Men and mice
may look different, but genetically they are very similar.
For nearly every gene in man, there is a similar gene in mouse.
And, mouse of course, outperform us with respect to smell genes,
but we outperform mice a little bit with respect to brain related genes.
But overall, you can say that men and mice
have roughly the same set of genes.
But these genes are arranged differently in human and mouse genomes.
And that's why explaining to my daughter how man and mice differ genetically,
I was telling her take 23 human chromosome, cut them
into 280 pieces, shuffle these pieces and glue them together
in a new order in 20 mouse chromosomes. You will get a mouse genome.
She seemed satisfied, but she asked me if you can transform
men into mice, can you transform mice into man as well.
And I responded, of course it's very easy.
You just need to reverse this operation of cutting and gluing,
and you will get, starting from mice, you will get man.
So today we'll focus on a slightly more simple problem of
transforming mouse X chromosome into human X chromosome.
X chromosomes in mammals are special because genes do
not jump from the sex chromosome to other chromosome.
And therefore you can think about X chromosomes in mammals as
separate sub-genomes. Making it a little bit easier to analyze.
And it turns out that human and mouse X chromosome, despite
the fact that they are very long strings, 150 million nucleotides long, they can
be thought of as just sequences of 11 large segments.
Each of these segments may contain hundreds of genes
but within each segment the genes are very similar.
However, these segments, called synteny blocks,
are arranged differently in mouse and human.
And a number of questions arise. First, how can we transform a
long strand consisting of 150 million nucleotides into just
11 synteny blocks.
And what is the evolutionary scenario that nature used to transform
mouse arrangement of blocks into human arrangement of blocks.
You may notice that I show every block as a directed block, which is oriented
either to the left or to the right. And I will explain later
what precisely these directions mean, but you may recall that
two complimentary strands of DNA ran opposite to each other.
And depending on what strand a gene is located, we may assign
the gene's orientation, left or right, or plus or minus,
as we show in this slide. Now nature doesn't use this
dramatic cut and glue together operations that I described
when I was explaining the process to my daughter.
It uses a simpler operation called "reversal".
And reversal simply takes a segment of the genome and flip it over like
this, reversing the directions of full blocks within the segments.
Lets try to see step
by step of what this particular evolutionary
scenario for transforming mouse into human, amounts to.
At the first step, we simply revent the orientation of block 6.
In the next step we revert the orientation of block 9.
Then we take two blocks and
reverse their orientation, and continue, continue, continue,
until we transform the mouse gene arrangement into the human gene
arrangement on the X chromosome. I emphasize that this
is just a hypothetical scenario. Nobody knows today what
really happened during 75 million years of evolution while
nature will has been transforming, mouse gene arrangement
into human gene arrangement. But if the scenarios that I've
showed here were correct, then one of the intermediate
arrangements of blocks would correspond to arrangement of
blocks on the X chromosome of the human-mouse ancestor.
That's shown here, and we have to realize that
on the way from mouse to the human-mouse ancestor, we're actually moving in back in
time, and then from the human-mouse ancestor to human, we are moving
forward 75 million years in time. Now,
rearrangements are of course dramatic events happening within genomes.
And you can think about rearrangements as earthquakes,
because many bad things may happen.
For example, every rearrangement, every reversal has two end points.
And these endpoints, after a reversal happens, may actually
disrupt the gene, or they may bring a gene
to a completely foreign territory and put it under
the influence of the wrong transcription factor, thus disrupting gene regulations.