53
nucleotides into a primer.
Template
strand
5 3
Overall direction of replication
RNA primer3
5
35
DNA pol III addsDNA nucleotides tothe primer, formingan Okazaki fragment.
Okazaki
fragment3
5
5
3
After reaching thenext RNA primer (not
shown), DNA pol IIIfalls off.
LE 16-15_4Primase joins RNA
l tid i t i
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53
nucleotides into a primer.
Template
strand
5 3
Overall direction of replication
RNA primer3
5
35
DNA pol III addsDNA nucleotides tothe primer, formingan Okazaki fragment.
Okazaki
fragment3
5
5
3
After reaching thenext RNA primer (not
shown), DNA pol IIIfalls off.
33
5
5
After the second fragment isprimed, DNA pol III adds DNAnucleotides until it reaches thefirst primer and falls off.
LE 16-15_5Primase joins RNA
l tid i t i
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53
nucleotides into a primer.
Template
strand
5 3
Overall direction of replication
RNA primer3
5
35
DNA pol III addsDNA nucleotides tothe primer, formingan Okazaki fragment.
Okazaki
fragment3
5
5
3
After reaching thenext RNA primer (not
shown), DNA pol IIIfalls off.
33
5
5
After the second fragment isprimed, DNA pol III adds DNAnucleotides until it reaches thefirst primer and falls off.
33
5
5
DNA pol I replacesthe RNA with DNA,adding to the 3 endof fragment 2.
LE 16-15_6Primase joins RNA
nucleotides into a primer
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53
nucleotides into a primer.
Template
strand
5 3
Overall direction of replication
RNA primer3
5
35
DNA pol III addsDNA nucleotides tothe primer, formingan Okazaki fragment.
Okazaki
fragment3
5
5
3
After reaching thenext RNA primer (not
shown), DNA pol IIIfalls off.
33
5
5
After the second fragment isprimed, DNA pol III adds DNAnucleotides until it reaches thefirst primer and falls off.
33
5
5
DNA pol I replacesthe RNA with DNA,adding to the 3 endof fragment 2.
3
3
5
5
DNA ligase forms abond between the newestDNA and the adjacent DNAof fragment 1.
The laggingstrand in the regionis now complete.
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Animation: Lagging Strand
Other Proteins That Assist DNA Replication
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Other Proteins That Assist DNA Replication
Helicase untwists the double helix and separatesthe template DNA strands at the replication fork
Single-strand binding protein binds to andstabilizes single-stranded DNA until it can be used
as a template
Topoisomerase corrects overwinding ahead ofreplication forks by breaking, swiveling, and
rejoining DNA strands
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Primase synthesizes an RNA primer at the 5 ends
of the leading strand and the Okazaki fragments
DNA pol III continuously synthesizes the leading
strand and elongates Okazaki fragments
DNA pol I removes primer from the 5 ends of the
leading strand and Okazaki fragments, replacing
primer with DNA and adding to adjacent 3 ends
DNA ligase joins the 3 end of the DNA that
replaces the primer to the rest of the leading
strand and also joins the lagging strand fragments
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Animation: DNA Replication Review
The DNA Replication Machine as a Stationary
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p y
Complex The proteins that participate in DNA replication
form a large complex, a DNA replication machine
The DNA replication machine is probably
stationary during the replication process
Recent studies support a model in which DNApolymerase molecules reel in parental DNA andextrude newly made daughter DNA molecules
Proofreading and Repairing DNA
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g p g
DNA polymerases proofread newly made DNA,replacing any incorrect nucleotides
In mismatch repair of DNA, repair enzymes correct
errors in base pairing In nucleotide excision repair, enzymes cut out and
replace damaged stretches of DNA
LE 16-17A thymine dimer
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DNA
ligase
DNA
polymerase
DNA ligase seals the
free end of the new DNA
to the old DNA, making the
strand complete.
Repair synthesis by
a DNA polymerase
fills in the missing
nucleotides.
A nuclease enzyme cuts
the damaged DNA strandat two points and the
damaged section is
removed.
Nuclease
distorts the DNA molecule.
Replicating the Ends of DNA Molecules
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Limitations of DNA polymerase create problemsfor the linear DNA of eukaryotic chromosomes
The usual replication machinery provides no wayto complete the 5 ends, so repeated rounds of
replication produce shorter DNA molecules
LE 16-185
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End of parental
DNA strands
3
Lagging strand 5
3
Last fragment
RNA primer
Leading strand
Lagging strand
Previous fragment
Primer removed but
cannot be replaced
with DNA because
no 3end available
for DNA polymerase5
3
Removal of primers and
replacement with DNA
where a 3 end is available
Second round
of replication
5
3
5
3
Further rounds
of replication
New leading strandNew leading strand
Shorter and shorter
daughter molecules
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Eukaryotic chromosomal DNA molecules have attheir ends nucleotide sequences called telomeres
Telomeres do not prevent the shortening of DNA
molecules, but they do postpone the erosion of
genes near the ends of DNA molecules
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If chromosomes of germ cells became shorter inevery cell cycle, essential genes would eventually
be missing from the gametes they produce
An enzyme called telomerase catalyzes the
lengthening of telomeres in germ cells