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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 22 (including selenocysteine and pyrrolysine) amino acids, 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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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. –  mgkrebbs Jan 14 '12 at 21:07
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@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. –  Mad Scientist Jan 14 '12 at 22:30
    
@MadScientist, No, this was pure speculation on my part. Indeed present mechanisms are highly oriented to triple nucleotide codons. Smaller codons would only have occurred back in the RNA world, before DNA was used. The pattern of redundancy in the code is compatible with the 2-nucleotide idea, but could also be explained in other ways, such as selective pressure for synonymous translations of single-base mutations. –  mgkrebbs Jan 14 '12 at 23:49
    
A quick look for literature doesn't show much, but this review paper shows that the idea of two-nucleotide codons is not unknown: "It is usually assumed that the primitive genetic code was simpler (for instance with a two-nucleotide codon and less amino acids) and expanded in the course of evolution." –  mgkrebbs Jan 14 '12 at 23:51
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@J.M. selenocysteine is in no way restricted to microbes. In fact, all animals except a few insects encode selenocysteine. –  terdon Oct 24 '12 at 16:06
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4 Answers

up vote 32 down vote accepted

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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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. –  terdon May 16 '13 at 1:08
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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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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. –  nico Jan 15 '12 at 9:59
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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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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. –  user132 Jan 16 '12 at 23:43
    
thanks, fixed -its been a while since i did any organic chemistry. –  shigeta Jan 17 '12 at 23:13
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With only 2 nucleotides per codon, a codon could only encode 16 amino acids (actually just 15, because you need at least one stop codon), which isn't enough to encode the 20 acids we require (actually 21). So 3 is the bare minimum. (Of course another option would have been to introduce two new nucleotides, but evidence suggests that just using 3 nucleotides per codon was easier)

Nature has a tendency to minimize everything (except entropy :D). And apparently evolution selected those who understand that:

Simplicity is the ultimate sophistication.
- Leonardo da Vinci

Perfection is finally attained not when there is no longer anything to add, but when there is no longer anything to take away.
- Antoine de Saint Exupéry

It's rather safe to assume that the 20 acids we use are the bare minimum we require to function and that's why we don't have more.
Ultimately, RNA/DNA is there to store amino acid sequences. So the number of nucleotides in a codon is determined by the number of acids that need to be encoded and not the other way round.

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The 20 amino acids are not the minimum, see this question about the topic. –  Mad Scientist Jan 17 '12 at 7:47
    
@MadScientist: What works in E.Coli doesn't necessarily work in humans. I agree that "we" is a little ambiguous, but I think it's rather obvious, that I was talking about the naturally occurring complex organisms that we are (or at least anything remotely similar). But even then, your argument is void. You can create a surprising number of things in a lab, but whether they actually "function" is a different matter. Unless a strain of 13 amino-acid E.Coli can survive in competition with a strain of naturally occuring E.Coli in a typical habitat, "functioning" is not a word I'd choose. –  back2dos Jan 17 '12 at 9:16
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