-DNA Replication-mutation

UNIT 4

DNA Replication

Objectives Discuss experimental evidence supporting semi-

conservative mechanism of DNA replication Explain DNA replication in Prokaryotes and Eukaryotes Define mutation Identify different types of mutations and their effects on

the protein products produced

DNA runs 5’ to 3’ and the two strands run anti-parallel to each other

This thus suggests a method by which DNA replication might occur

RECAP

1. Conservative replication

Following replication, one daughter molecule contains both of the parental strands.

The other daughter molecule contains two newly synthesized DNA strands

However three theories were put forward as to how DNA replication may occur

2. Dispersive replication

Both strands of each daughter molecule contain nucleotides derived from the parental molecule.


3. Semi- conservative replication

molecules are produced with both old and new DNA each molecule would be composed of one old strand and one new one.


Which is correct?

Each new double helix retains or conserves one of the two strands of the original double helix

This proven by experiments conducted by two scientist.

DNA Replication is semi-conservative

(1957) Mathew Meselson and Franklin Stahl conducted an experiment to prove that DNA replication was semi- conservative.

1. They used two N (nitrogen)

isotopes (Isotopes are variants of a particular chemical element)

2. 15N heavy isotope and 14N light isotope

3. They made 2 growth media one with each isotope and grew E. coli on each

DNA Replication is semi-conservativeExperimental Proof

5. They allowed the bacteria to grow for several generations ( E.coli reproduces every 20 mins)

6. This allowed the 15N isotope and the 14N to be incorporated into the E. coli DNA and label it.

7. Thus the DNA contained either light or heavy DNA but not both


8. They took samples from each bacterial culture

9. The two cultures were then mixed together.

10. Cesium chloride (CsCl) was then added to the mixture


11. They sample was placed on a centrifuge and spun at high speed for 20 hrs

12. After centrifugation a consentration gradient is formed in the tube with the densest area being at the bottom

13. The lighter DNA containing the 14N floats to the top and the heavier DNA containing 15N is found close to the bottom


Since Meselson and Sathl now knew how they could differentiate the DNA based on density then they could test the semi-conservative replication using this newly found basis


1. They made medium with the 15N heavy isotope and added E. coli they allowed the E. coli to grow for 14 generations to make sure that all the DNA would be contain the isotope

2. They then isolated a sample extracted the DNA and added CsCl


3. They made medium with the 14N light isotope and transferred some of the bacteria from the 15N heavy isotope media to it.

4. They were left to grow on the 14N for a few generations

5. Thy called the first sample from the 15N medium generation 0

6. They took a sample every 20 mins from the 14N with mixed with bacteria from the 15N

7. They called the 1st sample generation 1 and the other after 20 mins generation 2 and so on


8. They added CsCl to every sample and centrifuged for 20 hrs

9. Generation 0 -all the DNA was found to be heavy DNA (as expected)

10. Generation 1- all DNA were in the neither heavy or light but found in between the two (intermediate)

11. Generation 2- 50% heavy and 50% intermediate

Why did this occur if only heavy and light isotopes were used?


Why did this occur if only heavy and light isotopes were used?

The answer must be that the two combined therefore DNA replication must be SEMI -CONSERVATIVE


In that one strand that contained the 15N isotope acted as a template

so that during replication the new DNA strand being synthesized had to incorporate the light 14N isotope the two separate strands then recombined so that the resulting DNA would have both light 14N and heavy 15N isotpoes incorporated


This finding supported the semi-conservative model - each double helix would contain one previously synthesized strand and a newly synthesized strand.

http://highered.mcgraw-hill.com/sites/0072437316/student_view0/chapter14/animations.html

Self help Tutorial http://www.sumanasinc.com/webcontent/ani

mations/content/meselson.html

Animation of DNA Replication Experimental Proof




http://www.sumanasinc.com/webcontent/animations/content/meselson.html

http://www.sumanasinc.com/webcontent/animations/content/meselson.html

In general, DNA is replicated by:◦ uncoiling of the helix◦ strand separation by breaking of the

hydrogen bonds between the complementary strands

◦ synthesis of two new strands by complementary base pairing

DNA Replication

• Recap- bacterial DNA is circular

• Replication begins at a specific site in the DNA

called the origin of replication

(ori)

DNA Replication in Bacteria

DNA replication is bidirectional from the origin of replication

DNA replication occurs in both directions from the origin of replication in the circular DNA found in most bacteria.


To begin DNA replication, unwinding enzymes called DNA helicases bind to the DNA molecule

This causes the two parent DNA

strands to unzip and unwind thus separating from each other separate from one another at the origin of replication to form two "Y"-shaped replication forks.

These replication forks are the actual site of DNA copying

Two replication forks are actually formed in bacteria that is why DNA replication is bidirectional

DNA Replication in BacteriaDNA Helicase

Replication Fork

http://highered.mcgraw-hill.com/sites/0072437316/student_view0/chapter14/animations.html#

Animation of Replication Fork




Helix destabilizing proteins bind to the single-stranded regions so the two strands do not rejoin

Enzymes called topoisimerases produce breaks in the DNA and then rejoin them in order to relieve the stress in the helical molecule during replication.


As the strands continue to unwind in both directions around the entire DNA molecule, new complementary strands are produced by the hydrogen bonding of free DNA nucleotides with those on each parent strand

As the new nucleotides line up opposite each parent strand by hydrogen bonding, enzymes called DNA polymerases join the nucleotides by way of phosphodiester bonds.


The nucleotides lining up by complementary base pairing are deoxynucleoside triphosphates. (sugar and base together are called nucleosides)

As the phosphodiester bond forms between the 5' phosphate group of the new nucleotide and the 3' OH of the last nucleotide in the DNA strand, two of the phosphates are removed providing energy for bonding



Animation of How Nucleotides are added




DNA replication in a 5' to 3' direction

DNA replication is more complicated than this because of the nature of the DNA polymerases.

DNA polymerase enzymes are only able to join the phosphate group at the 5' carbon of a new nucleotide to the hydroxyl (OH) group of the 3' carbon of a nucleotide already in the chain.

As a result, DNA can only be synthesized in a 5' to 3' direction while copying a parent strand running in a 3' to 5' direction.


Since DNA runs from 5’to 3’ this poses a problem at the replication fork

Recap the double helix has a unique form of polarity determined by the way each sugar is linked to the next and the two strands run in opposite directions


This therefore means that at the replication fork one new strand of DNA is being made on a template that runs in one direction 3’ to 5’

Where as the other strand is made on a template running 5’ to 3’


The replication fork is therefore asymmetrical at first glance the both new strands seem to be running in the same direction that is the direction in which the replication fork is moving

It then suggest that one strand is being synthesized 3’ to 5’ and the other 5’ to 3’


DNA polymerase can however only catalyze the growth of DNA chain in one direction

It can only add new subunits only to the 3’ end

As a result a new DNA strand can only be synthesized in the 5’ to 3’ direction

This can thus account for synthesis on one strand called the leading strand

But what about the other strand that runs in the opposite direction? Lagging strand)This means another DNA polymerase would have to add to the 5’ end

NO SUCH DNA POLYMERASE EXISTS


The two strands are antiparallel

• one parent strand - the one running 3' to 5' is called the leading strand can be copied directly down its entire length Continously

• the other parent strand - the one running 5' to 3' is called the lagging strand

• but there is a problem how can this be copied?


So how can this problem be fixed? This is done by “ Backstiching”

Thus one strand must grow discontinuously (while the other is continuously being synthesized) in separate small pieces with DNA polymerase moving backward to the movement of the replication fork as each new piece is made in the 5’ to 3’ direction


These resulting small pieces of DNA are called Okazaki fragments

These fragments later join together to make one continuous strands

How is this done?


DNA polymerase enzymes cannot begin a new DNA chain from scratch.

Recap It can only attach new nucleotides onto 3' OH group of a nucleotide in a pre-existing strand.


Therefore a new enzyme is needed one that can begin a new polynucleotide chain by simply joining two nucleotides together

Without the need for a base paired end

This enzyme cannot synthesize DNA

One such enzyme is called RNA polymerase

Which can make short single stranded RNA pieces approx 10 nucleotides long which can be base paired to the 3’ end as a starting point for DNA polymerase


◦ To start the synthesis of the leading strand and each DNA fragment of the lagging strand, an RNA polymerase complex called a primosome or primase is required

◦ The primase is capable of

joining RNA nucleotides without requiring a preexisting strand of nucleic acid - forms what is called an RNA primer


After a few nucleotides are added, primase is replaced by DNA polymerase.

DNA polymerase can now add nucleotides to the 3' end of the short RNA primer.

The primer is later degraded and filled in with DNA by DNA Ligase


Bacteria have 5 known DNA polymerases: Pol I:

◦ DNA repair◦ has 5'→3' (Polymerase) activity ◦ both 3' → 5' and 5' → 3' exonuclease activity (in

removing RNA primers).

DNA polymerase I is not the replicative polymerase.The enzyme is too slow!

adds dNTPs at a rate of 20 nt/sec. So it would require 460,000 sec (= 7667 min = 128 hr = 5.3 days) to replicate the E. coli chromosome! Too slow for an organism which can divide every 20 mins.

The enzyme is too abundantThere are 400 molecules per E. coli cell. This is excessive given that there are generally only 2 replication forks per cell.

The enzyme is not processive enoughDNA polymerase I dissociates after catalysing the incorporation of 20-50 nucleotides.


Pol II: ◦ involved in repair of damaged DNA◦ has 3' → 5' exonuclease activity.

Strains lacking the gene show no defect in growth or replication.

Synthesis of Pol II is induced during the stationary phase of cell growth - a phase in which little growth and DNA synthesis occurs. But DNA can accumulate damage such as short gaps

Pol II has a low error rate but it is much too slow to be of any use in normal DNA synthesis.


Pol III: ◦ the main polymerase in bacteria (elongates in DNA

replication)◦ has 3' → 5' exonuclease proofreading ability.

is the principal replicative enzyme is highly processive catalyses polymerization at a high rate.

There are two forms of the enzyme.Core enzyme - consists of only those subunits that are required for the basic underlying enzymatic activity: alpha (a), epsilon (e) and theta (q).

Holoenzyme- the fully functional form of an enzyme, complete with all of its necessary accessory subunits. The DNA polymerase III holoenzyme consists of the core enzyme, the b sliding clamp and the clamp-loading complex.


Pol IV: a Y-family DNA polymerase. Pol V: a Y-family DNA polymerase;

participates in bypassing DNA damage



Animation of bidirectional replication of DNA




Unusual features of DNA polymerase functionFigure 11.9

Problem is overcome by the RNA primers

synthesized by primase

DNA polymerases cannot initiate DNA synthesis

DNA polymerases can attach nucleotides only in

the 5’ to 3’ direction

Problem is overcome by synthesizing the 3’ to 5’

strands in small fragments

Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display

The two new daughter strands are synthesized in different ways Leading strand

One RNA primer is made at the origin DNA pol III attaches nucleotides in a 5’ to 3’ direction

as it slides toward the opening of the replication fork

Lagging strand Synthesis is also in the 5’ to 3’ direction

However it occurs away from the replication fork Many RNA primers are required DNA pol III uses the RNA primers to synthesize small

DNA fragments (1000 to 2000 nucleotides each) These are termed Okazaki fragments after their discoverers


DNA pol I removes the RNA primers and fills the resulting gap with DNA It uses its 5’ to 3’ exonuclease activity to digest the RNA

and its 5’ to 3’ polymerase activity to replace it with DNA

After the gap is filled a covalent bond is still missing

DNA ligase catalyzes a phosphodiester bond Thereby connecting the DNA fragments

Breaks the hydrogen bonds between the

two strands

Alleviates supercoiling

Keep the parental strands apart

Synthesizes an RNA primer

Synthesizes daughter DNA strands

III

Covalently links DNA fragments together

Eukaryotic DNA replication is not as well understood as bacterial replication

◦ The two processes do have extensive similarities,

◦ Nevertheless, DNA replication in eukaryotes is more complex Large linear chromosomes Tight packaging within nucleosomes More complicated cell cycle regulation

11.3 EUKARYOTIC DNA REPLICATION

Eukaryotes have long linear chromosomes They therefore require multiple

origins of replication To ensure that the DNA can

be replicated in a reasonable time

In 1968, Huberman and Riggs provided evidence for the multiple origins of replication

DNA replication proceeds bidirectionally from many origins of replication.

Multiple Origins of Replication

multiple origins of replication in eukaryotes ◦ human genome about 30,000 origins

each origin produces two replication forks◦ moving in opposite direction

DNA Replication in Eukaryotes

Origin recognition complex (ORC) A six-subunit complex that acts as the initiator of

eukaryotic DNA replication It appears to be found in all eukaryotes

Multiple Origins of Replication


Mammalian cells contain well over a 15 different DNA polymerases

Four: alpha (a), delta (d), epsilon (e) and gamma (g) have the primary function of replicating DNA a, d and e Nuclear DNA g Mitochondrial DNA

Eukaryotes Contain Several Different DNA Polymerases

11-68


Pol α : act as a primase (synthesizing an RNA primer), elongates the primer

Pol β : repairs DNA, (excision repair and gap-filling).

Pol γ: Replicates and repairs mitochondrial DNA and has proofreading 3' → 5' exonuclease activity.

Pol δ: Highly processive and has proofreading 3' → 5' exonuclease activity.

Pol ε: Highly processive and has proofreading 3' → 5' exonuclease activity.

η, ι, κ, Rev1 and Pol ζ are involved in the bypass of DNA damage.

θ, λ, φ, σ, and μ are not as well characterized: There are also others, but the nomenclature has become quite jumbled.

Eukaryotes have at least 15 DNA Polymerases:

the polymerases that deal with the elongation arePol α, Pol ε,Polδ.

Pol α : forms a complex to act as a primase (synthesizing an RNA primer), and then elongates that primer with DNA nucleotides. After around 20 nucleotides elongation is taken over by Pol ε (on the leading strand) and δ (on the lagging strand).



DNA replication occurs until a series of termination sequences are identified and then the enzymes are removed


DNA replication exhibits a high degree of fidelity Mistakes during the process are extremely rare

DNA pol III makes only one mistake per 108 bases made

There are several reasons why fidelity is high

1. Instability of mismatched pairs 2. Configuration of the DNA polymerase active site 3. Proofreading function of DNA polymerase

Proofreading Mechanisms

11-42

1. Instability of mismatched pairs Complementary base pairs have much higher stability

than mismatched pairs This feature only accounts for part of the fidelity

It has an error rate of 1 per 1,000 nucleotides

2. Configuration of the DNA polymerase active site DNA polymerase is unlikely to catalyze bond formation

between mismatched pairs This induced-fit phenomenon decreases the error rate to

a range of 1 in 100,000 to 1 million


3. Proofreading function of DNA polymerase

DNA polymerases can identify a mismatched nucleotide and remove it from the daughter strand

The enzyme uses its 3’ to 5’ exonuclease activity to remove the incorrect nucleotide

It then changes direction and resumes DNA synthesis in the 5’ to 3’ direction


A schematic drawing of proofreading

Site where DNA backbone is cut

DNA polymerases also play a role in DNA repair DNA pol b is not involved in DNA replication It plays a role in base-excision repair

Removal of incorrect bases from damaged DNA

Recently, more DNA polymerases have been identified Lesion-replicating polymerases

Involved in the replication of damaged DNA They can synthesize a complementary strand over the

abnormal region

DNA damage bypass All organisms need to deal with the problems that arise when

a moving replication fork encounters damage in the template strand.

The best way to deal with this situation is to repair the damage by excision mechanisms.

In some cases, however, the damage may not be repairable, or the advancing replication fork may already have unwound the parental strands, thus preventing excision mechanisms from using the complementary strand as template for repair, or excision repair may not yet have had an opportunity to repair the damage.

DNA damage bypass

It is important for the cell to be able to move replication forks past unrepaired damage:◦ Long-term blockage of replication forks leads

to cell death. ◦Replication of damaged DNA provides a sister

chromatid that can be used as template for subsequent repair by homologous recombination.

Replication fork bypass mechanisms cannot, strictly speaking, be considered examples of DNA repair, because the damage is left in the DNA, at least temporarily.

Rate of Replication

In prokaryotes replication proceeds at about 1000 nucleotides per second, and thus is done in no more than 40 minutes.

In Eukaryotes replication takes proceeds at 50 nucleotides per second, and is completed in 60 minutes.

Mutations changes in the nucleotide sequence of the

DNA.

organisms have special systems of enzymes that can repair certain kinds of alterations in the DNA.

once the DNA sequence has been changed, DNA replication copies the altered sequence just as it would copy a normal sequence.

provide the variation necessary for evolution to happen in a given species.

Types of MutationsSomatic mutations Occurs in cells not dedicated to sexual

reproduction

The mutant genes disappear when the cell in which it occurred dies and can only be passed on through asexual reproduction.

Germline mutations found in every cell descended from the

zygote to which that mutant gamete contributed.

If an adult is successfully produced, every one of its cells will contain the mutation.

often caused by chemicals or malfunction of DNA replication, exchange a single nucleotide for another.

These changes are classified as transitions or transversions.

Most common is the transition that exchanges a purine for a purine (A ↔ G) or a pyrimidine for a pyrimidine, (C ↔ T).

Less common is a transversion, which exchanges a purine for a pyrimidine or a pyrimidine for a purine (C/T ↔ A/G). An example of a transversion is adenine (A) being converted into a cytosine (C).

Types of Mutations- Point mutations

In short a point mutation is a Single-base Substitution

exchanges one base for another◦ If one purine [A or G] or pyrimidine [C or T] is

replaced by the other, the substitution is called a

transition. ◦ If a purine is replaced by a pyrimidine or vice-versa,

the substitution is called a transversion

Original: The fat cat ate the wee ratPoint Mutation: The fat hat ate the wee rat

Types of Mutations- Point mutations

Point mutations

Point mutations causes changes in the amino acids the bases code for

Three bases make a codon one condon codes for an amino acid example CTG codes for valine GAG codes for glutamic acid

Types of Point mutations

1. Missense mutation. A change in a codon to one that encodes a different amino acid and cause a small change in the protein produced.

Example sickle-cell disease

A → T at the 17th nucleotide of the gene for the beta chain of hemoglobin changes the codon GAG (glutamic acid) to GTG (valine)

Therefore: 6th amino acid glutamic acid → valine

Missense mutation


2. Silent mutations change a codon to one that encodes the same

amino acid and causes no change in the protein produced

Cys

CysT G T

T G C

No detrimental effect

Silent mutation

nonsense mutationchange an amino-acid-coding codon to a single "stop" codon → an incomplete protein

◦ can have serious effects since the incomplete protein probably won't function.

◦ protein wont function because protein synthesis is stopped prematurely


Nonsense Mutation

Examples of Diseases caused by point mutations

Color blindness- is the inability or decreased ability to see colour, or perceive colour differences, under normal lighting conditions. Eg. red/ green

Cystic fibrosis- affects the lungs, and also the pancreas, liver, and intestine. It is characterized by abnormal transport of chloride and sodium across an epithelium , leading to thick, viscous secretions.

Haemophilia- impair the body's ability to control blood clotting or coagulation, which is used to stop bleeding when a blood vessel is broken.

Phenylketonuria - Phenylketonuria (PKU) is a rare condition in which a baby is born without the ability to properly break down an amino acid called phenylalanine.

Tay Sachs- Tay-Sachs disease is a deadly disease of the nervous system passed down through families Tay-Sachs disease occurs when the body lacks hexosaminidase A, a protein that helps break down a chemical found in nerve tissue called gangliosides. Without this protein, gangliosides, particularly ganglioside GM2, build up in cells, especially nerve cells in the brain

Types of Mutations- InsertionInsertion

extra base pairs are inserted into a new place in the DNA.

Original: The fat cat ate the wee rat.Insertion: The fat cat xlw ate the wee rat.

Insertion mutation

Types of Mutations

An example of a human disorder caused by insertion is Huntington’s disease.

In this disorder, the repeated trinucleotide is CAG, which adds a string of glutamines (Gln) to the encoded protein (called huntingtin).

The abnormal protein increases the level of the p53 protein in brain cells causing their death by apoptosis.

Huntington’s

Types of Mutations- Deletion

Deletion

a section of DNA is lost, or deleted.Original: The fat cat ate the wee rat.Deletion: The fat ate the wee rat.

Deletion Mutation

Examples of Diseases caused by deletions

Cri du chat syndrome,-is a rare genetic disorder due to a missing part of chromosome 5. Its name is a French term (cat-cry or call of the cat) referring to the characteristic cat-like cry of affected children

De Grouchy syndrome- is a genetic condition caused by a deletion of genetic material within one of the two copies of chromosome 18 De Grouchy syndrome manifests clinically as mental retardation.

Shprintzen syndrome- is a syndrome caused by the deletion of a small piece of chromosome 22 A congenital anomaly with cleft palate, heart defect, abnormal face, learning defects, short stature, microcephaly, mental retardation, ear anomalies, slender hands/digits, inguinal hernia

Wolf-Hirschhorn syndrome- It is a characteristic phenotype resulting from a partial deletion of chromosomal material of the short arm of chromosome 4 growth and mental retardation, muscle hypotonia, seizures, and congenital heart defects

Duchenne muscular dystrophy- is an inherited disorder that involves muscle weakness, which quickly gets worse. The disorder is caused by a mutation in the dystrophingene, located on the human X chromosome, which codes for the protein dystrophin, an important structural component within muscle tissue that provides structural stability to the dystroglycan complex (DGC) of the cell membrane. While both sexes can carry the mutation, females rarely exhibit signs of the disease.

Types of Mutations

Insertion and deletions involving one or two base pairs (or multiples ) ◦ can have devastating consequences to the gene

because translation of the gene is "frameshifted"

◦ DNA reads in sequences of three bases therefore the addition or removal of one or more bases alters the sequence that follows as the bases all shifted.

◦ The entire meaning of the sequence has changed.

Frameshifts often create new STOP codons → nonsense mutationsOriginal: The fat cat ate the wee rat.Frame Shift: The fat caa tet hew eer at.

Frame shift mutation

Types of Mutations-Duplications

Duplications

Duplications are a doubling of a section of the genome.

During meiosis, crossing over between sister chromatids that are out of alignment can produce one chromatid with an duplicated gene and the other having two genes with deletions.◦ Example of disease :DM1 (Myotonic dystrophy)

Types of Mutations-TranslocationsTranslocations

Translocations are the transfer of a piece of one chromosome to a nonhomologous chromosome.

Translocations are often reciprocal; that is, the two nonhomologues swap segments.

Types of Mutations

Translocations can alter the phenotype in several ways:

the break may occur within a gene ◦ destroying its function ◦ creating a hybrid gene.

translocated genes may come under the influence of different promoters and enhancers so that their expression is altered.

Types of Mutations- InversionsInversion

an entire section of DNA is reversed.

A small inversion may involve only a few bases within a gene, while longer inversions involve large regions of a chromosome containing several genes.

Original: The fat cat ate the wee rat.Insertion: The fat tar eew eht eta tac.

Inversion

Types of Mutations-SuppressorSuppressor mutation

partially or completely masks phenotypic expression of a mutation but occurs at a different site from it (i.e., causes suppression)

may be intragenic or intergenic.

It is used particularly to describe a secondary mutation that suppresses a nonsense codon created by a primary mutation.

Naming genes given an official name and symbol by a formal committee

The HUGO Gene Nomenclature Committee (HGNC) – US and UK designates an official name and symbol (an abbreviation of the name) for each known human gene.

Some official gene names include additional information in

parentheses, such as related genetic conditions, subtypes of a condition, or inheritance pattern.

The Committee has named more than 13,000 of the estimated 20,000 to 25,000 genes in the human genome.

a unique name and symbol are assigned to each human gene, which allows effective organization of genes in large databanks, aiding the advancement of research.

How are genetic conditions named?

Disorder names are often derived from one or a combination of sources:

The basic genetic or biochemical defect that causes the condition (alpha-1 antitrypsin deficiency)

One or more major signs or symptoms of the disorder (sickle cell anemia)

The parts of the body affected by the condition (retinoblastoma)

The name of a physician or researcher, often the first person to describe the disorder (Marfan syndrome - Dr. Antoine Marfan)

A geographic area (familial Mediterranean fever)

The name of a patient or family with the condition (Lou Gehrig disease)

Disorders named after a specific person or place are called eponyms.

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http://www.google.com.jm/url?sa=t&rct=j&q=&esrc=s&source=web&cd=10&ved=0CE8QFjAJ&url=http%3A%2F%2Fwww.csus.edu%2Findiv%2Fd%2Fdulaik%2FGeneticsLectures07%2Fchapt11_lecture.ppt&ei=-WhoULPgJYHu9ATTjYC4DA&usg=AFQjCNESac2iCvfwRMIo7DqnpdJs_C7HTQ&sig2=17FVyTgpt7Ga-ChOgmRBEA&cad=rja

http://www.google.com.jm/url?sa=t&rct=j&q=&esrc=s&source=web&cd=9&ved=0CEoQFjAI&url=http%3A%2F%2Fwww.bath.ac.uk%2Fbio-sci%2Foer%2Fincluder.php%3Fid%3D52%26nocache%3D1267210964&ei=-WhoULPgJYHu9ATTjYC4DA&usg=AFQjCNHs4JKyIJUJsOAEaJL0ezkkhuycLg&sig2=ulH7EZlRZrXKWRfSkApACQ&cad=rja

http://www.google.com.jm/url?sa=t&rct=j&q=&esrc=s&source=web&cd=2&ved=0CCMQFjAB&url=http%3A%2F%2Felearning.najah.edu%2FOldData%2Fpdfs%2F3765DNA%2520Replication%2520euk11.ppt&ei=-WhoULPgJYHu9ATTjYC4DA&usg=AFQjCNEVhFx8F6GEJcAgIrWaSKWDh4Ir1w&sig2=-cMNgmgOJYT8_yeuwhrYdw&cad=rja

References/ sources of images

http://www.google.com.jm/url?sa=t&rct=j&q=&esrc=s&source=web&cd=10&ved=0CE8QFjAJ&url=http://www.csus.edu/indiv/d/dulaik/GeneticsLectures07/chapt11_lecture.ppt&ei=-WhoULPgJYHu9ATTjYC4DA&usg=AFQjCNESac2iCvfwRMIo7DqnpdJs_C7HTQ&sig2=17FVyTgpt7Ga-ChOgmRBEA&cad=rja



http://www.google.com.jm/url?sa=t&rct=j&q=&esrc=s&source=web&cd=9&ved=0CEoQFjAI&url=http://www.bath.ac.uk/bio-sci/oer/includer.php?id=52&nocache=1267210964&ei=-WhoULPgJYHu9ATTjYC4DA&usg=AFQjCNHs4JKyIJUJsOAEaJL0ezkkhuycLg&sig2=ulH7EZlRZrXKWRfSkApACQ&cad=rja



http://www.google.com.jm/url?sa=t&rct=j&q=&esrc=s&source=web&cd=2&ved=0CCMQFjAB&url=http://elearning.najah.edu/OldData/pdfs/3765DNA%20Replication%20euk11.ppt&ei=-WhoULPgJYHu9ATTjYC4DA&usg=AFQjCNEVhFx8F6GEJcAgIrWaSKWDh4Ir1w&sig2=-cMNgmgOJYT8_yeuwhrYdw&cad=rja



Documents

-DNA Replication-mutation