- We are the paradoxical ape,
bipedal naked large-brained,
long the master of fire tools and language
but still trying to understand ourselves,
aware that death is inevitable, yet filled with optimism.
We grow up slowly,
we hand down knowledge,
we empathize and deceive
we shape the future
from our shared understanding of the past.
Carta brings together experts
from diverse disciplines
to exchange insights on who we are
and how we got here,
an exploration made possible
by the generosity of humans like you.
(light upbeat music)
- You know congratulations first and foremost
to Ajit, Margaret, and Rusty, and Pascal
because I know your passion
for this really this Carta meeting has been spectacular,
and always has impressed me
every time I've come to visit.
So since I've been a graduate student,
I've been interested in the genetic differences
that make humans unique,
and if you're interested in this question,
you have to be interested in essentially
what I think is the one of the most remarkable things
which is the expansion of the frontal cortex.
So showing here are two radiograms
comparing essentially human and chimp
and what's remarkable, and I'm non anatomical expert,
but what is remarkable to me at least,
is that this expansion appears to have occurred
over a relatively short period of evolutionary time.
It's thought that most of the expansion
from a 400 cubic centimeter brain
to one of 1,300 cubic centimeters
happened over a couple million years,
and then while there's still some debate on this,
this is generally associated with the increase
in the overall neuronal count.
Perhaps more impressively
an increase in number of synaptic connections,
in the human lineage,
and actually an increase in specialization, plasticity
and a delay in maturation
which seems to be what often
some people refer to neoteny in the human branch.
Along with all of this
has been increased metabolic demands,
so the brain actually of humans
sucks up about 40% of our caloric intake,
and the question I've always wondered is,
how did that machine
called the human brain really evolve
and how did it evolve so quickly?
As a geneticist,
we've always had a problem,
and the problem is is that humans and chimps
at least at the single base pair level,
are very very similar to one another.
So in the old days when people looked at chromosomes,
they looked at the chromosomes of chimps and humans
and they found that they were relatively few
large-scale genetic differences that would distinguish them.
In fact there were ten
that were identified back in the 1980s
and most of those events actually happened
on the chimp lineage compared to the human.
When we had the ability
to sequence genomes for the first time
and we sequenced that of the chimp,
one of the first genomes after humans and mouse,
we found that we were almost 99% identical,
so the current number is about 98.7% identical
to single base pair level.
This means that the proteins
that are found in our cells
are more than 99% identical
with estimates of close to 30% being identical
between a chimp and human.
And to make matters a little bit more worse,
when people have started to carefully
analyze most mutational processes,
you've heard people refer to this already as the slowdown,
chimps and humans are retarded
with respect to mutational process
our processes have slowed in general,
compared to almost every other primate.
So for species that are so,
appear to us at least being so radically different,
the question is how did that happen?
So geneticists have come up
with different approaches to explain this,
some have argued that,
no maybe it's just a few key transcription factors,
so regulators, master regulator genes,
that could affect a lot of cascading differences,
maybe that's the key.
And you can think of FOXP2,
some of you have heard of this gene,
this is the gene that Svante Paabo
has characterized with respect to language development
is one of those master regulators
where changes for some reason
happened specifically
on the human lineage,
other people have argued that,
well maybe it's many different genes
but it's how they're regulated themselves,
so instead of the proteins,
it's when and where these genes are expressed.
So this is kind of this regulatory hypothesis
put forward by King and Wilson in the 1970s.
Maynard Olson when he was
an active member of Carta,
talked a lot about the less-is-more hypothesis,
he referred to humans as the hastily made over ape,
and that the way we emerged was by losing genes,
instead of actually gaining genes,
and so there's evidence for this,
so genes important in terms of myosin
and particularly in the muscles of the jaw,
we've lost genes that are important in terms of function.
Some work from Majid
in terms of characterizing genes important
in terms of sialic biology,
sialic acid biology,
have been lost specifically in our branch.
I have been interested in a fourth of really model
and that is I referred to at one time with Maynard
as more is better,
so if his is less is more, mine is more is better,
and it's like the idea of duplicated genes.
So genes that have actually
are different between humans and chimps
that we haven't recognized,
that have emerged since we diverged as a species
from the other Apes.
So there's evidence for this,
and I'm not going to describe
how this was generated,
this took several students lives,
(Audience laughing) at least when
they were in my lab.
Each line here represents essentially a different
human or non-human ape.
So there's a hundred
or technically 96 different genomes
that you're looking at,
and what I'm showing you here, in color,
are all the copy number of variable regions
that exist between humans,
we are technically the top ten lines
which you can't see,
and then all the other apes.
And I show you this and so the copy number
is indicated by that color scheme at the bottom,
so whenever you see red
that means that that piece of DNA
exists ten times in one species
as opposed to let's say others,
black means it's a single copy.
So the really important thing
is that when you look at this map
and you actually just do simple arithmetic
and ask how much of our genome is different
between humans and apes,
as a result of copy number differences
in duplicated sequences?
It's about three times the number
that you see for single base pair changes.
So big changes that involve the gain and loss of genes
but particularly the gain of extra genes,
is a very prominent or prevalent mechanism
for creating genetic variation,
not just between the Apes and us
but also among us as a species.
So we can do it, when you do the math
it's about three times the amount of genetic bases
that are affected by this process,
it affects about 745 genes
and most of these regions,
are not sequenced and dissembled
when we generate draft genomes of any species,
this isn't specific to humans or apes.
If we project this onto
a generally accepted phylogeny of humans and apes,
where the thickness here,
represents the amount of duplicated material
that has been added
at different time points during evolution,
something really striking emerges,
is in this period of time,
before chimps humans and gorillas separated,
the African Apes, there was a huge excess
of duplication in the ancestral lineage.
So for every base that was actually changed
as a result of single base pair substitution,
there were 2.6 bases that were added
as a result of duplication.
So remember I told you all mutational processes slowed
moving toward the Apes, not this one,
this one actually picked up,
we don't know why,
but we know that there's a huge amount
of that variation that you see,
as a result of this duplication activity.
So is there any evidence
that the genes that make us human
at least in terms of the expansion of the brain,
have anything to do with duplications?
There have been in the last six years,
papers that have come out,
pretty much from every corner
that have suggested that these genes
in particular are contributing
to the evolution of a large brain.
So the first is a gene called SIRGAP2C
and just to tell you what that gene does,
that gene is expressed early in development,
and it's important for producing dendrites
on the surface on your neurons,
so dendrites go to form spine,
spines go to form synapses
and the reason you can listen to me right here,
is because of those connections
that are being fired as a result of those synapses.
This gene has duplicated specifically in humans
since divergence starting about 3.2 million years ago,
and the duplicate actually interferes
with the function of the ancestor
such that it takes longer for dendrites to actually form,
such that when dendrites form,
they are in fact more of them,
resulting in an increase
in the number of synaptic connections.
So is work from largely Franck Polleux's group.
So this would explain increased connectivity
as a result of a duplicate gene
that interferes with function of the ancestor.
This is a gene called ARHGAP11B, it's a duplicate gene
it's specifically in the human lineage,
it diverged right after humans and chimps separated
about 5.2 or 3 million years ago,
it's expressed specifically in cells
in the developing brain
which are progenitors for the production of your neurons
and it's been shown by beautiful work
but largely by Vielen Hudner
that the expression of this gene
if you put it in other organisms
will actually increase the number of cell divisions
of these progenitor cells
such that when neurons are produced,
there are more them
because you've actually increased
the number of neuronal progenitor cells
as a result of the expression of this gene
so this would be a gene that's responsible
for increasing the number of neurons in the frontal cortex
and actually in most experiments,
they can show that the mice brains
begin to girephy
when you introduce this gene into the mouse.
This last example is when we worked with
David Haussler on NOTCH2NL,
this is a duplicate gene
that duplicated just less than three million years ago
in the human lineage,
it's again expressed in these neuronal progenitor cells
but its role appears to actually
delay neuronal progenitor differentiation
so neurons are ultimately produced
but when they're produced,
there's a delay in their production
which is one of those hallmark features
of the development of the human brain.
So what's remarkable to me about these is that
most of these are nearly fixed in the human population
even though they arose very, very recently
so every human in this room has
two copies of the functional copy,
almost each one of these genes is incomplete
with respect to the ancestral function
so if you think about a gene being so big,
these are almost always truncated versions,
in fact their action depends upon
essentially them not being complete.
And the thing I don't have time to go into
is that these same regions
actually create instability in our genome
that leads to us having children with autism,
developmental delay and epilepsy.
So the liability in part
for us having increased risk of these diseases
is due to the emergence of these novel genes
that confer we think function
in terms of the human brain.
The last one I'll mention
which I think is absolutely one of the most interesting
is that when we looked at archaic genomes
that of Denisova and Neanderthal,
the biggest difference that exists
between us and Neanderthal and Denisova
is a large duplication
that has expanded specifically not just in humans
but on the Homo sapiens lineage
since divergence from these from these other species
500,000 years ago.
This duplicated segment is expanded in all of you,
it's not found in any of the
sequences of Denisova and Neanderthal
that we've looked at with Svante Paabo,
it contains four genes, those genes are important
in terms of essentially neurotransmitter reuptake,
their genes are important in terms of recombination
and interestingly their genes are important
in terms of iron metabolism
so there's a gene in this particular region
that seems to be associated with
more stable iron recruitment,
I'm speaking to the last speaker,
this is I think quite interesting.
Coming back to the disease angle,
this duplication which is Homosapien specific
contributes to the second leading cause,
at least genetically, of autism in human population,
in other words the placement
of these duplicated sequences
creates instability that doesn't exist or wouldn't exist
in Denisova or Neanderthal or chimpanzee
and this is the second most common cause of autism
in the human population.
What's the future and what's the problem?
The problem is what I'm showing you here,
is that our sequencing of genomes
has been largely incomplete over the last
10 to 20 years and the number,
and the best way to look at that
is to look at these different genomes
that have been sequenced
and look at the number of gaps that remain
or at least remained as of two years ago
in each of these genomes,
we've put far more money
into the sequencing of the human genome
for many good reasons but really it's like
apples and oranges when you start comparing it
to other organisms, other primates
and you want to actually discover the differences
that make us uniquely different or unique.
So new technology has emerged over the last
three or four years,
in the sequencing world we call it long reads
so instead of using short reads,
we're now using reads
that are 15, 20 hundred thousand base pairs in length
and we can now sequence and assemble genomes
at a scale that was really unparalleled,
we can now sequence
and we show a proof of principle of this
when we sequence the gorilla genome,
it was an 800 fold improvement of the previous genome
which we had essentially 400,000 gaps
and now we have less than 1,000 gaps
so when we analyzed those genomes
we can now discover structural differences
that are actually specific to gorilla,
specific to human as a result
so we've done, and I'm an advocate for this,
sequencing great apes at a higher quality
than what we've done before,
not just one from each species,
I think we need to do all subspecies
and we need to do all,
we do need to do multiple representations.
As you can imagine,
the money for doing humans is already there,
the money to actually do apes is not
but NIH in a moment of weakness
actually gave us the money to do three or four
and so we've been able to complete that
and what I'm really excited about
is that we're now assembling genomes of
gorillas, chimps, and orangutans
without guidance from the human reference,
we're doing it from first principles
and this is revealing large amounts of genetic difference
that we previously didn't recognize,
we're also sequencing the genes
instead of borrowing them from the human genome,
we actually now have the ability
with the same technology
to sequence entire genes from that species
and from the tissues of those species
that we're interested in.
So the good news is that we can now build trees like this
for more complex genetic variation,
this is just showing you
insertions, deletions, and inversions
that are specific to the human lineage
as a result of that sequencing
and as a result,
we've actually doubled
the number of regions of the genome
that we think are functional
in terms of regulation
that actually had been lost
on the human lineage since diversions
so we essentially doubled
the number of candidate genes to study going forward
and we've also been combining this data
with people like Rusty Gage and Franck Polleux
as well as Alex Pollan
to look at the areas
where there's structural differences in genes
and look at the essentially the brains of humans, chimps
well we can't look at chimp brains per se,
we can actually use something called cerebral organoids
which is a surrogate
for the development of those brains
as well as Macaque primary tissue
and look for the intersection between genes
that have undergone structural change
versus genes that now show specific differences
in the expression of the human brain
compared to the other apes
and I won't go through this diagram
other than to say there's two important conclusions
that we've made,
when we look at the genes
that are differentially expressed
between a chimp developing brain
as determined by cerebral organoids
versus a human what we find is that
genes that essentially are associated
with the lesions of regulatory sequences
tend to be the genes
that we see more likely to be
reduced in expression in the human brain
so this is the less the more hypothesis
and genes that are upregulated in the human brain
tend to be associated with those genes
that I showed you in that color map
that have specifically duplicated on our lineage,
so very non-random, new set of genetic variation
that is largely coming from the ability
to sequence genomes at a higher quality.
So in summary there's been a lot of progress,
I would argue over the last two decades
in terms of identifying candidate genes,
it was probably at least
and no geneticists would agree upon this
but on the order of 25 I think good candidates
that have functional data that are out there.
Copy number changes between the genomes of the apes
is in fact much more abundant
than single base pair changes,
that seems to be of irrefutable at this point,
this has accumulated in a non-random fashion
over evolutionary time with most,
over a third of that activity
happening in a common ancestor
leading to human, chimps, and gorillas
and I would argue that somewhere between
a third to the half of the best candidates
that are out there for the differences
that make at least the human brain unique
involve expression differences of genes
that have undergone structural changes
between humans and chimps
including the emergence of entirely new genes
on our lineage and if you're a student in this area,
it's a wonderful time to be alive
because you can actually do
what used to cost us you know a billion dollars
to do for the very first human genome
in an individual lab working on projects
to identify the genic differences
that make us human.
Thanks.
(audience applauding)
(upbeat music)