unit 2

UNIT 2 UNIT 2

DNA DNA ReplicationReplication

ObjectivesObjectives Discuss experimental evidence supporting semi- Discuss experimental evidence supporting semi-

conservative mechanism of DNA replicationconservative mechanism of DNA replication Explain DNA replication in Prokaryotes and Explain DNA replication in Prokaryotes and

EukaryotesEukaryotes Define mutationDefine mutation Identify different types of mutations and their Identify different types of mutations and their

effects on the protein products producedeffects on the protein products produced

Eukaryotic genes have interrupted coding Eukaryotic genes have interrupted coding sequences. sequences.

That is, there are long sequences of bases That is, there are long sequences of bases within the protein-coding sequences of the within the protein-coding sequences of the gene that do not code for amino acids in the gene that do not code for amino acids in the final protein product. final protein product.

The nocoding regions within the gene are The nocoding regions within the gene are

called introns (intervening sequences).called introns (intervening sequences).

The exons (expressed sequences) which are The exons (expressed sequences) which are part of the protein-coding sequence.part of the protein-coding sequence.

A typical eukaryotic gene may have multiple A typical eukaryotic gene may have multiple exons and introns and the numbers are quite exons and introns and the numbers are quite variable.variable.

Eg. the β-globulin gene has 2 and the Eg. the β-globulin gene has 2 and the ovalbumin gene of egg white has 7. ovalbumin gene of egg white has 7.

In many cases the lengths of the introns are In many cases the lengths of the introns are

much greater than those of the exon much greater than those of the exon sequences. sequences.

For instance the ovalbumin gene contains For instance the ovalbumin gene contains about 7700 base pairs, 1859 of them in exons.about 7700 base pairs, 1859 of them in exons.

DNA ReplicationDNA ReplicationThree theories were suggested:Three theories were suggested:

Conservative replicationConservative replication intact the original DNA molecule and generate intact the original DNA molecule and generate

a completely new molecule.a completely new molecule.

Dispersive replicationDispersive replication produce two DNA molecules with sections of produce two DNA molecules with sections of

both old and new DNA interspersed along both old and new DNA interspersed along each strand. each strand.

Semi-conservative replicationSemi-conservative replication produce molecules with both old and new produce molecules with both old and new

DNA - each molecule would be composed of DNA - each molecule would be composed of one old strand and one new one. one old strand and one new one.

DNA Replication is semi-DNA Replication is semi-conservativeconservative

Experimental ProofExperimental Proof

(1957) Mathew Meselson and Franklin Stahl (1957) Mathew Meselson and Franklin Stahl grew the bacterium grew the bacterium Escherichia coliEscherichia coli on on medium that contained medium that contained 1515N in the form of N in the form of ammonium chloride. ammonium chloride.

The The 1515N became incorporated into DNA N became incorporated into DNA (nitrogenous bases). (nitrogenous bases).

The resulting heavy nitrogen-containing DNA The resulting heavy nitrogen-containing DNA molecules were extracted from some of the molecules were extracted from some of the cells. cells.


Experimental ProofExperimental Proof When subject to density gradient When subject to density gradient

centrifugation, they accumulated in the centrifugation, they accumulated in the high-density region of the gradient. high-density region of the gradient.

The rest of the bacteria were transferred The rest of the bacteria were transferred to a new growth medium in which to a new growth medium in which ammonium chloride contained the ammonium chloride contained the naturally abundant, lighter naturally abundant, lighter 1414N isotopeN isotope. .


Experimental ProofExperimental Proof The newly synthesized strands were expected to The newly synthesized strands were expected to

be less dense since they incorporated bases be less dense since they incorporated bases containing the lighter containing the lighter 1414N isotope. N isotope.

The DNA from cells isolated after one generation The DNA from cells isolated after one generation had an intermediate density, indicating that they had an intermediate density, indicating that they contained half as many contained half as many 1515N isotope as the parent N isotope as the parent DNA. DNA.

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


Experimental ProofExperimental Proof It is also consistent with the dispersive model It is also consistent with the dispersive model

which would yield one class of molecules, all which would yield one class of molecules, all with intermediate density. with intermediate density.

It was inconsistent with the conservative It was inconsistent with the conservative model which predicted that there would be two model which predicted that there would be two classes of double-stranded molecules, those classes of double-stranded molecules, those with two heavy strands and those with two with two heavy strands and those with two light strands. light strands.

After another cycle of cell division in the After another cycle of cell division in the medium with the lighter medium with the lighter 1414N isotope, two types N isotope, two types of DNA appeared in the density gradient. of DNA appeared in the density gradient.


Experimental ProofExperimental Proof One with hybrid DNA helices ( one strand One with hybrid DNA helices ( one strand 1515N N

isotope and the other strand isotope and the other strand 1414N), whereas the N), whereas the other contained only strands of the light isotope. other contained only strands of the light isotope.

This finding refuted the dispersive model, which This finding refuted the dispersive model, which predicted that all stands should have predicted that all stands should have intermediate density. intermediate density.

It however supported the semiconservative It however supported the semiconservative method which predicted that each parent strand method which predicted that each parent strand would act as a template for the synthesis of new would act as a template for the synthesis of new strands. strands.

Animation of Animation of DNA DNA Replication Experimental Replication Experimental

ProofProof

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TutorialTutorial http://www.sumanasinc.com/http://www.sumanasinc.com/

webcontent/animations/content/webcontent/animations/content/meselson.htmlmeselson.html

DNA Replication in DNA Replication in BacteriaBacteria

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

hydrogen bonds between the hydrogen bonds between the complementary strandscomplementary strands

synthesis of two new strands by synthesis of two new strands by complementary base pairingcomplementary base pairing

Replication begins at a specific site in the DNA Replication begins at a specific site in the DNA called the called the origin of replicationorigin of replication ( (oriori))


DNA replication is DNA replication is bidirectionalbidirectional from the origin of replicationfrom the origin of replication

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


To begin DNA replication, unwinding To begin DNA replication, unwinding enzymes called enzymes called DNA helicasesDNA helicases cause cause the two parent DNA strands to unwind the two parent DNA strands to unwind and separate from one another at the and separate from one another at the origin of replication to form two "Y"-origin of replication to form two "Y"-shaped shaped replication forksreplication forks..

These replication forks are the actual These replication forks are the actual site of DNA copyingsite of DNA copying

Replication ForkReplication Fork

Animation of Replication Animation of Replication ForkFork

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

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


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

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


The nucleotides lining up by The nucleotides lining up by complementary base pairing are complementary base pairing are deoxynucleoside triphosphatesdeoxynucleoside triphosphates

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

DNA Replication by DNA Replication by Complementary Base Complementary Base

Pairing Pairing

Animation of How Animation of How Nucleotides are addedNucleotides are added


DNA replication in a 5' to 3' DNA replication in a 5' to 3' direction direction


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

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

As a result, DNA can only be synthesized in a As a result, DNA can only be synthesized in a 5' to 3' direction5' to 3' direction while copying a parent while copying a parent strand running in a 3' to 5' direction. strand running in a 3' to 5' direction.

DNA Replication in DNA Replication in BacteriaBacteria The two strands are antiparallelThe two strands are antiparallel – –

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

the other parent strand - the one the other parent strand - the one running 5' to 3' is called the running 5' to 3' is called the lagging lagging strandstrand must be copied discontinuously must be copied discontinuously in in short fragmentsshort fragments – –

Okazaki fragmentsOkazaki fragments of around 100-1000 of around 100-1000 nucleotides each as the DNA unwinds. nucleotides each as the DNA unwinds.


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

can only attach new nucleotides onto 3' OH group can only attach new nucleotides onto 3' OH group of a nucleotide in a preexisting strand. of a nucleotide in a preexisting strand.

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

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

RNA primerRNA primer


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

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

The primer is later degraded and filled The primer is later degraded and filled in with DNA.in with DNA.


Bacteria have 5 known DNA Bacteria have 5 known DNA polymerases:polymerases:

Pol IPol I: :

DNA repairDNA repair has 5'→3' (Polymerase) activity has 5'→3' (Polymerase) activity both 3' → 5' (proof reading) and 5' → 3' both 3' → 5' (proof reading) and 5' → 3'

exonuclease activity (in removing RNA exonuclease activity (in removing RNA primers). primers).

DNA polymerase I is not the replicative DNA polymerase I is not the replicative polymerase:polymerase:

1. The enzyme is too slow!1. The enzyme is too slow!adds dNTPs at a rate of 20 nt/sec. So it would adds dNTPs at a rate of 20 nt/sec. So it would require 460,000 sec (= 7667 min = 128 hr = 5.3 require 460,000 sec (= 7667 min = 128 hr = 5.3 days) to replicate the days) to replicate the E. coliE. coli chromosome! Too chromosome! Too slow for an organism which can divide every 20 slow for an organism which can divide every 20 mins.mins.

2. The enzyme is too abundant2. The enzyme is too abundantThere are 400 molecules per There are 400 molecules per E. coliE. coli cell. This is cell. This is excessive given that there are generally only 2 excessive given that there are generally only 2 replication forks per cell.replication forks per cell.

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

DNA Replication in DNA Replication in BacteriaBacteria Pol IIPol II: :

involved in repair of damaged DNAinvolved in repair of damaged DNA has 3' → 5' exonuclease activity. has 3' → 5' exonuclease activity.

Proof that this is not the main polymerase:Proof that this is not the main polymerase:1.1.Strains lacking the gene show no defect in Strains lacking the gene show no defect in

growth or replication. growth or replication.

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

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

DNA Replication in DNA Replication in BacteriaBacteria Pol IIIPol III: :

the main polymerase in bacteria the main polymerase in bacteria (elongates in DNA replication)(elongates in DNA replication)

has 3' has 3' →→ 5' exonuclease proofreading 5' exonuclease proofreading ability. ability.

is the principal replicative enzymeis the principal replicative enzyme

Proof of function:Proof of function:

1.1. is highly processive is highly processive

2.2. catalyses polymerization at a high catalyses polymerization at a high rate. rate.

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

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


Pol IVPol IV and and Pol VPol V: :

Are Y-family DNA polymerasesAre Y-family DNA polymerases participates in bypassing DNA damageparticipates in bypassing DNA damage

Animation of bidirectional Animation of bidirectional replication of DNAreplication of DNA


DNA Replication in DNA Replication in EukaryotesEukaryotes

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

each origin produces two replication each origin produces two replication forksforks moving in opposite direction moving in opposite direction

DNA Replication in EukaryotesDNA Replication in EukaryotesEukaryotes have at least 15 DNA PolymerasesEukaryotes have at least 15 DNA Polymerases ::

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

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

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

Pol δPol δ: Highly processive and has proofreading 3' : Highly processive and has proofreading 3' → 5' exonuclease activity, reposible for → 5' exonuclease activity, reposible for replication of lagging strand. replication of lagging strand.

Pol εPol ε: Highly processive and has proofreading 3' : Highly processive and has proofreading 3' → 5' exonuclease activity, reponsible for → 5' exonuclease activity, reponsible for replication of leading strand. replication of leading strand.

ηη, , ιι, , κκ, , Rev1Rev1 and and Pol ζPol ζ are involved in the are involved in the bypass of DNA damage. bypass of DNA damage.

θθ, , λλ, , φφ, , σσ, and , and μ areμ are not as well characterized: not as well characterized: There are also others, but the nomenclature has There are also others, but the nomenclature has

become quite jumbled. become quite jumbled.

DNA Replication in EukaryotesDNA Replication in Eukaryotes the polymerases that deal with the elongation arethe polymerases that deal with the elongation are

Pol α,Pol α, Pol ε,PolδPol ε,Polδ..

Pol αPol α : forms a complex to act as a primase : forms a complex to act as a primase (synthesizing an RNA primer), and then (synthesizing an RNA primer), and then elongates that primer with DNA nucleotides. elongates that primer with DNA nucleotides.

After around 20 nucleotides elongation by After around 20 nucleotides elongation by Pol α is taken over by Pol ε (on the leading strand) and is taken over by Pol ε (on the leading strand) and δ (on the lagging strand).δ (on the lagging strand).

Other enzymes are responsible for primer Other enzymes are responsible for primer remover in Eukaryotes as none of their remover in Eukaryotes as none of their polymerases have 5′→3′ exonuclease activitypolymerases have 5′→3′ exonuclease activity

DNA damage bypassDNA damage bypass All organisms need to deal with the problems All organisms need to deal with the problems

that arise when a moving replication fork that arise when a moving replication fork encounters encounters damage in the template stranddamage in the template strand. .

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

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

DNA damage bypassDNA damage bypass It is important for the cell to be able to It is important for the cell to be able to

move replication forks past unrepaired move replication forks past unrepaired damage:damage: Long-term blockage of replication Long-term blockage of replication

forks leads to cell death. forks leads to cell death. Replication of damaged DNA provides Replication of damaged DNA provides

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

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

Rate of ReplicationRate of Replication

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

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

MutationsMutations

changes in the nucleotide sequence of the changes in the nucleotide sequence of the DNA. DNA.

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

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

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

Types of MutationsTypes of MutationsSomatic mutationsSomatic mutations Occurs in cells not dedicated to sexual Occurs in cells not dedicated to sexual

reproductionreproduction

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

Germline mutationsGermline mutations found in every cell descended from the found in every cell descended from the

zygote to which that mutant gamete zygote to which that mutant gamete contributed. contributed.

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

Types of MutationsTypes of MutationsSingle-base Substitution/point mutationSingle-base Substitution/point mutation exchanges one base for another. exchanges one base for another.

If one purine [A or G] or pyrimidine [C or T] is If one purine [A or G] or pyrimidine [C or T] is replaced by the other, the substitution is called areplaced by the other, the substitution is called a

transitiontransition.. If a purine is replaced by a pyrimidine or vice-If a purine is replaced by a pyrimidine or vice-

versa, the substitution is called aversa, the substitution is called a transversiontransversion..

Original:Original: The fat cat ate the wee The fat cat ate the wee ratrat

Point Mutation:Point Mutation: The fat The fat hhat ate the wee at ate the wee ratrat

Types of MutationsTypes of Mutations

Point mutations continued Point mutations continued A change in a codon to one that encodes a A change in a codon to one that encodes a

different amino acid and cause a small different amino acid and cause a small change in the protein produced = change in the protein produced = missense mutationmissense mutation..

Example Example sickle-cell diseasesickle-cell disease

A → A → TT at the 17th nt of the gene for the at the 17th nt of the gene for the beta beta chain of hemoglobin changes the chain of hemoglobin changes the codon GAG codon GAG (glutamic acid) to G(glutamic acid) to GTTG (valine)G (valine)

Therefore: 6th amino acid glutamic acid → Therefore: 6th amino acid glutamic acid → valine valine

Missense mutationMissense mutation

Examples of Diseases Examples of Diseases caused by point mutationscaused by point mutations

Color blindnessColor blindness Cystic fibrosisCystic fibrosis HemophiliaHemophilia PhenylketonuriaPhenylketonuria Tay SachsTay Sachs


Point mutations continuedPoint mutations continued change a codon to one that encodes the change a codon to one that encodes the

same amino acid and causes no change in same amino acid and causes no change in the protein produced = the protein produced = silent mutationssilent mutations. .

change an amino-acid-coding codon to a change an amino-acid-coding codon to a single "stop" codon → an incomplete single "stop" codon → an incomplete protein protein = = a nonsense mutationa nonsense mutation can have serious effects since the incomplete can have serious effects since the incomplete

protein probably won't function. protein probably won't function.

Nonsense MutationNonsense Mutation

Types of MutationsTypes of MutationsInsertionInsertion

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

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

Insertion: The fat cat Insertion: The fat cat xlwxlw ate the wee rat. ate the wee rat.

DeletionDeletion

a section of DNA is lost, or deleted.a section of DNA is lost, or deleted.

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

Deletion:Deletion: The fat ate the wee rat. The fat ate the wee rat.

Insertion mutationInsertion mutation


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

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

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

Huntington’sHuntington’s

Deletion MutationDeletion Mutation

Examples of Diseases Examples of Diseases caused by deletionscaused by deletions

Cri du chatCri du chat De Grouchy syndromeDe Grouchy syndrome Shprintzen syndrome Shprintzen syndrome Wolf-Hirschhorn syndromeWolf-Hirschhorn syndrome Duchenne muscular dystrophyDuchenne muscular dystrophy


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

gene because translation of the gene isgene because translation of the gene is "frameshifted""frameshifted"

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

The entire meaning of the sequence has changed. The entire meaning of the sequence has changed.

FrameshiftsFrameshifts often create new often create new STOPSTOP codons → codons → nonsense mutationsnonsense mutationsOriginal:Original: The fat cat ate the wee rat. The fat cat ate the wee rat.Frame Shift:Frame Shift: The fat caa tet hew eer at. The fat caa tet hew eer at.

Frame shift mutationFrame shift mutation


DuplicationsDuplications

Duplications are a doubling of a section Duplications are a doubling of a section of the genome. of the genome.

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

dystrophy)dystrophy)


TranslocationsTranslocations

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

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


Translocations can alter the phenotype is Translocations can alter the phenotype is several waysseveral ways::

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

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


InversionInversion

an entire section of DNA is reversed. an entire section of DNA is reversed.

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

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

InversionInversion

Types of MutationsTypes of MutationsSuppressor mutationSuppressor mutation

partially or completely masks phenotypic partially or completely masks phenotypic expression of a mutation but occurs at a expression of a mutation but occurs at a different site from it different site from it

(i.e., causes suppression)(i.e., causes suppression) may be intragenic or intergenic. may be intragenic or intergenic.

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

Naming genesNaming genes

given an official name and symbol by a formal given an official name and symbol by a formal committeecommittee

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

Some official gene names include additional Some official gene names include additional information in parentheses, such as related genetic information in parentheses, such as related genetic conditions, subtypes of a condition, or inheritance conditions, subtypes of a condition, or inheritance pattern.pattern.

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

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

How are genetic conditions How are genetic conditions named?named?

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

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

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

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

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

A geographic area (familial Mediterranean fever)A geographic area (familial Mediterranean fever)

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

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

References/ sources of References/ sources of imagesimages

http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/M/Mutations.htmlhttp://users.rcn.com/jkimball.ma.ultranet/BiologyPages/M/Mutations.html http://www.genetichealth.com/g101_changes_in_dna.shtmlhttp://www.genetichealth.com/g101_changes_in_dna.shtml http://evolution.berkeley.edu/evolibrary/article/0_0_0/mutations_03http://evolution.berkeley.edu/evolibrary/article/0_0_0/mutations_03 usmlemd.wordpress.com/2007/07/14/dna-replication/usmlemd.wordpress.com/2007/07/14/dna-replication/ www.replicationfork.comwww.replicationfork.com// http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/D/DNAReplication.htmlhttp://users.rcn.com/jkimball.ma.ultranet/BiologyPages/D/DNAReplication.html http://upload.wikimedia.org/wikipedia/commons/1/12/DNA_exons_introns.gifhttp://upload.wikimedia.org/wikipedia/commons/1/12/DNA_exons_introns.gif http://employees.csbsju.edu/hjakubowski/classes/ch331/dna/centraldogma.jpghttp://employees.csbsju.edu/hjakubowski/classes/ch331/dna/centraldogma.jpg http://www.usask.ca/biology/rank/demo/replication/cons.rep.gifhttp://www.usask.ca/biology/rank/demo/replication/cons.rep.gif http://click4biology.info/c4b/3/images/3.4/SEMICON.gifhttp://click4biology.info/c4b/3/images/3.4/SEMICON.gif http://www.bio.miami.edu/~cmallery/150/gene/sf12x16.jpghttp://www.bio.miami.edu/~cmallery/150/gene/sf12x16.jpg http://publications.nigms.nih.gov/findings/sept08/images/hunt_gene_big.jpghttp://publications.nigms.nih.gov/findings/sept08/images/hunt_gene_big.jpg http://ghr.nlm.nih.gov/handbook/illustrations/duplication.jpghttp://ghr.nlm.nih.gov/handbook/illustrations/duplication.jpg http://images.google.com.jm/imgres?imgurl=http://ghr.nlm.nih.gov/handbook/illustrations/http://images.google.com.jm/imgres?imgurl=http://ghr.nlm.nih.gov/handbook/illustrations/

duplication.jpg&imgrefurl=http://ghr.nlm.nih.gov/handbook/illustrations/duplication.jpg&imgrefurl=http://ghr.nlm.nih.gov/handbook/illustrations/duplication&usg=__BgKRLXXos-duplication&usg=__BgKRLXXos-xRaUqN5EyP7qchszc=&h=400&w=370&sz=38&hl=en&start=2&tbnid=ZfARmmvAKG02xxRaUqN5EyP7qchszc=&h=400&w=370&sz=38&hl=en&start=2&tbnid=ZfARmmvAKG02xM:&tbnh=124&tbnw=115&prev=/images%3Fq%3Dduplication%2Bmutation%26gbvM:&tbnh=124&tbnw=115&prev=/images%3Fq%3Dduplication%2Bmutation%26gbv%3D2%26hl%3Den%26client%3Dfirefox-a%26rls%3Dorg.mozilla:en-US:official%26sa%3DG%3D2%26hl%3Den%26client%3Dfirefox-a%26rls%3Dorg.mozilla:en-US:official%26sa%3DG

http://members.cox.net/amgough/mutation_chromosome_translocation.gifhttp://members.cox.net/amgough/mutation_chromosome_translocation.gif http://employees.csbsju.edu/HJAKUBOWSKI/classes/ch331/dna/mutation2.gifhttp://employees.csbsju.edu/HJAKUBOWSKI/classes/ch331/dna/mutation2.gif http://www.embryology.ch/images/kimgchromaber/02abweichende/k2f_inversionPara.gifhttp://www.embryology.ch/images/kimgchromaber/02abweichende/k2f_inversionPara.gif http://www.montana.edu/wwwai/imsd/diabetes/mutation.gifhttp://www.montana.edu/wwwai/imsd/diabetes/mutation.gif http://staff.jccc.net/pdecell/proteinsynthesis/bidirection.gifhttp://staff.jccc.net/pdecell/proteinsynthesis/bidirection.gif

unit 2

Documents

dna molecules

new dna

types of dna

parent dna

semiconservative replication

original dna molecule

dna nitrogenous bases

hybrid dna helices