biology 201 chapter 15
TRANSCRIPT
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Chapter 15
Lecture and Animation Outline
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Chapter 15Genes and How They Work
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The Nature of Genes
• Early ideas to explain how genes work came from studying human diseases
• Archibald Garrod – 1902 – Recognized that alkaptonuria is inherited via a
recessive allele– Proposed that patients with the disease lacked a
particular enzyme• These ideas connected genes to enzymes
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Beadle and Tatum – 1941
• Deliberately set out to create mutations in chromosomes and verify that they behaved in a Mendelian fashion in crosses
• Studied Neurospora crassa– Used X-rays to damage DNA– Looked for nutritional mutations
• Had to have minimal media supplemented to grow
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• Beadle and Tatum looked for fungal cells lacking specific enzymes– The enzymes were required for the biochemical
pathway producing the amino acid arginine– They identified mutants deficient in each enzyme of
the pathway• One-gene/one-enzyme hypothesis has been
modified to one-gene/one-polypeptide hypothesis
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Experimental Procedure
Growth onminimalmediumplus arginine
Wild-typeNeurospora
crassaMutagenizewith X-rays
Grow onrich medium arg mutants
No growthon minimalmedium
Results
Mutationin Enzyme
PlusOrnithine
PlusCitruline
PlusArginosuccinate
PlusArginine
E
F
G
HE F G H
Glutamate Ornithine Citruline Arginosuccinate Arginine
Enzymesencodedby arggenes
arggenes
arg E arg F arg G arg H
Conclusion
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Central Dogma
• First described by Francis Crick• Information only flows from
DNA → RNA → protein• Transcription = DNA → RNA • Translation = RNA → protein• Retroviruses violate this order using reverse
transcriptase to convert their RNA genome into DNA
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3′3′
5′
5′
G
C
C
AT
T
C
G
G
UA
A
Transcription
Protein
Eukaryotes
Prokaryotes
Translation
DNA template strand
mRNA
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• Transcription– DNA-directed synthesis of RNA– Only template strand of DNA used– U (uracil) in DNA replaced by T (thymine) in RNA– mRNA used to direct synthesis of polypeptides
• Translation– Synthesis of polypeptides– Takes place at ribosome– Requires several kinds of RNA
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RNA
• All synthesized from DNA template by transcription
• Messenger RNA (mRNA)• Ribosomal RNA (rRNA)• Transfer RNA (tRNA)• Small nuclear RNA (snRNA)• Signal recognition particle RNA (SRP RNA)• Micro-RNA (miRNA)
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Genetic Code
• Francis Crick and Sydney Brenner determined how the order of nucleotides in DNA encoded amino acid order
• Codon – block of 3 DNA nucleotides corresponding to an amino acid
• Introduced single nulcleotide insertions or deletions and looked for mutations– Frameshift mutations
• Indicates importance of reading frame11
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One Bases Deleted
Met Pro Thr His Arg Asp Ala Ser
Met Pro HisAla
Met Pro Thr His Arg Asp Ala Ser
Met Pro His Arg Asp Ala Ser
Ser Thr Thr
Delete one bases
AUGCCUACGCACCGCGACGCAUCA
AUGCCUAGCACCGCGACGCAUCA
AUGCCUACGCACCGCGACGCAUCA
AUGCCUCACCGCGACGCAUCA
Amino acids do notchange after third deletion
All amino acids changedafter deletion
Amino acids
Amino acids
Delete three bases
Three Bases Deleted
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Spaced or unspaced codons
• Spaced– Codon sequence in a gene punctuated
• Unspaced– codons adjacent to each other
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SCIENTIFIC THINKING
Delete one letter
Only one word changed
WHY DID THE RED BAT EAT THE FAT RAT
WHY DID HE RED BAT EAT THE FAT RAT
Delete one letter
All words after deletion changed
WHYDIDTHEREDBATEATTHEFATRAT
WHYDIDHEREDBATEATTHEFATRAT
Sentence with Spaces
Sentence with No Spaces
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• Marshall Nirenberg identified the codons that specify each amino acid
• Stop codons– 3 codons (UUA, UGA, UAG) used to terminate
translation• Start codon
– Codon (AUG) used to signify the start of translation• Code is degenerate, meaning that some amino
acids are specified by more than one codon
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Code practically universal
• Strongest evidence that all living things share common ancestry
• Advances in genetic engineering
• Mitochondria and chloroplasts have some differences in “stop” signals
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Prokaryotic transcription
• Single RNA polymerase• Initiation of mRNA synthesis does not
require a primer• Requires
– Promoter – Start site Transcription unit– Termination site
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• Promoter– Forms a recognition and binding site for the
RNA polymerase– Found upstream of the start site– Not transcribed– Asymmetrical – indicate site of initiation and
direction of transcription
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Holoenzyme
׳
a.
Prokaryotic RNA polymerase
Coreenzyme
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Upstream
Downstream
5′b.
Codingstrand
Templatestrand
Start site (+1)
TATAAT– Promoter (–10 sequence)
TTGACA–Promoter (–35 sequence)
Holoenzyme
׳
a.
Prokaryotic RNA polymerase
Coreenzyme
3′
5′3′
TATAAT
TTGACA
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Upstream
Downstream
5′
binds to DNA
b.
Helix opens at–10 sequence
Codingstrand
Templatestrand
Start site (+1)
TATAAT– Promoter (–10 sequence)
TTGACA–Promoter (–35 sequence)
Holoenzyme
׳
a.
Prokaryotic RNA polymerase
Coreenzyme
3′
5′3′
5′ 3′
5′3′
TATAAT
TTGACA
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binds to DNA
dissociates
Start site RNAsynthesis begins
Transcriptionbubble
RNA polymerase boundto unwound DNA
Helix opens at–10 sequence
ATP
5′ 3′
5′3′
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Upstream
Downstream
5′
b.
Codingstrand
Templatestrand
Start site (+1)
TATAAT– Promoter (–10 sequence)
TTGACA–Promoter (–35 sequence)
Holoenzyme
׳
a.
Prokaryotic RNA polymerase
Coreenzyme
3′
5′3′
TATAAT
TTGACA
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• Elongation– Grows in the 5′-to-3′ direction as
ribonucleotides are added– Transcription bubble – contains RNA
polymerase, DNA template, and growing RNA transcript
– After the transcription bubble passes, the now-transcribed DNA is rewound as it leaves the bubble
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RNApolymerase
Start site
3'
5′
Codingstrand Unwinding
Template strand
Transcription bubble
Upstream
mRNA
Rewinding
5′
3'
3'
5′
DNA
Downstream
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• Termination– Marked by sequence that signals “stop” to
polymerase• Causes the formation of phosphodiester bonds to
cease• RNA–DNA hybrid within the transcription bubble
dissociates• RNA polymerase releases the DNA• DNA rewinds
– Hairpin
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DNA and RNAPolymerase dissociates
mRNAdissociatesfrom DNA
CytosineGuanineAdenineUracil
mRNA hairpincauses RNApolymerase to pause
RNA polymerase
DNA
3'
5′
3'
5′
Four or more Uribonucleotides
5′27
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• Prokaryotic transcription is coupled to translation– mRNA begins to be translated before
transcription is finished– Operon
• Grouping of functionally related genes• Multiple enzymes for a pathway• Can be regulated together
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0.25 µm
RNA polymerase DNA
mRNA
Ribosomes
Polyribosome
Polypeptidechains
© Dr. Oscar Miller
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Eukaryotic Transcription
• 3 different RNA polymerases– RNA polymerase I transcribes rRNA– RNA polymerase II transcribes mRNA and
some snRNA– RNA polymerase III transcribes tRNA and
some other small RNAs• Each RNA polymerase recognizes its own
promoter
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• Initiation of transcription– Requires a series of transcription factors
• Necessary to get the RNA polymerase II enzyme to a promoter and to initiate gene expression
• Interact with RNA polymerase to form initiation complex at promoter
• Termination– Termination sites not as well defined
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TATA box
Transcriptionfactor
EukaryoticDNA
Other transcription factors
1. A transcription factor recognizes and binds to the TATA box sequence, which is part of the core promoter.
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Other transcription factors RNA polymerase II
TATA box
Transcriptionfactor
EukaryoticDN A
1. A transcription factor recognizes and binds to the TATA box sequence, which is part of the core promoter.
2. Other transcription factors are recruited, and the initiation complex begins to build.
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Other transcription factors RNA polymerase II
TATA box
Transcriptionfactor
EukaryoticDNA
Initiationcomplex
1. A transcription factor recognizes and binds to the TATA box sequence, which is part of the core promoter.
2. Other transcription factors are recruited, and the initiation complex begins to build.
3. Ultimately, RNA polymerase II associates with the transcription factors and the DNA, forming the initiation complex, and transcription begins.
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• In eukaryotes, the primary transcript must be modified to become mature mRNA– Addition of a 5′ cap
• Protects from degradation; involved in translation initiation
– Addition of a 3′ poly-A tail• Created by poly-A polymerase; protection from
degradation– Removal of non-coding sequences (introns)
• Pre-mRNA splicing done by spliceosome
mRNA modifications
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A A A A A A A
Methyl group
3′poly-A tail
5′cap
CH2
HO OH
P P P
G
mRNA
PP
P
+N+
CH35′
3′
CH3
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Eukaryotic pre-mRNA splicing
• Introns – non-coding sequences • Exons – sequences that will be translated• Small ribonucleoprotein particles
(snRNPs) recognize the intron–exon boundaries
• snRNPs cluster with other proteins to form spliceosome– Responsible for removing introns
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E1 I1 E2 I2 E3 I3 E4 I4
Transcription
Introns are removed
a.
ExonsIntrons
Mature mRNA
cap ׳poly-A tail5 ׳33
cap ׳5 poly-A tail ׳3
Primary RNA transcript
DNA template
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b: Courtesy of Dr. Bert O’Malley, Baylor College of Medicine
E1 I1 E2 I2 E3 I3 E4 I4
Intron
Exon
DNA
1
2 34
5 67
a.
b. c.
ExonsIntrons
mRNA
Mature mRNA
3' poly-A tail5' cap
5' cap 3' poly-A tail
Primary RNA transcript
DNA template
Introns are removed
Transcription
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snRNPs
Exon 2Exon 1 Intron
Branch point A
snRNA
5′ 3′
1. snRNA forms base-pairs with 5′end of intron, and at branch site.
A
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snRNPs
Exon 2Exon 1 Intron
Branch point A
snRNA
5′
5′
3′
3′
2. snRNPs associate with other factors to form spliceosome.
1. snRNA forms base-pairs with 5′end of intron, and at branch site.
SpliceosomeA
A
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snRNPs
Exon 2Exon 1 Intron
Branch point A
snRNA
Lariat
5′
5′
3′
3′
5′ 3′
2. snRNPs associate with other factors to form spliceosome.
1. snRNA forms base-pairs with 5′end of intron, and at branch site.
3. 5′end of intron is removed and forms bond at branch site, forming a lariat. The 3′end of the intron is then cut.
SpliceosomeA
A
A
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snRNPs
Exon 2Exon 1 Intron
Branch point A
snRNA
Exon 1 Exon 2
Lariat
5′
5′
3′
3′
5′
5′
3′
3′
2. snRNPs associate with other factors to form spliceosome.
4. Exons are joined; spliceosome disassembles.
1. snRNA forms base-pairs with 5′end of intron, and at branch site.
3. 5′end of intron is removed and forms bond at branch site, forming a lariat. The 3′end of the intron is then cut.
Mature mRNA
Excisedintron
SpliceosomeA
A
A
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Alternative splicing
• Single primary transcript can be spliced into different mRNAs by the inclusion of different sets of exons
• 15% of known human genetic disorders are due to altered splicing
• 35 to 59% of human genes exhibit some form of alternative splicing
• Explains how 25,000 genes of the human genome can encode the more than 80,000 different mRNAs
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tRNA and Ribosomes
• tRNA molecules carry amino acids to the ribosome for incorporation into a polypeptide– Aminoacyl-tRNA synthetases add amino acids
to the acceptor stem of tRNA– Anticodon loop contains 3 nucleotides
complementary to mRNA codons
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4646
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c: Created by John Beaver using ProteinWorkshop, a product of the RCSB PDB, and built using the Molecular Biology Toolkit developed by John Moreland and Apostol Gramada (mbt.sdsc.edu). The MBT is financed by grant GM63208
2D “Cloverleaf” ModelAcceptor end
Anticodonloop
׳3׳5
3D Ribbon-like Model Acceptor end
Anticodon loop
3D Space-filled Model
Anticodon loop
Acceptor end Icon
Anticodon end
Acceptor end
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tRNA charging reaction
• Each aminoacyl-tRNA synthetase recognizes only 1 amino acid but several tRNAs
• Charged tRNA – has an amino acid added using the energy from ATP– Can undergo peptide bond formation without
additional energy• Ribosomes do not verify amino acid
attached to tRNA47
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tRNAPiPi
NH3+
O–
C OC O
OH
OAMP
Aminogroup
Carboxylgroup
TrpNH
3+
Trp
ATP
Aminoacid site
Acceptingsite
Anticodonspecific to tryptophan
Aminoacyl-tRNAsynthetase
tRNAsite
1. In the first step of the reaction, the amino acid is activated. The amino acid reacts with ATP to produce an intermediate with the carboxyl end of the amino acid attached to AMP. The two terminal phosphates (pyrophosphates) are cleaved from ATP in this reaction.
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PiPi
Aminogroup
Carboxylgroup
Trp
ATPAminoacid site
Aminoacyl-tRNAsynthetase
tRNAsite
NH3+ C
O–
O
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tRNAPiPi
NH3+
O–
C OC O C
O
OH
OAMP O
OH
AMP
Aminogroup
Carboxylgroup
TrpNH
3+ NH
3 +Trp Trp
ATPAminoacid site
Acceptingsite
Anticodonspecific to tryptophan
Aminoacyl-tRNAsynthetase
tRNAsite
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tRNAPiPi
NH3+
O–
C OC OC
O CO
COOH
OAMP O
OH
AMPAMP
O
O
Charged tRNA travels to ribosomeAminogroup
Carboxylgroup
TrpNH
3+ NH
3 +
NH3 +
NH3+Trp Trp
TrpATPAminoacid site
Acceptingsite
Anticodonspecific to tryptophan
Aminoacyl-tRNAsynthetase
tRNAsite
ChargedtRNA
dissociates
Trp
1. In the first step of the reaction, the amino acid is activated. The amino acid reacts with ATP to produce an intermediate with the carboxyl end of the amino acid attached to AMP. The two terminal phosphates (pyrophosphates) are cleaved from ATP in this reaction.
2. The amino acid-AMP complex remains bound to the enzyme. The tRNA next binds to the enzyme.
3. The second step of there action transfers the amino acid from AMP to the tRNA, Producing a charged tRNA and AMP. The charged tRNA consists of a specific amino acid attached to the 3′ accept or stem of it sRNA.
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• The ribosome has multiple tRNA binding sites– P site – binds the tRNA attached to the
growing peptide chain– A site – binds the tRNA carrying the
next amino acid– E site – binds the tRNA that carried the
last amino acid
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mRNA
90°
0°
3′
5′
Largesubunit
Smallsubunit
Largesubunit
Smallsubunit
LargesubunitSmallsubunit
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• The ribosome has two primary functions– Decode the mRNA– Form peptide bonds
• Peptidyl transferase– Enzymatic component of the ribosome– Forms peptide bonds between amino acids
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Translation
• In prokaryotes, initiation complex includes– Initiator tRNA charged with N-formylmethionine– Small ribosomal subunit– mRNA strand
• Ribosome binding sequence (RBS) of mRNA positions small subunit correctly
• Large subunit now added• Initiator tRNA bound to P site with A site
empty
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3′
5′
AUG
U CA
GTP GDP+Pi
Smallsubunit
Initiationfactor
Initiationfactor
fMet 3′
5′
mRNA
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U CAA GU
GTP GDP+
E site
Initiation complex Complete ribosomePi
tRNA inP site
A site
Largesubunit
5′ 5´
3′3′
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• Initiations in eukaryotes similar except– Initiating amino acid is methionine– More complicated initiation complex– Lack of an RBS – small subunit binds to 5′
cap of mRNA
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• Elongation adds amino acids– 2nd charged tRNA can bind to empty A
site– Requires elongation factor called EF-Tu
to bind to tRNA and GTP– Peptide bond can then form– Addition of successive amino acids
occurs as a cycle
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NH3+
3′
5′
OHO
CO
CO
OC OC
O
N
O
NH3+
Aminoacid 1
Aminoacid 2
Peptidebond
formation
Polypeptidechain
“Empty”tRNA
AminogroupAminoacid 1
Peptidebond
Aminoacid 2
Amino end(N terminus)
Aminoacid 1
Aminoacid 2
Aminoacid 3
Aminoacid 4
Aminoacid 5
Aminoacid 6
Aminoacid 7
Carboxyl end(C terminus)
COO–
P siteA site
NH3+ NH3
+
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3′
3′
3′ 3′
3′5′
5′
5′
5′
“Ejected” tRNA
E P A
E P A
E P AE P A
E P A
Sectioned ribosome
Pi
GTP
GTP
GDP +
Next round
Elongationfactor
Elongationfactor
+ Pi
Elongationfactor
Elongationfactor Growing
polypeptide GDP
GTP
5′
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• There are fewer tRNAs than codons• Wobble pairing allows less stringent
pairing between the 3′ base of the codon and the 5′ base of the anticodon
• This allows fewer tRNAs to accommodate all codons
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• Termination– Elongation continues until the ribosome
encounters a stop codon– Stop codons are recognized by release
factors which release the polypeptide from the ribosome
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3′
5′
3′
5′
EP
A
Dissociation
GC
GC
U
AAUA
Sectionedribosome
Releasefactor
Polypeptidechain releases
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Protein targeting
• In eukaryotes, translation may occur in the cytoplasm or the rough endoplasmic reticulum (RER)
• Signal sequences at the beginning of the polypeptide sequence bind to the signal recognition particle (SRP)
• The signal sequence and SRP are recognized by RER receptor proteins
• Docking holds ribosome to RER• Beginning of the protein-trafficking pathway
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Signal recognitionparticle (SRP)
Signal
Ribosomesynthesizingpeptide
Exit tunnel
Docking
Polypeptideelongationcontinues
Rough endoplasmicreticulum (RER)
Cytoplasm Lumen of the RER
SRP binds to signalpeptide, arresting
elongation
Protein channel
NH2
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1. RNA polymerase II in the nucleus copies one strand of the DNA to produce the primary transcript.
Primary RNA transcript
RNA polymerase IIRNA polymerase II
Primary RNA transcript5´
3´
5´
3´
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Primary RNA transcript
Poly-A tail
Mature mRNACut intron
5´ cap
1. RNA polymerase II in the nucleus copies one strand of the DNA to produce the primary transcript.
2. The primary transcript is processed by addition of a 5′ methyl-G cap, cleavage and polyadenylation of the 3′end, and removal of introns. The mature mRNA is then exported through nuclear pores to the cytoplasm.
Primary RNA transcript
RNA polymerase II
Primary RNA transcript
Poly-A tail
Mature mRNACut intron
5´ cap
RNA polymerase II
Primary RNA transcript5´
3´
5´
3´
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Primary RNA transcript
Poly-A tail
Mature mRNACut intron
5´ cap
1. RNA polymerase II in the nucleus copies one strand of the DNA to produce the primary transcript.
2. The primary transcript is processed by addition of a 5´ methyl-G cap, cleavage and polyadenylation of the 3´ end, and removal of introns. The mature mRNA is then exported through nuclear pores to the cytoplasm.
3. The 5′cap of the mRNA associates with the small subunit of the ribosome. The initiator tRNA and large subunit are added to form an initiation complex.
Primary RNA transcript
RNA polymerase II
Primary RNA transcript
Poly-A tail
Mature mRNACut intron
5´ cap
Largesubunit
mRNA 5´ cap
Smallsubunit Cytoplasm
RNA polymerase II
Primary RNA transcript5´
3´
5´
3´
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1. RNA polymerase II in the nucleus copies one strand of the DNA to produce the primary transcript.
2. The primary transcript is processed by addition of a 5′ methyl-G cap, cleavage and polyadenylation of the 3′end, and removal of introns. The mature mRNA is then exported through nuclear pores to the cytoplasm.
3. The 5′cap of the mRNA associates with the small subunit of the ribosome. The initiator tRNA and large subunit are added to form an initiation complex.
4. The ribosome cycle begins with the growing peptide attached to the tRNA in the P site. The next charged tRNA binds to the A site with its anticodon complementary to the codon in the mRNA in this site.
mRNA
Smallsubunit Cytoplasm
tRNA arrivesin A site Amino acids
mRNA
A siteP site
E site
Cytoplasm
3´
5′
3′
Primary RNA transcript
Cut intron
Largesubunit
5′cap
RNA polymerase II
Primary RNA transcript
Poly-A tail
Mature mRNACut intron
5′cap
Primary RNA transcript
5´
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1. RNA polymerase II in the nucleus copies one strand of the DNA to produce the primary transcript.
2. The primary transcript is processed by addition of a 5′ methyl-G cap, cleavage and polyadenylation of the 3′end, and removal of introns. The mature mRNA is then exported through nuclear pores to the cytoplasm.
3. The 5′cap of the mRNA associates with the small subunit of the ribosome. The initiator tRNA and large subunit are added to form an initiation complex.
4. The ribosome cycle begins with the growing peptide attached to the tRNA in the P site. The next charged tRNA binds to the A site with its anticodon complementary to the codon in the mRNA in this site.
5. Peptide bonds form between the amino terminus of the next amino acid and the carboxyl terminus of the growing peptide. This transfers the growing peptide to the tRNA in the A site, leaving the tRNA in the P site empty.
mRNA
Smallsubunit Cytoplasm
tRNA arrivesin A site Amino acids
mRNA
A siteP site
E site
Lengtheningpolypeptide chain
EmptytRNA
Cytoplasm
3´
5′
3′
5′
3′
Primary RNA transcript
Cut intron
Largesubunit
5′cap
RNA polymerase II
Primary RNA transcript
Poly-A tail
Mature mRNACut intron
5′cap
Primary RNA transcript
5´
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1. RNA polymerase II in the nucleus copies one strand of the DNA to produce the primary transcript.
2. The primary transcript is processed by addition of a 5′ methyl-G cap, cleavage and polyadenylation of the 3′end, and removal of introns. The mature mRNA is then exported through nuclear pores to the cytoplasm.
3. The 5′cap of the mRNA associates with the small subunit of the ribosome. The initiator tRNA and large subunit are added to form an initiation complex.
4. The ribosome cycle begins with the growing peptide attached to the tRNA in the P site. The next charged tRNA binds to the A site with its anticodon complementary to the codon in the mRNA in this site.
5. Peptide bonds form between the amino terminus of the next amino acid and the carboxyl terminus of the growing peptide. This transfers the growing peptide to the tRNA in the A site, leaving the tRNA in the P site empty.
mRNA
Smallsubunit Cytoplasm
tRNA arrivesin A site Amino acids
mRNA
A siteP site
E site
Lengtheningpolypeptide chain
EmptytRNA
3´
5′
3′
5′
3′
Primary RNA transcript
Cut intron
Largesubunit
5′cap
RNA polymerase II
Primary RNA transcript
Poly-A tail
Mature mRNACut intron
5′cap
Primary RNA transcript
5´
6. Ribosome translocation moves the ribosome relative to the mRNA and its bound tRNAs. This moves the growing chain into the P site, leaving the empty tRNA in the E site and the A site ready to bind the next charged tRNA.
Empty tRNA moves intoE site and is ejected
5′
3′
Cytoplasm
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Mutation: Altered Genes
• Point mutations alter a single base• Base substitution – substitute one base for
another– Silent mutation – same amino acid inserted– Missense mutation – changes amino acid
inserted• Transitions• Transversions
– Nonsense mutations – changed to stop codon74
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Stop
mRNA
Protein
Coding
CG
AT
AT
Template
Pro Thr ArgMet
a.
5′–ATGCCTTATCGCTGA–3′3′–TACGGAATAGCGACT–5′5′–AUGCCUUAUCGCUGA–3′
Stop
mRNA
Protein
Coding
CG
Template
Pro Thr ArgMet
b.
Silent Mutation
5′–ATGCCCTATCGCTGA–3′3′–TACGGGATAGCGACT–5′5′–AUGCCCUAUCGCUGA–3′
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Stop
mRNA
Protein
Coding
AT
Template
Pro Thr HisMet
c.
Missense Mutation
5′–ATGCCCTATCACTGA–3′3′–TACGGGATAGTGACT–5′5′–AUGCCCUAUCACUGA–3′
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Stop
mRNA
Protein
Coding
AT
Template
ProMet
d.
Nonsense Mutation
5′–ATGCCCTAACGCTGA–3′3′–TACGGGATTGCGACT–5′5′–AUGCCCUAACGCUGA–3′
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Polar
Normal HBB Sequence
Abormal HBB Sequence
Nonpolar (hydrophobic)
Amino acids
Nucleotides
Amino acids
Nucleotides
Leu
C C C CGT T TA GG A GAA
Thr Pro Glu Glu
CT TGAA
Lys Ser
Leu
C C C CGT T TA GG GAG
Thr Pro val Glu
CTT TGAA
Lys Ser
1
1
NormalDeoxygenated
Tetramer
AbnormalDeoxygenated
Tetramer
Tetramers form long chainswhen deoxygenated. Thisdistorts the normal red bloodcell shape into a sickle shape.
Hemoglobintetramer
"Sticky" non-polar sites
2
2
1
1
2
2
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• Frameshift mutations– Addition or deletion of a single base– Much more profound consequences– Alter reading frame downstream– Triplet repeat expansion mutation
• Huntington disease• Repeat unit is expanded in the disease allele
relative to the normal
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Chromosomal mutations
• Change the structure of a chromosome– Deletions – part of chromosome is lost– Duplication – part of chromosome is copied– Inversion – part of chromosome in reverse
order– Translocation – part of chromosome is moved
to a new location
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A B C D E F G H A E F G HI IJ J
B C D E F G H I J A B C D B C D E F G H I J
Duplication
Deletion
Deleted
Duplicated
a.
A
b.
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A B C D E F G H I J
A B C D E F G H I J
K L M N O P Q R
K L M D E F G H I J
A B C N O P Q R
A D C B E F G H I J
Inversion
Inverted
c.
d.
Reciprocal Translocation
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• Mutations are the starting point for evolution
• Too much change, however, is harmful to the individual with a greatly altered genome
• Balance must exist between amount of new variation and health of species