The Genetic Code Math-CS Camp, 19.07.06, Singapore Mikhail S. Gelfand Research and Training Center...
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Transcript of The Genetic Code Math-CS Camp, 19.07.06, Singapore Mikhail S. Gelfand Research and Training Center...
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The Genetic Code
Math-CS Camp, 19.07.06, Singapore
Mikhail S. Gelfand
Research and Training Center of Bioinformatics,Institute for Information Transmission Problems, Moscow, Russia
andDepartment of Bioengineering and Bioinformatics,
Moscow State University
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The Biological Code by Martynas Yčas (London, 1969)
Биологический код (Mосква, 1971)
0
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47 49 51 53 55 57 59 61 63 65 67 69 71
year(s)
refs
.
191X192X193X
18XX
190X
1941-451946-501951-551956
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To apply mathematics in biology, a mathematician has to understand biology. Israel Gelfand
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Plan
• Pre-history– Genetics– Evolutionary theory– Chemistry
• Cracking the Code
• Update
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Genetics: Gregor Mendel (1822-1884)
• Attended the Philosophical Institute in Olomouc
• Since 1843 – at the Augustinian Abbey of St. Thomas in Brno
• 1851-1853 – studied in the University of Vienna
• 1856-1863 – cultivated 28 thousand pea plants
• The Three Laws of Genetics (“Experiments on Plant Hybridization”)– Read to the Natural History Society of
Brunn in Bohemia (1865)– Published in Proceedings of the
Natural History Society (1866)• Since 1866 – abbot, stopped working
in science
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The seven traits of pea plants studied by Mendel
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The first law
Crossing two pure lines different in some trait (e.g. yellow / green seeds), one gets only one variant (allele) in the first generation (the dominant allele)
F0
F1
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The second law
Crossing two pure lines different in some trait (e.g. yellow / green seeds), one gets only one variant (allele) in the first generation (the dominant allele), and the distribution 3:1 of the dominant and recessive alleles in the second generation.
F0
F1
F2
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(Law of large numbers)
F0
F1
F2
The 3:1 ratio is seen only when the number of observations is sufficiently high.
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The third lawTwo different traits are inherited independently
(in the second generation the ratio is 9:3:3:1)
F0
F1
F2
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F2
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What if we take a pair with a different assortment of the same traits?
F0
F1
F2
F0
?
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Same F1
F0
F1
F2
F0
F1
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Same F2… regardless of the initial assortment
F0
F1
F2
F0
F1
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Incomplete dominance
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Incomplete dominance
?
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Incomplete dominance
?
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Incomplete dominance
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Charles Darwin (1809-1882)
• 1825-27 in Edinburgh University and 1827-31 in University of Cambridge – natural history, geology, botany
• 1831-1836 – Voyage of the Beagle
• Journal of Researches into the Geology and Natural History of the various countries visited by H.M.S. Beagle (1839)
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Origin of Species (1859)
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The Law of Natural Selection
• Species make more offspring than can grow to adulthood. • Populations remain roughly the same size. • Food resources are limited, but are relatively constant most of
the time.
• In such an environment there will be a struggle for survival among individuals.
• In sexually reproducing species, generally no two individuals are identical.
• Much of the variation is heritable.
• Individuals with the "best" characteristics will be more likely to survive …
• … those desirable traits will be passed to their offspring …• … and then inherited by following generations, becoming
prevalent and then fixed among the population through time.
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Thomas Huxley (1825-1895) “Darwin’s Bulldog”
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Origin of Homo sapiens
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Re-discovery of the Mendel laws and emergence of modern genetics
• Hugo de Vries (1900)• William Bateson
– genetics, gene, allele
• Walter Sutton – Link between genes and
chromosomes(1902)
• Archibald Garrod – Genetic cause of some
human disease (1902-08-23)
• Thomas Morgan, work on Drosophila. – Mutants: spontaneous
appearance of new alleles (a fly with white eyes in a population of flies with red eyes) (1908)
– Universal acceptance of chromosomes (1915)
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Gene = a set of non-complementing mutationsEdward Lewis: Do two recessive mutations occur in the same gene?
F1: Mutant phenotype
F1: Wild-type phenotype
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F2 Mutant phenotypes persist in cis (same gene). Mutant phenotypes reappear in trans (different genes)
F1: Mutant phenotype
F1: Wild-type phenotype
F2: All mutant phenotypes
F2
WT WT WT WTMut Mut Mut Mut Mut
1 2 2 41 2 1 2 1 9:7
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DNA
• Friedrich Miescher (1869)– Nucleolin– Richard Altmann: nucleic acid (1889). Only in chromosomes
• Phoebus Levene (1929)– Components (four bases, the sugar-phosphate chain)– Nucleotide: phosophate+sugar+base unit
• Hammarsten and Casperson (1930s)– DNA is a long polymer; crystals
• Astbury (1938)– X-ray photographs
• Chargaff rules (1947) – In many organisms, #A=#T, #C=#G
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Transforming factor (Frederick Griffith,1928)
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… = DNA (Oswald Avery, Colin McLeod, Maclyn MacCarthy,1944)
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DNA is the genetic medium of phages (Alfred Hershey and Martha Chase, 1948)
32P – radioactive DNA35S – radioactive proteins
Only DNA enters the cell
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… and only DNA is inherited by progeny phages
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Erwin Schrödinger
“What is life”, 1946: The gene is an aperiodic crystal
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The structure of DNA …
• Maurice Wilkins and Rosalind Franklin: high-resolution crystals (1950-1953)
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… is the double helixJames Watson and Francis Crick (1953)
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The Nature paper: a few lines more than one page
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The DNA chain
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Complementary pairs of nucleotides
С
Т
G
A
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Figures from the second
Watson-Crick paper
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The main distances are the same
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One base-pair in the double helix (axial view)
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The double helix, stick and ball models, axial view
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The double helix, stick and ball models, side view
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The semi-conservative one is correct (Matthew Meselson and Franklin Stahl, 1958)
Q: What would be the outcome if one of the two other models were correct?
Cells are grown on the 15N (heavy) medium for several generations, then transferred to 14N (light) medium
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Electron micrograph of replicating DNA
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The Central Dogma (F.Crick)DNA RNA protein
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Crossingover and recombination
• Genes from one chromosome are not inherited independently
• Recombination allows for relative mapping of gene positions on the chromosome:if two genes are close, the frequency of recombination will be lower
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Collinearity of the gene and the protein (Charles Yanofsky, 1967)
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The Genetic Code• The genetic code:
correspondence between DNA and protein (George Gamow, 1954) (Георгий Гамов)
• Crick and co-authors (1961):– Non-overlapping (one mutation affects one amino
acid)– Degenerate (many codons for one amino acid)– Comma-less (no specific markers between codons)– Periodic
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The codon is a triplet• Mutations caused by acridine
– Non-leaky (instead of weakened function, simply no function)– Mechanism: insertions and deletions of nucleotides
(the downstream part of the gene completely scrambled the code is comma-less)
CUACUACUACUACUACUACUACUACUACUACUACUACUALeuLeuLeuLeuLeuLeuLeuLeuLeuLeuLeuLeuLeu
insertionCUACUACUACGUACUACUACUACUACUACUACUACUACULeuLeuLeuArgThrThrThrThrThrThrThrThrThr
deletionCUACUACUACUACUACUACUACUACUACACUACUACUACLeuLeuLeuLeuLeuLeuLeuLeuLeuHisTyrTyrTyr
U
G
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Double mutants and revertants
• Two classes of mutations: (+) and (–) • Double mutants (+)¤(+) and (–)¤(–) still produce loss-of-
function phenotypes• Double mutants (+)¤(–) and (–)¤(+) produce leaky
phenotypes
CUACUACUACGUACUACUACUACUACUACUACUACUACULeuLeuLeuArgThrThrThrThrThrThrThrThrThr
¤CUACUACUACUACUACUACUACUACUACACUACUACUACLeuLeuLeuLeuLeuLeuLeuLeuLeuHisTyrTyrTyr
CUACUACUACGUACUACUACUACUACUACACUACUACUALeuLeuLeuArgThrThrThrThrThrThrLeuLeuLeu
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Triple mutants are revertants!
• Triple mutants of the same class, (+)¤(+)¤(+) and (–)¤(–)¤(–), produce leaky phenotypes
CUACUACUACGUACUACUACUACUACUACUACUACUACUACULeuLeuLeuArgThrThrThrThrThrThrThrThrThrThr¤CUACUACUACUACUACUACGUACUACUACUACUACUACUACULeuLeuLeuLeuLeuLeuArgThrThrThrThrThrThrThr
double mutant – loss of function phenotype
CUACAUCUACGUACUACUACGUACUACUACUACUACUACUACLeuLeuLeuArgThrThrThrTyrTyrTyrTyrTyrTyrTyr¤CUACUACUACUACUACUACUACUACUACGUACUACUACUACULeuLeuLeuLeuLeuLeuLeuLeuLeuArgThrThrThrThr
triple mutant – leaky phenotype
CUACUACUACGUACUACUACGUACUACUACGUACUACUACUALeuLeuLeuArgThrThrThrTyrTyrTyrValLeuLeuLeu
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Cracking the Code (F.Crick, M.Nirenberg, J.Matthaei, S.Ochoa,
G.Khorana, … and you)
• Regular oligonucleotides– … UUUUUUUUUU …– … UCUCUCUCUC …– … UCAUCAUCAU …
• Random oligonucleotides with known composition• Changes in proteins caused by deamination-
caused mutations: CU, AG• Changes in proteins caused random mutations• (tRNA binding in the presense of trinucleotides)
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20 amino acids and 64 codons
• Alanine• Cysteine• Aspartate• Glutamate• Phenylalanine• Glycine• Histidine• Isoleucine• Lysine• Leucine• Methionine• Asparagine• Proline• Glutamine• Arginine• Serine• Threonine• Valine• Tryptophan• Tyrosine
UUU Phe UCU UAU UGU
UUC UCC UAC UGC
UUA UCA UAA UGA
UUG UCG UAG UGG
CUU CCU CAU CGU
CUC CCC Pro CAC CGC
CUA CCA CAA CGA
CUG CCG CAG CGG
AUU ACU AAU AGU
AUC ACC AAC AGC
AUA ACG AAA Lys AGA
AUG ACA AAG AGG
GUU GCU GAU GGU
GUC GCC GAC GGC
GUA GCA GAA GGA
GUG GCG GAG GGG
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Triplet binding data (from Crick’s Croonian lecture, 1966)
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Reading the code: The ribosome
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Translation
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Polysomes
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Adaptors (F.Crick and S.Brenner)
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tRNA: secondary structure
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tRNA: three-dimensional structure
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tRNA and aminoacid-tRNA-synthetase
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Initiation of translation
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Translation start sitesdnaN ACATTATCCGTTAGGAGGATAAAAATG
gyrA GTGATACTTCAGGGAGGTTTTTTAATG
serS TCAATAAAAAAAGGAGTGTTTCGCATG
bofA CAAGCGAAGGAGATGAGAAGATTCATG
csfB GCTAACTGTACGGAGGTGGAGAAGATG
xpaC ATAGACACAGGAGTCGATTATCTCATG
metS ACATTCTGATTAGGAGGTTTCAAGATG
gcaD AAAAGGGATATTGGAGGCCAATAAATG
spoVC TATGTGACTAAGGGAGGATTCGCCATG
ftsH GCTTACTGTGGGAGGAGGTAAGGAATG
pabB AAAGAAAATAGAGGAATGATACAAATG
rplJ CAAGAATCTACAGGAGGTGTAACCATG
tufA AAAGCTCTTAAGGAGGATTTTAGAATG
rpsJ TGTAGGCGAAAAGGAGGGAAAATAATG
rpoA CGTTTTGAAGGAGGGTTTTAAGTAATG
rplM AGATCATTTAGGAGGGGAAATTCAATG
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Translation start sites aligned
dnaN ACATTATCCGTTAGGAGGATAAAAATG
gyrA GTGATACTTCAGGGAGGTTTTTTAATG
serS TCAATAAAAAAAGGAGTGTTTCGCATG
bofA CAAGCGAAGGAGATGAGAAGATTCATG
csfB GCTAACTGTACGGAGGTGGAGAAGATG
xpaC ATAGACACAGGAGTCGATTATCTCATG
metS ACATTCTGATTAGGAGGTTTCAAGATG
gcaD AAAAGGGATATTGGAGGCCAATAAATG
spoVC TATGTGACTAAGGGAGGATTCGCCATG
ftsH GCTTACTGTGGGAGGAGGTAAGGAATG
pabB AAAGAAAATAGAGGAATGATACAAATG
rplJ CAAGAATCTACAGGAGGTGTAACCATG
tufA AAAGCTCTTAAGGAGGATTTTAGAATG
rpsJ TGTAGGCGAAAAGGAGGGAAAATAATG
rpoA CGTTTTGAAGGAGGGTTTTAAGTAATG
rplM AGATCATTTAGGAGGGGAAATTCAATG
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Elongation
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Termination of translation
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Dialects
• The genetic code is not universal• … but the differences are relatively minor• … occur mainly in small genomes of organelles• … and involve specific codon families.• In many cases symmetry is increased, or entire families
reassigned.• Many changes involve stop codons
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Reassignment
CUN (=CUU, CUC, CUA, CUG): LeuThr
Possible initiation codons in addition to AUG (Met):NUG (=GUG,UUG,CUG), AUN (=AUU,AUC,AUA)
UAA, UAG: stop Gln
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More symmetry
AUU IleAUC IleAUA IleMetAUG Met
AGU SerAGC SerAGA ArgSerAGG ArgSer
UGU CysUGC CysUGA stopTrpUGG Trp
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Vulnerable codon families
CGU ArgCGC ArgCGA Arg noneCGG Arg none
AGU Ser AGC SerAGA Arg Ser Gly stop AGG Arg Ser Gly stop none
GGU GlyGGC GlyGGA GlyGGG Gly
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Stop-containing families
UGU CysUGC CysUGA stop Trp Cys SecUGG Trp
UAU TyrUAC TyrUAA stop Tyr GlnUAG stop Gln (Pyl)
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How many letters are there in the English alphabet?
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How many letters are there in the English alphabet?
• 26 (everybody knows) …
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How many letters are there in the English alphabet?
• 26 (everybody knows) …
• … but we are discussing the book by Yčas …
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How many letters are there in the English alphabet?
• 26 (everybody knows) …
• … but we are discussing the book by Yčas …
• … so everybody are naïve
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How many amino acids?
• Chemists: hundreds– many occur in proteins:
post-translation modifications
• How many amino acids are encoded by DNA?
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Crick:
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Is formyl-methionine a “standard” amino acid?
• Occurs in bacteria at N-termini of all recently synthesized proteins (may be enzymatically removed later on)
• Has three codons: AUG, GUG, UUG– unlike “inernal” methionine encoded only
by AUG– by the way, internal GUG encodes Valine
and internal UUG encodes Leucine
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Selenocysteine• In all three domains of life (bacteria, eukaryotes, archaea)• Encoded by UGA followed by a special hairpin structure
(SECIS)– without this hairpin UGA is a stop-codon– several genes for selenoproteins per genome (or none)– corresponds to cysteine in homologs (more efficient in enzymes)
• Complicated mechanism of incorporation (specific tRNA, seryl-tRNA-synthetase, conversion to SeCys on tRNA, specific elongation factor)
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Alignment of SECIS elements
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The consensus
SECIS structure
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SECIS elements: examples
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Pyrrolysine
• In methanogenic archaea• A derivative of lysine• Directly encoded (unlike selenocysteine).
Standard mechanism: – UAG codon– specific tRNA – aminoacyl-tRNA
• UAG rarely used as a stop codon– never as the only stop of a gene
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Thanks
• Wikipedia• Ergito• Authors of papers,
photographs and Internet resources
• Professor Leong Hon Wai• The organizers• The assistants• The students