Now comes almost my favorite part of this lecture where I get to say why I do not like
neo-Darwinists and do not worry I have not become a creationist. So this is not going
to be a religious file. Let us consider the distributions, the frequencies of the different
kinds of amino acid. Think about amino acid sequences. We have 20 amino acid types. Do
you see them all equally commonly? So are you made up of 1 20th, 5% of alanine, leucine,
cysteine? No, you are not. Some amino acids are rather rare. You do not have so much tryptophan,
for example. Some amino acids are very common like leucine and alanine. And let us quantify
this in a rough sense. If I look at a survey of protein sequences, I see something a bit
unexpected. This is going to be dependent upon the organism and the kind of protein you are
looking at. But these are pretty typical numbers. This is the frequency of an amino acid. So that
is 10% up there, 5%. This is what you would expect if the amino acids were distributed evenly. And
this is of course zero, which does not happen. Leucine and alanine are both around 8-9% of all
amino acids. So leucine and alanine are extremely common. At the other end of the scale, you can see
that we do not have very much tryptophan, cysteine, histidine or methionine. And the question is,
why is this? And how would a Darwinist attempt to explain this? Why do I have so little cysteine,
for example? So let us consider Darwinism. I do hope that this will be a surprise and new to you,
even if you have done protein structure lectures in biology or biochemistry.
So what would Darwin say? And what do the biochemists in the room, if we had a room,
what do you guess? Why is there so much alanine and leucine and so little tryptophan and cysteine
and histidine? So let me tell you a story, first of all, Darwinist and then a non-Darwinist side.
So Darwin would say, we are looking at selection, survival of the fittest. There must be a chemical
or biological reason. And we can think of some. So the empirical fact is that tryptophan, cysteine
and methionine are rare. And then how would you explain this? Would you say,
maybe too much tryptophan is bad for you. Maybe it costs metabolic energy to make a tryptophan
residue. Maybe free tryptophan in a cell is dangerous or toxic. So does it cost energy to
make a tryptophan? Is cysteine difficult to make because it has this thiol group in there.
And maybe so it has to do with protein structure. Maybe you say, look at the different kinds of
chemistry that we have. So if you put lots of tryptophan or cysteine or methionine and protein,
do proteins not fold so well? Do they become unstable? You can think of all kinds of things.
They are probably mostly going to be wrong.
Look at the common amino acids, leucine and alanine. Are they cheap in terms of biochemical
energy to synthesize? Do you perhaps get them as byproducts from some other kind of biochemistry?
Or are leucine and alanine very good for protein structure? Do they do something for stability or
rigidity or flexibility? What I'm going to do is say, forget all of these ideas and think
neutral evolution. First of all, what is the opposite of Darwinism? And I know everybody
says, yeah, we learnt Darwinism at school, but bear with me for a moment.
So let's be very Darwinist. We have protein sequences. We get hit by cosmic rays and we
mutate and we get new sequences. And then you ask the question, does the protein still work?
If so, maybe the mutation gets accepted and you get to go around and around through
on the evolutionary timescale, visiting sequences which still work. If your protein does not work,
if the enzyme does not function, if the protein does not fold, you go into the evolutionary
garbage bin. Let's look at it a little bit differently. Darwinism focuses on this question,
are you fit or not? Neutral evolutionary people look at other issues. So what determines the
sequences that you see? According to a Darwinist, it's whether the protein works. That's what
determines if you go into the garbage bin or if you get to pass your genes on. However,
what really also will determine what you see in the world is this step here, the mutation step.
And this looks pretty easy. We tend to say that mutation is just when you smoke too many cigarettes
and eat carcinogens, or you get hit by cosmic rays, you mutate and you pick an amino acid
randomly. Is that the case? No. Let's consider this mutation step and biases in this mutation step.
Consider the issue of codon bias. So compare rare amino acids here with common amino acids here.
Now you remember that each amino acid is coded for by a triplet or a codon. So three bases,
for example, UGG, code for tryptophan. If you look at the rare amino acids like tryptophan
or methionine, there is only one codon that results in a tryptophan. If you look at a common
amino acid like leucine, there are six different triplets, six possible codons that code for a
leucine. So you can see where this is going. If I make up random DNA sequences, I'm going to get
lots of leucine, serine and alanine and others just by chance. So it says these amino acids have
not been selected for because they have magical biochemical properties or they are expensive or
cheap to synthesize. It looks as if somebody took a lot of random bases, went splat and then out came
the proteins. Of course, it's not that simple. If we want to see if this model is correct, we can be
a little bit more sophisticated and we can take into account the base frequencies. So if you do
a survey of DNA sequences, you find that the most common base is actually adenosine followed by
guanosine and so on. And there's a little bit less uracil and cytosine. If we want to make a prediction
using this model for the frequency of histidine, we could do the following. We say for histidine,
the probability of finding a histidine from random bases is the probability of this codon here.
So the probability of a C, A and U. So the probability of a C, A and U, which are these
numbers here, so 0.22 times 0.3 times 0.22 plus the probability of this codon, so the probability
of a C times the probability of an A times the probability of a C, and that would give you a
number of about 3%. So is this a good way to explain amino acid distributions?
If it is, it means that, in fact, there's not a lot of selective pressure on amino acids,
which sounds a bit unexpected. So can we predict the probability of each of the amino acids
using this kind of calculation? And you can do that. And in fact, this was done in 1969.
And here's the reference for it. So if you use that model, we have the predicted amount of the
amino acid here and the observed amount of the amino acid here. And it forms this cloud of data
points here, which means that for most of the amino acids, there is not much evidence of real
selection. It's not zero. The amino acids are not totally determined by the frequency of bases.
You could say, for example, that alanine aspartate is quite away from the line here.
But mostly, there's a really serious trend to follow this line. And the only exception
over here is arginine. So it looks as if arginine is the only amino acid which is really totally
magical, or it occurs much less than you would expect given the genetic code. So it looks as if
arginine is a little bit less used. So what it means to me is I won't say that there is no
selection on proteins, but it suggests that there are many sites in proteins where it is not so
important which amino acid is used. So we're not talking about the active site from an enzyme.
We're talking about most of the residues in a protein. If something's on the surface,
it can be substituted by another hydrophilic residue in the middle of a protein. You can
often make a hydrophobic substitution, and it does not seem to be that important.
So should we forget Darwinism? No, obviously not. Remember that arginine is saying,
yeah, there are some selection forces acting. And we have lots of mutation data from multiple
sequence alignments. And what we know is that most mutations are bad, and some do not matter.
And it's these ones that determine the statistics that we see. So what it says to me is don't be a
pure Darwinist, and do not interpret everything that you see in the world in terms of fitness.
People make an observation of an organism, and they say there must be a reason for that.
Probably not. Very often, it's just statistics.