So, why don’t we look at the numbers that are involved here;
give us an idea about how incredible this mechanism is.
There are less than 200 genes involved, yet those
genes can encode millions of different antibodies.
So we’ve already heard that around about 40
Variable gene segments for the immunoglobulin
heavy chain, 27 Diversity gene segments and
half a dozen or so Joining gene segments.
And we’ve heard that this
recombination is a random process.
So a given B-cell can pick any one out of the 40, any one
out of the 27, any one out of the six for the V, D and J.
So because any of those can be picked, you can
multiply those three numbers by each other.
40 x 27 x 6.
So that gives us nearly six and a half thousand
different possible sequences, protein sequences.
From, what have we got there?
40 plus 27, that’s 67, plus 6.
73 if my maths is right.
Okay, so a very small number of genes producing
thousands of different protein sequences.
And for the kappa (k) light chain, 40 Variable gene
segments, any of which, any one of which can be chosen.
No D remember, in the light chain.
But five J.
So we can multiply 40
by 5, that gives us 200.
That’s quite a simple sum to do, and in
a given B-cell, it may make exactly the
same heavy chain rearrangement as another
B-cell, but a different light chain.
So we can actually take those two
numbers and multiply them together.
6480 x 200, as I’m sure you all already
worked out by mental arithmetic is
1.3 x 10^6;
1.3 million different protein sequences from
that, way under 200 different gene segments.
And of course there’s also the lambda (λ) light chain, 30
Variable gene segments, 5 Joining gene segments, gives us 150.
That gives us a figure of nearly
a million different sequences.
You can add those two together, so over 2 million
different protein sequences from less than 200 genes.
That’s only the start of it.
The antibodies can have much
more variability than that.
There are a variety of mechanisms
that create additional variability.
Maybe you’re wondering where this
additional variability comes from.
Essentially there are three mechanisms that create
variability that goes way beyond what occurs
due to the recombination of V, D and J in the
heavy chain, and V and J in the light chain.
First of all, when that recombination process
occurs, there’s not an absolutely set point at which
the splicing of D to J, and then V to DJ in the
heavy chain, and V to J in the light chain occurs.
In other words, there are
Now this isn’t always a good thing.
This is one of the ways in which
for example a stop codon might be
inserted, and you make… you’re not
able to make an antibody molecule.
But it does greatly
increase the diversity.
And that’s beneficial because there are lots and lots of
different pathogens out there, and
they’re mutating all the time.
So we need to have an enormous diversity of
antibody molecules and T-cell receptor molecules.
Secondly, there is a process referred to as N-nucleotide
addition; now the N stands for Non-templated.
And this is a mechanism that as we’ll see is mediated
by an enzyme Terminal deoxynucleotidyl Transferase.
I’ve already mentioned that enzyme
a little bit earlier in this lecture.
Terminal deoxynucleotidyl Transferase or
TdT, mediates this N-nucleotide addition.
And then finally,
Now all genes mutate, but in the immunoglobulin genes, one
observes a much higher rate of mutation than in other genes.
About a thousand times more mutations are permitted within
the immunoglobulin genes by a variety of mechanisms.
And this means that the diversity of
antibodies can be increased enormously.