©2001 timothy g. standish john 1:1-3 1in the beginning was the word, and the word was with god, and...
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©2001 Timothy G. Standish
John 1:1-3
1 In the beginning was the Word, and the Word was with God, and the Word was God.
2 The same was in the beginning with God.
3 All things were made by him; and without him was not any thing made that was made.
©2001 Timothy G. Standish
The Genetic Code:The Genetic Code:The Language of LifeThe Language of Life
Timothy G. Standish, Ph. D.
©2001 Timothy G. Standish
Information Only Goes One WayInformation Only Goes One WayThe central dogma states that once “information” has
passed into protein it cannot get out again. The transfer of information from nucleic acid to nucleic acid, or from nucleic acid to protein, may be possible, but transfer from protein to protein, or from protein to nucleic acid, is impossible. Information means here the precise determination of sequence, either of bases in the nucleic acid or of amino acid residues in the protein.
Francis Crick, 1958
©2001 Timothy G. Standish
The Universal LanguageThe Universal Language
“[The universe] is written in the language of mathematics, and its characters are triangles, circles, and other geometrical figures, without which it is humanly impossible to understand a single word of it. . . .”
Galileo Galilei, The Controversy on the Comets of 1618
©2001 Timothy G. Standish
The Genetic LanguageThe Genetic Language The genetic code is a written language not
unlike English or German While English uses 26 letters to spell out
words, genetic languages use only 4 nucleotide “letters”
The DNA nucleotide language is transcribed into the RNA nucleotide language
The nucleotide language must be translated into the amino acid language to make proteins
©2001 Timothy G. Standish
The Nucleotide LanguageThe Nucleotide Language DNA - ATGCATGCATGC RNA - AUGCAUGCAUGC It is not unlike different Bible versions. Psalm 139:14 KJV I will praise thee; for I am fearfully and
wonderfully made: marvelous are thy works; and that my soul knoweth right well.
NIV I praise you because I am fearfully and wonderfully made; your works are wonderful, I know that full well.
©2001 Timothy G. Standish
Nucleotide WordsNucleotide Words Words in the nucleotide language are all 3 letters or
bases long This means that there can only be 43 = 64 unique words If each codon was only 2 bases long, there would be 42
= 16 possible unique codons This would not provide enough unique meanings to
code for the 22 things (20 amino acids plus start and stop) that have to be coded for.
SU
GA
R-P
HO
SP
HA
TE
BA
CK
BO
NE
B A
S E
S
H
PO
O
HO
O
O
CH2NH2N
NH
N
N
HOH
P
O
O
HO
O
O
CH2
NH2
N
N
N
N
H
P
O
OH
HO
O
O
CH2
NH2
N
N
N
N
O
A CodonA Codon
GuanineGuanine
AdenineAdenine
AdenineAdenine
Arginine
©1998 Timothy G. Standish
©2001 Timothy G. Standish
The Genetic CodeThe Genetic CodeHelps To Control Helps To Control
The Impact Of The Impact Of Point MutationsPoint Mutations
©2001 Timothy G. Standish
Redundancy in the CodeRedundancy in the Code Codons code for only 20 words, or amino
acids. In addition to the amino acids, the start and
stop of a protein need to be coded for There are thus a total of 22 unique meanings
for the 64 codons Because all codons are used many act as
synonyms, having different sequences, but the same meaning
The fact that many amino acids are coded for by several codons is called degeneracy
©2001 Timothy G. Standish
SentencesSentences Genes can be thought of as sentences in the
nucleic acid language Each gene contains a sequence of codons that
describe the primary structure (amino acid sequence) of a polypeptide (protein).
At the beginning of each gene, acting like a capital letter is the start codon
In the middle is a sequence of codons for amino acids
The period at the end is a stop codon
©2001 Timothy G. Standish
The Protein LanguageThe Protein Language The protein language is very different from the nucleotide
language Polypeptides are the sentences It is analogous to pictographic languages like Chinese or
Egyptian Hieroglyphics. Each symbol has a meaning in pictographic languages; and in
proteins, each amino acid has a unique meaning or specific effect.
Words are not a sequence of nucleotides, but each AA in the primary structure
©2001 Timothy G. Standish
Comparison of LanguagesComparison of LanguagesEnglish - GodChinese - Hieroglyphics -
DNA - CGTRNA - CGUAmino Acid -
Arginine
©2001 Timothy G. Standish
Redundancy:Redundancy:Synonyms and Codon DegeneracySynonyms and Codon Degeneracy
English - Synonyms for God:
Lord Father Deity the Almighty Jehovah
Nucleic acids - Synonyms for Arginine:
CGU CGC CGA CGG AGA AGG
©2001 Timothy G. Standish
S E C O N D B A S E
A
GGUGGCGGAGGG
Gly*
AGUAGCAGAAGG
Arg
G
CGUCGCCGACGG
Arg
GUGUUGCUGAUGG
C
GAUGACGAAGAG
AAUAACAAAAAG
Glu
CAUCACCAACAG
AUAUUACUAAUAG
Stop
Tyr
GUUGUCGUAGUG
Val
AUUAUCAUAAUG start
Ile
CUUCUCCUACUG
Leu
UUUUUUCUUAUUG
Leu
Phe
Met/
GCUGCCGCAGCG
Ala
ACUACCACAACG
Thr
CCUCCCCCACCG
Pro
CUCUUCCUCAUCG
Ser
UCAG
U
UCAG
UCAG
UCAG
Gln†
His
Trp
Cys THIRD
BASE
FIRST
BASE
The Genetic CodeThe Genetic Code
Asp
Lys
Asn†
Stop
Ser
Neutral Non-polarPolarBasicAcidic
†Have aminegroups
*Listed as non-polar bysome texts
Stop Codon Names - Ochre- Amber-Not named
UAAUAGUGA
UAAUAGUGA
©2001 Timothy G. Standish
Codon AssignmentCodon AssignmentIs FortuitousIs Fortuitous
Effect of mutations is minimized in the genetic code:
Mutation of the third base in a codon changes the codon meaning only 1/3 of the time
In AAs with only two codons, the mutation always has to be purine to pyrimidine or vice versa to change the AA coded for.
This is much harder than purine to purine or pyrimidine to pyrimidine mutation
©2001 Timothy G. Standish
Codon AssignmentCodon AssignmentIs FortuitousIs Fortuitous
Because of wobble base pairing, less than 61 tRNAs have to be made
53% of purine to purine or pyrimidine to pyrimidine mutations in the second position result in codons with either the same meaning (i.e., UAA to UGA both = stop) or coding for chemically related amino acids
©2001 Timothy G. Standish
The Genetic CodeThe Genetic CodeIs Improbable And Is Improbable And
Does Not Look Does Not Look RandomRandom
©2001 Timothy G. Standish
Possible Codon AssignmentsPossible Codon Assignments The probability of getting the assignment of codons to
amino acids we have can be calculated as follows:– There are 21 meanings for codons:
20 amino acids 1 stop 1 start, which doesn’t count because it also is assigned to methionine
– 64 Codons
If we say that each codon has an equal probability of being assigned to an amino acid, then the probability of getting any particular set of 64 assignments is:
1
21
64
2.4 10 850.0000000000000000000000000
0000000000000000000000000000000000000000000000000000000000024
or
©2001 Timothy G. Standish
Problems With Codon Problems With Codon AssignmentAssignment
Under Miller-Urey type conditions, more than the 20 amino acids would have been available
To estimate probability, we assume only 20, but this changes the odds
As all 20 amino acids and “stop” must be assigned one codon, only 64 - 21 = 43 codons could be truly randomly assigned
Net probability is the likelihood of initial assignment times probability of random assignment of remaining codons
1
21
1
64
1
21
43
1.0 10 60
©2001 Timothy G. Standish
Initial Codon AssignmentInitial Codon Assignment Theory would indicate initial codon assignment must have been
random Lewin in Genes VI, p 214, 215 suggests the following scenario:1 A small number of codons randomly get meanings representing a few
amino acids or possibly one codon representing a “group” of amino acids
2 More precise codon meaning evolves perhaps with only the first two bases having meaning with discrimination at the third position evolving later
3 The code becomes “frozen” when the system becomes so complex that changes in codon meaning would disrupt existing vital proteins
©2001 Timothy G. Standish
Codon AssignmentCodon Assignmentdoes not look randomdoes not look random
0
1
2
3
4
5
6
7
8
9
AminoAcids
1 2 3 4 5 6
Number of Codons
The genetic code does not like uneven numbers.
©2001 Timothy G. Standish
Initial Codon AssignmentInitial Codon Assignment If natural selection worked on codons,
the most commonly used amino acids might be expected to have the most codons
If there was some sort of random assignment, the same thing might be expected
This is not the case
©2001 Timothy G. Standish
Codon AssignmentCodon AssignmentIs Not Strongly Correlated to UseIs Not Strongly Correlated to Use
Met
TrpCysHis
Tyr
Phe
ThrArg
Ser
Leu
Pro
Ile
GlnAsp
Lys
Glu
Asn
Val
GlyAla
1 2 3 4 5 6 Number of Codons
10
8
6
4
2
%In
Proteins
©2001 Timothy G. Standish
The Genetic CodeThe Genetic CodeIs Not Completely Is Not Completely
UniversalUniversal
©2001 Timothy G. Standish
Variation In Codon MeaningVariation In Codon Meaning Lack of variation in codon meanings across almost all phyla is
taken as an indicator that initial assignment must have occurred early during evolution and all organisms must have descended from just one individual with the current codon assignments
Exceptions to the universal code are known in a few single-celled eukaryotes and mitochondria and at least one prokaryote
Most exceptions are modifications of the stop codons UAA, UAG and UGA
serine
Stop
Stop
Common Meaning
Stop
CandidaA yeast
Euplotes octacarinatusA ciliate
ParameciumA ciliate
OrganismTetrahymena thermophila
A ciliate
leucine
cysteine
glutamine
Modified Meaning
CUG
UGA
UAA UAG
Codon/sUAA UAG
glutamine
StopMycoplasma capricolumA bacteria tryptophanUGA
Neutral Non-polar, Polar
©2001 Timothy G. Standish
Variation in Mitochondrial Variation in Mitochondrial Codon AssignmentCodon Assignment
UGA/G=Stop
UniversalCode
Cyt
opla
sm/
Nu
cleu
s
Pla
nts
Yea
st/
Mol
ds
Pla
tyh
elm
ith
s
Ech
inod
erm
s
Mol
lusc
s
Inse
cts
Ver
teb
rate
s
UGA=Trp
AGA/G=Ser
AUA=Met
AUA=MetCUN=Thr
AUA=IleAAA=Asn
AAA=AsnN
emat
odes
NOTE - This would mean AUA changed from Ile to Met, then changed back to Ile in the Echinoderms
UGA must have changed to Trp then back to stop Differences in mtDNA lower the number of tRNAs needed
AAA must have changed from Lys to Asn twice
©2001 Timothy G. Standish
Reassignment of Stop CodonsReassignment of Stop Codons Changes in stop codon meaning must have occurred after
meanings were “frozen” in other organisms; alternatively organisms that exhibit them must have evolved from organisms that never shared the universal genetic code
All changes in stop codons must include three changes:1. Replacement of former stop codons in genes vital for life, and
whose activity will be destroyed, with still functional stop codons
2. Production of new tRNAs with anticodons that recognize the codon as an amino acid and not stop anymore
3. Modification of the release factor (eRF) to restrict its binding specificity so that it no longer binds the former stop codon
All changes “appear to have occurred independently in specific lines of evolution” (Lewin, Genes VI)
©2001 Timothy G. Standish
Changing Initial Codon Changing Initial Codon AssignmentAssignment
Once codons have been assigned to an amino acid, changing their meaning would require:– Changing the tRNA anticodon or, much harder,
changing the aminoacyl-tRNA synthetase– Changing all codons to be reassigned in at least the vital
positions in those proteins needed for survival This seems unlikely The situation is complicated in cases where genes
seem to have been swapped between the nucleus and mitochondria
©2001 Timothy G. Standish
Wobble Base Wobble Base PairingPairing
©2001 Timothy G. Standish
The Rules of Codon The Rules of Codon Anticodon Base PairingAnticodon Base Pairing
Three things affect the way in which base pairing occurs between codons on mRNA and anticodons on tRNA:
1 How the two molecules “twist” when annealing - They are not free to form a perfect A helix
2 The environment of the Ribosome A site
3 Chemical modification of bases These three factors change the usual base pairing
seen in DNA and RNA, particularly at the first base of anticodons/third base of codons
©2001 Timothy G. Standish
D Arm - Contains dihydrouridine
Acceptor Arm - A specific amino acid is attached to the 3’ end
TC arm - stands for pseudouridine
Extra Arm - May vary in size
Anticodon
Transfer RNA (tRNA)Transfer RNA (tRNA)
U*
9
262223Pu
16
12Py 10
25
20:1
G*
17:1
Pu
A20:2
1713
20G
A5051
656463
G
62
52
CPu
59
A*
C
Py
T49
39
4142
31
2928
Pu*
43127
U35
38
36
Py*
34
403047:1
47:15
46
Py47:16
4544
47
73CCA
707172
66676869
321
7654
©2001 Timothy G. Standish
D Arm - Contains dihydrouridine
TC arm - stands for pseudouridine
Anticodon
Transfer RNA (tRNA)Transfer RNA (tRNA)
U*
9
262223Pu
16
12Py 10
25
20:1
G*
17:1
Pu
A20:2
1713
20G
A5051
656463
G
62
52
CPu
59
A*
C
Py
T49
39
4142
31
2928
Pu*
43127
U35
38
36
Py*
34
403047:1
47:15
46
Py47:16
4544
47
73CCA
707172
66676869
321
7654
Dihydro-uridine
O
O
NHHH
HH N
Pseudo-uridine
O
O
HN NH
C
NO
H
NO
N
NH C
ytosine
H
O
NN
N
N
N
H
H
Guanine -+
+
+
-
-
Base PairingBase PairingGuanine And CytosineGuanine And Cytosine
N
O
N
ON
H+
- UracilN
NN
N
HN H
-
+Adenine
Base PairingBase PairingAdenine And UracilAdenine And Uracil
Base PairingBase PairingAdenine And CytosineAdenine And Cytosine
NO
H
NO
N
NH C
ytosine-
+
-
N
NN
N
HN
H
-
+
Adenine
N
O
N
ON
H+
- Uracil
Base PairingBase PairingGuanine And UracilGuanine And Uracil
H
O
NN
N
N
N
H
H
Guanine
+
+
-
NO N
O
NHUracil
+
-
Wobble Base PairingWobble Base PairingGuanine And UracilGuanine And Uracil
H
O
NN
N
N
N
H
H
Guanine
+
+
-
NS
N
ON
H+
-2 Thio-
uracilN
NN
N
HN H
-
+Adenine
Base PairingBase PairingAdenine And 2-ThiouracilAdenine And 2-Thiouracil
S N
O
NH
Wobble Base PairingWobble Base PairingGuanine And 2-ThiouracilGuanine And 2-Thiouracil
H
O
NN
N
N
N
H
H
Guanine
+
+
-
2-Thiouracil forms only one hydrogen bond with guanine which is not enough to form a stable pair in the environment of the ribosome A site
+2 Thio-
uracil
NO
H
NO
N
NH C
ytosine
O
NN
N
N
H
H
Inosine -
+
-
+
-
Wobble Base PairingWobble Base PairingInosine And CytosineInosine And Cytosine
O
NN
N
N
H
H
Inosine
-
+ NO N
O
NHUracil
+
-
Wobble Base PairingWobble Base PairingInosine And UracilInosine And Uracil
N
NN
N
H
NH
-
+ Adenine
O
NN
N
N
H
H
Inosine +
-
Wobble Base PairingWobble Base PairingInosine And AdenineInosine And Adenine
©2001 Timothy G. Standish
The Wacky Rules ofThe Wacky Rules ofWobble Base PairingWobble Base Pairing
-------------A or G
-------A
-------------G
-------------U
-------------C or U
-------------C U or G
First anticodon base:
U2-S-UCAGI
Third codon base:
©2001 Timothy G. Standish
Modified RNA Bases: UridineModified RNA Bases: Uridine
H
O
C
C
N
C
C
N
Ribothymidine (T)
OH
CH
H H
H
H
O
C
C
N
C
C
N
H
Dihydrouridine (D)
O
H
H
H
S
C
C
N
C
C
N
H
4-thiouridine (S4U)
OH
H
O
C
C
C
H
OH
N N
C
Pseudouridine ()
H
O
C
C
N
C
C
N
HUridine
OH
©2001 Timothy G. Standish
Wobbling and tRNA NumbersWobbling and tRNA Numbers The net effect of wobble base pairing is to reduce the
number of tRNAs that must be produced by a cell In reality cells do not make 61 different tRNAs, one for each
codon Many tRNAs have anticodons that anneal to several
different codons Codons are known for which there are more than one tRNA,
although each tRNA carries the same amino acid (i.e., methionine)
©2001 Timothy G. Standish
Summary:Summary:Are Codons The Language of God?Are Codons The Language of God?
The genetic code appears to be non-random in nature and designed with considerable safeguards against harmful point mutations
An evolutionary model suggests at least at some level of randomness in assignment of amino acids to codons
No mechanism exists for genetic code evolution Thus variation in the genetic code suggests a polyphyletic origin for
life Taken together, this evidence indicates the hand of a Designer in the
genetic code and does not support the theory that life originated due to random processes or that all organisms share a common ancestor
©2001 Timothy G. Standish
©2001 Timothy G. Standish
Modified RNA Bases: UridineModified RNA Bases: Uridine
H
O
C
C
N
C
C
N
Ribothymidine
OH
CH
HH
H
H
O
C
C
N
C
C
N
H
Dihydrouridine
O
H
H
H
O
C
C
N
C
C
N
H
Uridine
OH
H
O
C
C
C
H
OH
N N
C
Pseudouridine
©2001 Timothy G. Standish
H
Other Modified RNA Bases:Other Modified RNA Bases:CytidineCytidineO
H
C
N
C
N
C
C
N
H
H
Cytidine
O
©2001 Timothy G. Standish
Other Modified RNA Bases:Other Modified RNA Bases:AdenosineAdenosineOO
H
CN
N
C
C
N
N
C
C
N
H
H
H
Adenosine
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