Who proposed that genetic code should be a triplet code (three nucleotides coding for one amino acid)? | NeetCrackers

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Who proposed that genetic code should be a triplet code (three nucleotides coding for one amino acid)?

Options

1

Francis Crick

2

George Gamow

3

Marshall Nirenberg

4

Har Gobind Khorana

Correct Answer

George Gamow

Solution

1

Proposed triplet nature of genetic code:

George Gamow (physicist, 1954): argued mathematically that 3-nucleotide codons give 4^3 = 64 combinations, sufficient for 20 amino acids.

2

Crick (1961): experimentally proved code is triplet using T4 phage frameshift mutations.

Nirenberg+Matthaei (1961): cracked first codon (UUU = Phe).

Khorana: synthesised polynucleotides to decipher full code.

Answer: George Gamow

George Gamow (1954): proposed triplet code
Mathematical logic: 4^3 = 64 codons for 20 amino acids

Theory: Molecular Biology

1. History of Genetic Code Discovery

George Gamow (physicist, 1954): first proposed genetic code is a triplet code. Mathematical argument: doublet (4^2 = 16) insufficient for 20 amino acids. Triplet (4^3 = 64) gives 64 combinations, more than enough for 20 amino acids. Francis Crick, Sydney Brenner et al. (1961): proved code is triplet using frameshift mutations in T4 bacteriophage rII gene. Adding or deleting 1 or 2 nucleotides = mutant. Adding or deleting 3 nucleotides = reading frame restored = near-normal function. Marshall Nirenberg and Johann Matthaei (1961): broke first codon. Cell-free protein synthesis system. Poly-U RNA produced poly-phenylalanine = UUU codes for Phe. Nobel Prize 1968: Nirenberg, Khorana, Holley. Khorana: synthesised poly-AC, poly-AG etc. to decipher code. Holley: determined tRNA structure.

2. Properties of the Genetic Code

Universal: nearly same in all organisms. Exceptions: some mitochondria (UGA = Trp not stop), Mycoplasma (UGA = Trp). Triplet: 3 nucleotides per codon. Degenerate: multiple codons for same amino acid. Serine has 6 codons (UCU, UCC, UCA, UCG, AGU, AGC). Leucine has 6. Arginine has 6. Methionine has 1 (AUG). Tryptophan has 1 (UGG). Degeneracy mostly at 3rd position (Wobble). Unambiguous: each codon specifies only one amino acid. Non-overlapping: each nucleotide belongs to only one codon. Commaless (non-punctuated): no spacers between codons - read continuously. Start codon: AUG (Met in eukaryotes, fMet in prokaryotes). Stop codons: UAA, UAG, UGA. Sense strand: same sequence as mRNA. Template strand: antisense, used as template by RNA polymerase.

3. Cracking the Genetic Code

Nirenberg-Matthaei (1961): cell-free protein synthesis. poly-U = poly-Phe (UUU = Phe). poly-A = poly-Lys (AAA = Lys). poly-C = poly-Pro (CCC = Pro). Khorana (1960s): synthesised defined polynucleotides. Alternating AC (poly-ACACAC): produced alternating Thr-His-Thr-His. Therefore ACA = Thr and CAC = His (or ACA = His and CAC = Thr). Combined with other data = both assignments confirmed. Trinucleotide binding technique (Nirenberg and Leder, 1964): specific trinucleotides cause specific aminoacyl-tRNA to bind ribosomes. Tested all 64 triplets. By 1966: all 64 codons assigned. Wobble hypothesis (Crick, 1966): explains degeneracy at 3rd codon position.

4. Central Dogma of Molecular Biology

Francis Crick (1958): proposed Central Dogma. Information flow: DNA to RNA to Protein. DNA replication: DNA to DNA. Transcription: DNA to RNA. Translation: RNA to Protein. Reverse transcription: RNA to DNA (retroviruses, discovered by Temin and Baltimore, 1970 - Nobel 1975). Reverse translation does NOT occur (protein cannot be back-translated to RNA). Central Dogma exceptions: RNA replication in RNA viruses (RNA to RNA by RNA-dependent RNA polymerase). Prions: protein-based inheritance (no nucleic acid template). The central dogma is the fundamental principle of molecular biology. "The sequence information cannot be transferred back from protein to either nucleic acid." - Crick.

5. DNA Structure and Replication

Watson-Crick double helix (1953). Complementary base pairs: A=T (2 H-bonds), G=C (3 H-bonds). Antiparallel strands. Right-handed B-form (most common). A-form (RNA:DNA hybrid, dsRNA). Z-form (left-handed, GC-rich sequences). DNA replication: semi-conservative (Meselson-Stahl experiment, 1958 - definitive proof using 15N/14N isotopes). Enzymes: Helicase (unwinds), Primase (makes RNA primer), DNA polymerase III (prokaryotes, extends 5 to 3), DNA polymerase I (removes primer, fills gap), DNA ligase (seals nicks). Leading strand: continuous synthesis. Lagging strand: discontinuous (Okazaki fragments). Telomerase: adds TTAGGG repeats to chromosome ends. Absent in most somatic cells (cellular aging). Active in cancer cells (immortalisation), germ cells, stem cells.

6. Transcription

Transcription: DNA to RNA by RNA polymerase. Template strand used. Transcription bubble: RNA pol unwinds ~17 bp. mRNA synthesised 5 to 3. Prokaryotic RNA polymerase: core enzyme (alpha2, beta, beta prime, omega) + sigma factor (recognises promoter). Promoters: -10 box (Pribnow box, TATAAT) and -35 box (TTGACA). Sigma factor: recognises and binds promoter, dissociates after initiation. Rho factor: involved in some prokaryotic termination. Eukaryotic transcription: 3 RNA polymerases: Pol I (rRNA, 28S, 18S, 5.8S, in nucleolus), Pol II (mRNA, snRNA), Pol III (tRNA, 5S rRNA). Many transcription factors. TATA box (Hogness box) at -25. CAAT box, GC box upstream elements. General transcription factors (GTFs) assemble preinitiation complex. Enhancers: distant regulatory elements (can be thousands of bp away).

7. Post-transcriptional Processing

Eukaryotic mRNA processing: 5 capping: 7-methylguanosine cap added to 5 end. Functions: protects from exonucleases, promotes ribosome recognition (cap-dependent translation). 3 polyadenylation: poly-A tail (100-250 A residues) added to 3 end after cleavage. Functions: mRNA stability, nuclear export, translation initiation. RNA splicing: introns removed, exons joined. Carried out by spliceosome (complex of snRNPs: U1, U2, U4, U5, U6 snRNPs). GT-AG rule: introns start with GU and end with AG. Alternative splicing: same pre-mRNA can produce different mRNAs by using different exons. Allows one gene to encode multiple proteins. Human genome: ~20,000 genes but ~100,000+ different proteins (mostly via alternative splicing). RNA editing: ADAR enzymes change A to I (inosine read as G) in some mRNAs.

8. Regulation of Gene Expression

Operon concept (Jacob and Monod, 1961): groups of genes controlled together. Lac operon (E. coli): genes for lactose metabolism (lacZ, lacY, lacA) regulated together. Negative regulation: lac repressor (encoded by lacI) binds operator when no lactose present - blocks transcription. Inducer (allolactose) binds repressor - repressor released - transcription occurs. Catabolite repression: CAP (CRP) protein + cAMP activates transcription. Low glucose = high cAMP = CAP active = lac operon on. High glucose = low cAMP = CAP inactive = lac operon off (even if lactose present). Trp operon: biosynthetic operon. Trp repressor + tryptophan (corepressor) = active repressor blocks transcription. Attenuation: ribosome stalls when Trp rare, RNA forms anti-terminator structure, transcription continues. Eukaryotic gene regulation: chromatin remodelling, histone modification (acetylation, methylation), DNA methylation, transcription factors, enhancers, silencers, microRNAs, long non-coding RNAs.

Frequently Asked Questions

1. What was the mathematical logic behind Gamow's triplet proposal? ⌄

Gamow (1954) reasoned: there are 4 different nucleotide bases (A, U, G, C in RNA). There are 20 different amino acids to be coded. A singlet code (1 base per amino acid): 4^1 = 4 possible codons. Insufficient for 20 amino acids. A doublet code (2 bases): 4^2 = 16 possible codons. Still insufficient for 20 amino acids. A triplet code (3 bases): 4^3 = 64 possible codons. More than enough for 20 amino acids (with many codons left over for degeneracy and stop signals). This mathematical logic exactly matches reality: the code IS triplet, with 61 sense codons and 3 stop codons, encoding 20 amino acids with degeneracy. Gamow even proposed a specific "diamond code" model for how codons specified amino acids - this turned out to be wrong, but his triplet proposal was exactly right.

2. How did Crick prove the code is triplet using frameshift mutations? ⌄

Crick, Brenner et al. (1961) used T4 bacteriophage gene rIIB. Acridine dyes cause frameshift mutations (add or delete single bases). Experiment: One deletion (-1): mutant (reading frame shifted throughout gene, wrong protein). Two deletions (-2): still mutant. Three deletions (-3): near wild-type function restored! The three deletions compensate each other by restoring the reading frame. They also showed: one insertion (+1) = mutant. Two insertions (+2) = mutant. Three insertions (+3) = near wild-type. One insertion + one deletion = wild-type if close together (cancel out). This directly proved the code is read in triplets. No experimental artifact could explain why specifically adding or removing 3 bases restores function unless the code is read 3 nucleotides at a time.

3. Who are the key figures in deciphering the genetic code? ⌄

1954: George Gamow - proposed triplet code (mathematical argument). 1958: Francis Crick - proposed Central Dogma. 1961: Crick, Brenner et al. - proved triplet code experimentally. 1961: Nirenberg and Matthaei - first codon cracked (UUU = Phe). 1961-1966: Marshall Nirenberg and Har Gobind Khorana - systematic deciphering of all 64 codons. 1966: Wobble hypothesis (Crick). Nobel Prize 1968: Nirenberg, Khorana (chemistry), Robert Holley (tRNA structure). Note: Gamow did not receive Nobel Prize for his proposal despite it being correct - Nobel is only awarded to those who provide experimental proof, not theoretical proposals. Watson, Crick, Wilkins (1962): Nobel for DNA double helix structure. Rosalind Franklin: died 1958, not eligible for Nobel.

4. What is the wobble hypothesis and how does it explain codon degeneracy? ⌄

Crick (1966) proposed that the first two positions of a codon base-pair with strict Watson-Crick rules (A-U, G-C), but the third position (3 prime of codon, 5 prime of anticodon) can "wobble" - tolerate non-standard base pairs. Wobble pairs at this position: G-U (wobble), I-U, I-C, I-A (inosine, modified base in anticodon, can pair with U, C, or A). This means one tRNA can recognise multiple codons that differ only at the 3rd position. Example: one serine tRNA with anticodon 3-AGI-5 can read codons UCU, UCC, and UCA (all serine). Result: fewer tRNA types are needed than the number of sense codons. Humans have ~45 functional tRNA genes (plus copies) to read 61 sense codons. Mitochondria have only 22 tRNA genes but read 60 codons (extreme wobble, 2-out-of-3 reading).

5. What did Nirenberg and Khorana do to decipher all 64 codons? ⌄

Nirenberg-Matthaei (1961): Cell-free protein synthesis system (E. coli extract + ATP + amino acids). Added synthetic poly-U RNA = produced polyphenylalanine. Therefore UUU = Phe. Extended: poly-A = poly-Lys (AAA = Lys), poly-C = poly-Pro (CCC = Pro). Limitation: only homopolymers or random copolymers - could not identify all codons precisely. Nirenberg and Leder (1964): trinucleotide binding assay. Specific triplets (e.g., UUU) cause specific aminoacyl-tRNA to bind ribosomes. Each of 64 trinucleotides tested with all 20 aminoacyl-tRNAs. Khorana: chemically synthesised polyribonucleotides of known defined repeating sequences. ACAC... produced alternating Thr-His. UGUG... produced alternating Cys-Val. By combining all approaches: all 64 codons assigned by 1966. Complete genetic code table published. This was one of the greatest achievements of 20th century biology.

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