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This question got me thinking about amino acids and the ambiguity in the genetic code. With 4 nucleotides in RNA and 3 per codon, there are 64 codons. However, these 64 codons only code for 20 amino acids (or 22 if you include selenocysteine and pyrrolysine), so many of the amino acids are coded by multiple codons.

Is there any hypothesis as to why there are only 22 amino acids and not 64? Is it possible that there were 64 (or at least more than 22) at an earlier time?

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    $\begingroup$ It seems more likely that once there were fewer than 16 amino acids and codons were 2 nucleotides. In earliest form, codons may have been 1-to-1 with nucleotides, with three or four amino acids used. The redundancy in the present code may simply have remained in place after the extension of 2-nucleotide codons into 3-nucleotide codons. $\endgroup$
    – mgkrebbs
    Jan 14, 2012 at 21:07
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    $\begingroup$ @mgkrebbs Do you have any reference for that idea? It seems exceedingly unlikely to me. From tRNA to the ribosome, every part of protein translation seems to be adapted to triple nucleotide codons. $\endgroup$
    – Mad Scientist
    Jan 14, 2012 at 22:30
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    $\begingroup$ @J.M. selenocysteine is in no way restricted to microbes. In fact, all animals except a few insects encode selenocysteine. $\endgroup$
    – terdon
    Oct 24, 2012 at 16:06
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    $\begingroup$ Remember also that there are plenty of non-proteinogenic amino acids, such as hydroxyproline, which are nevertheless found in proteins despite not being encoded in the genetic code. $\endgroup$
    – Chinmay Kanchi
    May 24, 2013 at 17:47
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    $\begingroup$ well you need at least one STOP codon so at max you could have 63. $\endgroup$
    – John
    Mar 22 at 19:43

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Brian Hayes wrote a very interesting article from a mathematical point of view:

http://www.americanscientist.org/issues/pub/the-invention-of-the-genetic-code

especially the "Reality intrudes" section. Basically people had created fancy mathematical reasons why it has to be exactly 20. Nature, being nature, does not follow the reasoning, but has its own ideas. In other words there was nothing especially special about 20. In fact there seems to be a slow grafting of a 21st amino acid, selenocysteine using the codon UGA. Also pyrrolysine is considered the 22nd. The last section suggests that the code was originally doublet, so coded for <16 amino acids. This can partly explain why the third base in each codon is not as discriminating.

So perhaps in the year 2002012 someone will be asking on biology.stackexchange why there are only 40 amino acids.

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    $\begingroup$ There is no evidence of selenocysteine being "grafted" in. Much the opposite actually, it has even been suggested that "UGA was originally a codon for Sec in the anaerobic world, perhaps two to three billion years ago, and after introduction of oxygen into biosphere this highly oxidizable amino acid could be maintained only in anaerobic organisms or in aerobic systems which evolved special protective mechanisms". If anything it is cysteine that has been taking over. $\endgroup$
    – terdon
    May 16, 2013 at 1:08
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    $\begingroup$ @John Smith The link is down. I have found another link: bit-player.org/wp-content/extras/bph-publications/…. $\endgroup$
    – user38945
    Nov 24, 2018 at 18:01
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The first position of the anti-codon, the "Wobble" position, forms hydrogen bonds less well than do the second two. This means that the last position of the codon has less coding potential than the first two. The reason is that the anticodon is at the bottom of the anticodon loop of the tRNA, and so there backbone of the tRNA is bending back to pair with itself. The nucleotides do not hold their bases flat and regular in relation to each other.

Here is a picture of the anticodon loop. In this case 5'-CAU-3' is the anticodon for 5'-AUG-3', so it would be the C, right at the sharpest part of the bend in the anticodon loop, that would pair poorest.

Here is an interactive model where you can spin the tRNA/mRNA around and see that not all the hydrogen bonds are equal length, nor are all the bases coplanar.

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    $\begingroup$ I am not convinced that is a cause, as much as a consequence of the redundancy. It could be that cells used to have a lower number of aa (<16), that could then be coded with only 2 nucleotides. As new aa entered the game, a triplet system developed, but this introduced (unharmful) redundancy in the code, which did not put any selective pressure towards having a strong bond in the 3rd position. $\endgroup$
    – nico
    Jan 15, 2012 at 9:59
  • $\begingroup$ The first link is dead. $\endgroup$
    – Gavin S. Yancey
    May 27, 2015 at 1:02
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There are two other ideas to throw in here.

1) just to add to KAM's thoughtful answer. There was also a thought that the last base also gives a lot of flexibility for GC content which responds to some

2) lets not forget that redundancy in the genetic code helps give some resistance to mutations which might be disruptive. the amino acids less disruptive to a typical protein fold are more common in the code. (we have some idea of this from studying mutations of protein structures.)

3) some biochemists have proposed that there is a sense that the 20 amino acids we have are a fairly stable set - that adding other amino acids don't help create better proteins. Peter Schultz learned some of this as his group really wanted to add extra, human synthesized amino acids into native proteins. I was at a talk where he noted that attempts to make cysteine with a longer side chain caused the amino acid to cyclize to form a thioolactone.

Thinking along these lines adding another CH2 group to proline might not make packing better. There is probably some value, but just not enough to disrupt all the sensitive machinery for making and realizing the genetic code.

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  • $\begingroup$ Maybe you mean "thiolactone", not "sulfolactone" (which is a different sort of chemical group that one can't really form with cysteine homologs). There's a mercapto group in cysteine and (possible) homologs that the carboxyl group could react with, if the amino acid isn't in zwitterionic form. With cysteine, kinetic and thermodynamic factors heavily disfavor the cyclization to a four-membered ring. The four-carbon and five-carbon analogs can respectively cyclize to five- and six-membered rings, and those are kinetically easy to make. $\endgroup$
    – user132
    Jan 16, 2012 at 23:43
  • $\begingroup$ thanks, fixed -its been a while since i did any organic chemistry. $\endgroup$
    – shigeta
    Jan 17, 2012 at 23:13

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