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Welcome to today's talk.


Today I'm going to discuss comparative and
developmental genomics and how you can use
the fact that we're quite similar
genetically
to many other organisms to our benefit.
In studying human genetics.
It's difficult to study the function of
genes in
humans since currently, the easiest way to
study the
function of a gene, is to see what happens
when there's mutation and that gene no
longer functions properly.
So to study human diseases, we'd need
to examine people afflicted by a disease
naturally.
Well, that presents a problem if we
want to study the 22,500 genes in humans.
We'd have to look at the entire population
and wait for a person to have a disease.
And then try to figure out which of 22,500
genes is broken, and then examine the
symptoms that way.
Well, that's a lot of work and a lot of
waiting.
But what we found is we can create mice
called knock-out mice
where we intentionally remove a gene or
knock out a specific gene's function.
This us, allows us to control specifically
which genes we
want to remove and we can observe the
resulting phenotype or symptoms.
A Nobel prize was awarded to the scientist
who
developed this technique of studying gene
function in knock-out mice.
What we see is when you knock out a
mouse's function for a specific
gene, it often affects many aspects of the
phenotype.
Remember that term, pleiotropy?
We can't just do this in humans, because
it's not ethical to
remove the function of a gene just to see
what it does.
So we study mice, and try to examine human
diseases.
That leads us to another interesting field
of genetics called comparative genomics.
Genomics is the study of whole genomes.
Insects
and other model organisms like mice can
provide
insight to humans through the power of
comparison.
By comparing the genomes of different

organisms we
line up the sequences and look for
similarities or
differences and of course bonding regions,
and what
we see is that we're really all genetic
relatives.
One interesting example of these relations
can be
seen by examining an enzyme class called
kinases.
When we compare these kinases
in humans to drosophila or fly families we
see
that some kinase proteins are only found
in humans.
Well it's quite interesting as we see that
many more kinases are shared with flies.
More so than are human specific.
And what that demonstrates is a level of
homology or
similarity between humans and the
seemingly unrelated organism, the fly.
Flies can give us a lot of insight about
the human
genome and the human condition.
We can look at
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and see that there are hundreds of
disease associated genes that have already
been identified
and a lot of these disease causing genes
have been identified, that have been
identified in
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also cause similar diseases in humans.
Some examples are, cancer and tinman gene
I discussed earlier.
And diseases like Parkinson's and
Huntington's can
be studied using flies as a model system.
So, insects are great for studying human
diseases and its progression because
they're inexpensive,
easy to rear, quick to grow, they
have relatively small genomes and minimal
ethical implications.
That means we can use flies
to develop.
And test drugs which could possibly treat
or cure human diseases.
We can make fly genes non-functional and
absorb
the phenotype, like what we saw with
knock-out mice.
One way we can do that is to remove or
disrupt
the gene's functions by using a technique
called RNAi or RNA interference.
Flies have less than 15,000 genes compared

to our
22,500 genes and their genome is very well
annotated.
There's a lot of data and analyses that
are available about flies.
They're also
significantly similar to humans and we've
examined or reported a lot
of conserved biochemical pathways in flies
that are also seen in humans.
There are Drosophila homologs for 60% of
the genes involved in human cancers.
One example is p53, the tumor suppressor
gene,
which is implicated in a host of human
cancers.
Beyond cancer, we can use model organisms
to research where and when developmental
genes are expressed, and how these genes
influence one another.
This study is called developmental
genetics, and what we see is that
mRNA and proteins affect development based
on their concentration and location within
cells.
And in early embryonic development, the
body, the
major axes, the number and orientation of
segments
in a body, are determined, as well as
the identity of each segment, by proteins
and mRNA.
There's polarity,
a dorsal back region, a ventral front
region.
There's a head, anterior region and a
posterior hind region.
And a cascade of genes regulates and
establishes this polarity or identity
of the body parts, and in humans we call
those homeotic genes.
This tells your body where the head should
be, where your arms should
be, where the legs develop, and what
structures are on the face, for example.
These genes, again, are the major
regulators in development
that allow you to form properly.
In mammals, they're called hox genes.
Interesting, we even have hox genes that
are no longer functional.
And sometimes we see the expression of
such
hox genes, and we call that an atavism.
That's the reappearance of an ancestral
condition.
The same gene can be fully functional
on another organism but isn't functional
on us.
For example, the gene for tail formation,

that's broken in us, however,


every once in a while, human babies born
with vestigial tail and in this baby
there is a mutation that occurred that
allowed
the broken hox gene to be expressed again.
That's fascinating, because it shows us we
have many genes that
are broken or no longer expressed just
hanging out in our genome.
And we can use comparative genomics to
determine
which ancestor we inherited these broken
genes from.
The similarity among genes
in different species shows our genetic
homology.
And because of this, wee see structural
homologies and developmental homologies,
and all of this similarity is because life
has a common ancestor.
That's where our DNA ultimately came from.
A great example of this is with the gene
that controls eye coordination.
The eyeless gene in flies controls eye
development.
In mice and humans the gene that
controls eye development is similar to the
flies gene, in humans it's called the Pax6
gene and knocking out the Pax6 homolog in
mice creates an eyeless mouse.
The human homolog of Pax6 has been
conserved in this gene
is really some what in sequence to the fly
eyeless gene.
All of these genes are the master
controllers for eye development.
So, what we're talking about here are
three different species, flies, humans,
and mice, but one set of homologous genes
with
very similar DNA sequences that are nearly
identical in function.
These genes are so similar in the three
different species that the mouse
homolog for Pax6 can actually trigger
development of an eye in the fly.
Another question you may be asking
yourself is why do
we call the gene for eye development in
flies "eyeless"?
Well,
we can most easily observe what a gene
does when it's broken, so often
times we'll name a gene after its
phenotype that's observed when there's a
mutation.
So if you take a look at the human
chromosome and examine
the gene names, you think that most of our

genes actually cause diseases.


That's not the case though.
It's just the easiest way to observe
a specific gene's function, is when it
breaks.
So that's how a lot of genes got their
name, based on when they're broken.
Fortunately if you're watching this video,
the
genes you need to survive aren't broken.
Besides just examining structural genes,
such as
the ones that are required to form eyes.
We can understand, better understand human
behavior from fly behavior.
We can do this because of that genetic
homology that we were talking about.
Let's look at alcohol for instance.
After alcohol exposure flies become
hyperactive, then uncoordinated and
well, they pass out.
The behaviour of drunken flies is
virtually
identical to that of humans, which means
that
drugs that treat alcoholism in flies may
also be successful in treating alcoholism
in humans.
To quote Ulrike Heberlein, a drosophila
geneticist, I'm
still amazed that there are so many
similarities
between the behaviour of these little
flies and
the behaviours of humans when exposed to
drugs.
There also mutant
flies that are deprived of sleep much in
the same way a lot of humans are.
And these flies need sleep, they want
sleep, but they cant stay asleep.
They are great models for studying
insomnia and drugs to treat insomnia.
There's also a mutation of flies called
fruitless, and the
fruitless gene, among other genes, can
trigger, and effect, sexual orientation.
So by altering serotonin levels in these
flies, we see
that it causes male-to-male preference,
and this male-to-male preference due
to this mutation is actually seen in other
animals as well.
Also, remember a while back we discussed
aggression.
Well this can be studied and possibly
treated using flies as well.
Some genes of proteins that have been
researched include dopamine,
androgens like testosterone, and Maomine

Oxidase A, to name a few.


So scientists have studied
large human families with aggressive and
violent tendencies, and what they found is
it's mostly seen in men, and there's
a behavioural pattern of many violent
offences.
One of the potential reasons for this
could
be the genetic mutation mapped to the X
chromosome.
An allele of the monoamine oxidase A gene
that we already talked about called the
warrior allele.
So men have one copy of the X chromosome
where this gene is located.
Whereas women
have two copies.
So it's possible and very likely that
women have a dominant
version and most women have the dominant
version associated with normal behaviour.
That might be masking the warrior allele
version of this gene.
So like we discussed earlier the gene that
codes for monoamine
oxidase type A will affect the breakdown
of the neurotransmitter serotonin.
And the warrior version of this gene
causes a monoamine
oxidase type A deficiency which when
coupled with abusive
childhood tends to lead to aggressive
behavior in adulthood.
We can study those flies with this
mutation and observe their behavior to
better understand the underlying cause of
aggression,
but more importantly, how to treat it.
So you may be wondering, an aggressive
fruit fly?
Well, it sounds strange, but it's not.
Flies can be aggressive.
They demonstrate wing threats, they can
box and
fence using their legs, they'll push and
punch each other.
So, model organisms like mice and flies
are a
great way to study human diseases,
behavior and treatments.
Of course, you may never think of flies
the
same way again, knowing
they get drunk and
rowdy, just like humans.
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