CARTA 10th Anniversary Symposium: Matsuzawa Semendeferi Eichler


(whooshes) (clicks)
(beeping) (light piano music) – [Narrator] 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. (electronic chiming) (light music) – This is my pleasure to
talk about my study on comparative cognition in primates. Let me start from Japanese monkeys. Not many people recognize
there are no monkeys and apes in North America and Europe. You have no American monkeys. (crowd laughs) There are no British monkeys, French monkeys, German monkeys. But we have snow monkeys in Japan that helps us to do the study of primates that
is called primatology. In my case I have been
working with chimpanzees. Both in the wild in Africa and the laboratory in Japan. I have been to Congo, Zaire
to see the sister species called bonobos, very charming creature. And gorillas, mountain gorillas who live in Rwanda and Uganda. And I also went to Sumatra
and Borneo to see orangutans. So chimpanzees, gorillas, and orangutans, they make with us a family Hominidae. So traditional questions is as follows. What is uniquely human? Where did we come from? But however human is one of the primates, so a little bit new angle, new questions. I want to postulate, what
is uniquely primates? Where did we come from? So that is the key question today. So I’m focusing on horses. (crowd laughs) The representative of four leg animals. As you may know, the
common ancestor of mammals, four leg animals,
nocturnal small creatures in the era of dinosaurs. I like horseback riding and I
know many people love horses, but amazingly there are
very few scientific research on horses in comparison to dogs and cats. So human is unique. One family and only four genera, so humans, chimpanzees,
gorillas, and orangutans, but horses is also very
unique and special. Family horse has only one genera and one genus called Equus. So only one genus Equus
has similar species like horses, donkeys, and zebras. And a longtime friendship
between humans and horses going back to 5,500 years ago. But as I have told you, not
so many scientific publication about the horse as a whole, as a creature. So my talk is From
Primatology to Equinology, a new discipline that studies
the horses in the wild and in the laboratory. So my field site is in
Portugal called Serra D’Arga. We launched a new project
to study wild horses called Garrano in Portugal, using drones to know the spacial
distribution of individuals. And also we have identified
a total of 26 groups of more than 200 individuals. So application of primatology
as a way of research. Identification of each individual to do the longtime study. Even more in the parallel airport. We use touch screen computer apparatus. I have been using such
a thing for chimpanzees. So now horse can do it. (beeping) (crowd laughs) So touch the large one to the left, to the left, and to the right. So this is really brand new experiment to know the cognition of horses. And not only the size but also the shape. Please touch circle. (crowd laughs) Yes, that’s right. That’s right. So horse can do the
discrimination of the shape. Or even more, the number. Number of dots. Many? Which is many?
To the left. And to the right. And to the left. And to the right. Oops.
(crowd laughs) Or even more, horse succeeded to establish the concept of horse by always touching the picture of horses. The horse, four leg animals, the common ancestor of four leg animals, but 66 million years ago, a huge climate change
and all dinosaur gone. Then the common ancestor of mammals dispersed into different niches. For example, flying into the sky. So bats are mammals, giving
the milk to the offspring. So bats, please look at carefully. The fingers you can see. So four leg animals but flying to the sky. Now four leg turn to become like wing. And four leg animals
going down to the water like dolphins and whales. Now four legs transform to like fins. How about monkeys? Please imagine the monkeys in the tree. It’s not the sky, not the
ground, not the water, but in the trees. So this is really unique niche. To hold the branches the four leg turn to become four hands. So monkeys are four hands animals. Look like four legs, but if you carefully
look at the footprint, hand and foot, foot looks like hand. So four hands animals. Chimpanzees, yes. Hand look like hand, it’s foot. And even gorilla, it’s the same. The foot look like hands. Only human foot is unique. It’s not hands, people may misunderstand. Four leg animals walking and standing up and recreate unique hands. It’s completely wrong. Primatologist say four leg animals turn to become four hand animals. So what is uniquely primates? Where did we come from? We came from four leg
animals to four hands to adapt to our body and life. So lets go back to the
traditional questions. The answer is from four hands
primates to two feet humans. From four hands to two feet. That is my conclusion. So let me proceed to
my chimpanzee research to conclude my talk. I have been to Africa
to study chimpanzees. Chimpanzee do the vocal
communication called pant-hoot. (chimpanzee sounds) (crowd applauds) And you can hear the voice and then reply. (chimpanzee sounds) Is this language? It depends on the definition. So a completely different question. Do they learn human language or not? So my project is called Ai project is a sort of ape language study. I try to teach a chimpanzee in the primate research
in Kyoto University. So to make the long story short, I’m showing ongoing research, cognitive study in chimpanzees. So chimpanzee learn to
touch the Arabic numerals in an ascending order. And we tested the memory. (crowd exclaims) After touch one the other numerals gone. Okay, after touch one
the other numerals gone but chimpanzee can touch
two, three, four, five, six, seven, eight, nine in an ascending order, okay? Touch one, two, three, four,
five, six, seven, eight, nine. Touch one, two, three– Don’t worry, you cannot do it. (crowd laughs) Chimpanzee can do it but we cannot do it. So we are the first to
show that chimpanzee can be better than us. So I postulated cognitive
trade-off hypothesis. Trade-off between memory and language. Our common ancestor may have
this kind of immediate memory but we lost, in return
we got the language. So to know the details, please go to YouTube and
put Matsuzawa Tradeoff. There is a 24 minutes clip about this one. And already more than five million access in the past three months. So what is uniquely human? In short, my answer is imagination. The power of imagination makes us human. Power of imagination, we
can understand others mind. And based on understanding
of other’s mind, needs, we share, sharing and
giving is uniquely human. But chimpanzee also
show altruistic behavior in the forest giving a hand. Or chimpanzee there is a
unique way of education called master-apprenticeship to pass the cultural tradition from one generation to the next. Or even more, chimpanzee grandmother that were caught teaching
something grandson. So these kind of things are still waiting to be explored by the researchers. I want to continue the study
of chimpanzee in the wild and chimpanzee in the laboratory. So thank you very much for your attention. (crowd applauds) – So it’s great to be here. My colleague Jon Kaas
cannot be here today, but he shared a few slides with me and I’m gonna share them with you. It’s the first four
slides in my presentation. Primate brains very enlarged
in terms of variable size, so we have here a couple of examples. One is a human brain and
one is a microcebus brain. Huge differences in actual brain size. What we know is that we
can have mammalian brains that have similar brain sizes as a whole but many large differences in terms of the number of cells that they contain. In here we have an example of an owl monkey to the left, and an agouti mammalian
brain to the right. Early mammals, Jon
suggests, may have had about 20 cortical areas and this
construction is based on fossil records and also in comparison with extinct species. What you have here up left is a drawing that presents an earlier mammal. And from fossils of course,
we get information about shape, overall size, and some
patterns of convolutions. Recently, imaging studies
have reconstructed a couple of brains in
the context of a number of cortical areas that they have. So here we have an example
of a Macaque Cortex that is estimated to have about 140 areas according to this study. While the human cortex
according to another study has probably around 183. So the question that Jon poses is how many cortical areas do the rest of the primate species have
including the great apes. That’s an answer that is
not there in place yet. What is fascinating in
the line of research of mammalian evolution
is that things change not by just increasing in overall size, but also by actually
subdividing and multiplying. So what we have here is we have an example of a squirrel mammal
and a tree shrew that, if you see to the right of the image, to the histological section. It’s clear that these two animals have single nucleus that is
a posterior pulvinar. But if we look farther down to the galago, which is a prosimian, a primate prosimian, what we have is actually, we have a split of that
same nucleus into two. And a similar situation happens in other arthropod primates and so forth. So the question is how
do we get this new areas? What is the mechanism
that brings these areas and subdivisions about? Jon wants to remind us that
in primates, we have eight. Not three or four
parietal frontal networks like we have in other mammals. So actions like looking,
reaching, grasping, body or head protection, aggressive face, hand-to-mouth, running, are really controlled
by these neural networks in the parietal and frontal lobe. And the cortical area that
are involved in these networks are actually multiple,
they’re not just one. So he poses the questions, how are these networks organized in humans and do they differ between humans and our closest relatives, the great apes? So this is what brings us to
my part of the lecture today. How do we pursue human ape
neuroanatomical comparisons? So work on chimpanzees, gorillas, orangutans, gibbons and humans, are for some of us and
have been for pretty much everybody for the last
decades, out of reach. So the idea is a study of the
great apes and humans involved only noninvasive techniques and of course, also brain tissue, right? We need to have the brain
tissue to be able to study noninvasively the nervous system. The techniques that
exploded in the 60s and 70s and later in the field of neurosciences, were very promising and
very productive in terms of experimental and invasive
studies in animal models. We learned a lot and we
still learn a lot from that. But what about the human ape comparisons? So in the 90s, the
question of brain evolution after last common ancestor
was really out of reach. But if there is a will, there is a way. So there was an obvious
solution to that problem and that was reaching out
to zoos across the country and asking for brain tissue that results from natural
deaths of the animals. So that can be put
together with human tissue from donations from the
families of individuals who die. So that early effort,
collecting ape brain tissue and then also applying
those very, very new noninvasive techniques that started to become available for human studies. The structural MRIs got applied
to these postmortem scans and the brains that were, back then, put in these buckets and scanned in scanners meant to
be for human scanning. And then eventually that
project gave rise to living animals and living great apes. And those early seeds
of the work really moved to an organized, large
scale set of projects that gave us a lot of studies,
literally hundreds of studies since the 90s that involved
structural imaging, functional imaging of the
great apes and humans, and also a lot of valuable tissue. What have we learned? So we have learned a lot of things and it’s daunting of a
task to try to summarize, but I wanna bring up some,
really quickly, points that we learned that in some respects humans scale or exhibit
features just as expected for a primate or an ape including the white matter,
the corpus callosum size, the glia to neuron ratios, the proportion of inhibitory
GABAergic interneurons, the size and neuron of the
frontal lobe and frontal cortex. Yes, the frontal cortex
is three times larger in humans but so is the rest of the brain when compared to the great apes. We have macrostructural, microstructural and behavioral asymmetries
that are widespread and they’re not uniquely human as we used to think in the past. Dendritic branching gets larger in humans but overall follows primate trends. Axonal myelination also
is as expected for humans. Humans not as expected. So we have reduction of
the primary visual cortex, increase of the temporal lobe, we have increased size of neuropil space, and many other things. And I wanna focus on some of them in the time that I have. So number and size of cortical areas. Well, how many do we
have and how do we differ from other primates when it depends on what we compare ourselves to? So if we compare humans to macaques, we have the picture up there to the left. We have certain areas that are
much, much larger in humans. But if we compare ourselves
to the chimpanzees, then the picture changes. One area that seems to stand
out is the frontal pole of the prefrontal cortex, and yes even though the frontal lobe has not enlarged this
proportionally in human evolution, some cortical areas in the frontal lobe actually have changed. And the argument I want to
make here with you today is sort of in line with
what Evan and Dan brought up earlier today in the meeting, in that those areas that have
changed in human evolution may seem to be more
vulnerable to disorders, including neurodevelopmental disorders. The questions for the future are, well, what happens to the other cortical areas and how large are they? We still have not had a
chance to address that. Density and number of neurons, evolution. We have bigger brains, have more neurons. We have decrease in cell density. And there is a lot of variation and that depends on where
exactly we are in the brain. It’s not homogenous. In neurodevelopmental
disorders, interestingly, the prefrontal cortex is one of the areas that seems to be extremely
vulnerable to disease. And what I have here is an example from a study on autism and controls where we have an overproduction of neurons in the prefrontal cortex in autism. And we have also prefrontal
cortex been affected in other disorders like
William syndrome for example. Cortical minicolumns, so the density in the brain, in the cortex, does not just vary homogeneously
across cortical areas, but it’s specific to
where we are in the brain, what layer you are in
the brain, and so forth. So early in development in
the cortex, what we have is the cells align in columns
very closely, cluster together. And as individual grows
older, those minicolumns tend to go farther apart. If we compare monkeys to
chimpanzees and to humans, so very big difference in terms of size, humans have the wider space
between their minicolumns. What we found is that actually after the last common ancestor with great apes, these size of the minicolumns
again is very specific to where in the brain we look at. And one of the areas
that has changed the most seems to be in the frontal pole. So it is that area that
has really seen some dramatic changes in the
course of evolution. And on the right you see an example of minicolumns in autism and controls. In autism, the minicolumns
are actually collapsing. We have many, many more cells
than we have in controls. Dendritic branching. I did not pay, I want to
introduce that for me, but that’s what we see in
the phenotype in the brains. Dendritic branching is very important. So this is how neurons
communicate to each other. They determine the number of spines and interconnections that the cells have. So what you have here in
the big drawing on the left is typical cortical neurons in layer three in various parts of the cortex. And it just so happens that
areas that have high integration like area 10 and other parts
of the prefrontal cortex tend to have larger branch neurons than the lower integration in the cortex. In the chimpanzees we
have a similar pattern but the overall tree is
smaller across the brain. Interestingly,
neurodevelopmental disorders exhibit a lot of problems in the way that the cells branch and develop. And what you have at the bottom here is an example of how area 10 has been compromised in William syndrome. A fascinating story has
to do with the amygdala. So we think a lot about the cortex when we talk about brain evolution but the reality is that
everything in the brain works in terms of systems and circuits. So a very important finding replicated by different lines of work
in different laboratories has shown that the lateral
nucleus of the amygdala is actually much larger in
humans than in great apes and is also affected differentially in William syndrome and autism in exactly opposite directions. Of course that becomes
even more interesting when we think about the fact that the temporal lobe
in humans is actually larger than expected. Unlike the frontal lobe,
temporal is larger than expected and it just so happens
that the lateral nucleus is highly interconnected
with the temporal lobe. Of course neural systems, it is very important to bring up this very elegant line of
work by Leah Krubitzer here, because nothing in
evolution of humans and apes in terms of the brain makes sense outside the
light of mammalian evolution. The example here shows
you a blind mole rat that still has a visual
cortex in its brain and also an entire neural
system is still in place. It has not really
disappeared in this animal, but guess what, it has been
co-opted by other senses. So it functions in a different way, co-opted by the auditory system. Now experimental work in her lab has shown that if you bilaterally inoclate the normal opossum, what
you have is not only difference in the cortical
areas in that animal, but also a substantial change in how projections from the thalamus
go to the visual cortex. So it’s not only the cortex that changes, it’s also the subthalamic nuclei. And also the other nuclei
in whatever neural system we are thinking about. So I’m gonna skip these slides
in the interest of time, although we have very interesting findings on the striatum in the
myelnation of actions. The question now becomes
how can we blend the work on animal models with noninvasive studies on humans and the great apes. What is homologous in terms of function? Because that’s really what matters, right? What does it mean to
have a structure in place that no longer performs
its evolutionary function but is co-opted by another one? How do we tell them
apart in humans an apes? We have this new line of
work, this new technology than just peripartum stem cells, which is gonna be discussion probably in the next 10 year celebration of CARTA. But this gives us the power to describe and to experiment on
developmental differences on humans and the great apes in the dish. And I brought up a couple of examples on control and Williams syndrome
and then apes and humans, that show the power that putting together classical neuroanatomy techniques with this invasive experimental techniques in the dish can give us. So can we put the phenotype
and the mechanisms together? That’s a question for the future. The way I envision the
next 10 years of CARTA is putting together the
information from the genome to that of life near us in the dish. The tissue and the brains, the imaging, and then put that together with the bones in the fossil record, and of course all of that in the context of the whole organism
and the social context because we are social primates after all. And I would like to leave you with these three questions that
I think are very important, not specific to my field,
but are very important for our future. We are faced today with unprecedented technological advances. Should our future be driven by technology, or by our questions? What about the impact of our science, who will be in charge? Who is responsible? The STEM, so the sciences,
engineering, technology needs to work together
with social sciences, and the humanities. And I think that this combination is what makes CARTA training unique. And that’s the way of the future. So thank you very much. (crowd applauds) – Congratulations first and foremost to Ajhid, Margaret, and Rusty, and Pascal. ‘Cause I know your passion for this, for me this CARTA meeting
has been spectacular and always has impressed me
every time I 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 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 not 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 while there’s still
some debate on this, this is generally associated with an 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 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 it 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 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
there were relatively few large scaled genetic difference that would distinguish them. In fact, there were 10
that were identified back in 1980s and most of those events 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 a human. And to make matters a
little bit more worse, when people start to carefully analyze most mutational processes, you have heard people
referral to this already as the slow down, 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
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 could have think of FOXP2, some of you have heard of this genus as the gene that Svante
Pääbo was characterized as with respect to language development as one of those master regulators. Where changes for some reason happen specifically on the human lineage. Other people have argued that 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 Olsen 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
emerge was by losing genes instead of actually gaining genes. And so there’s evidence for this. Genes important in terms
of mice and particularly in the muscles of the jaw, we’ve lost genes that are
important in terms of function. Some work from Mahjeed on terms of characterizing genes
important in sialic biology, sialic acid biology, have been lost specifically in our branch. I have been interested
in a fourth early model and that is, I referred to
it one time with Maynard, as more is better. So if his is less is more,
mine is more is better. And it’s 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 gonna describe
how this was generated. This took several students’ lives, at least while they were in my lab. Each line here represents essentially a different human or nonhuman ape. So there’s 100, or technically 96 different genomes that you’re looking at. And what I’m showing you here in color are all the copy number variable regions that exist between humans, we are technically the top 10 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 10 times in one species as opposed
to lets say others. Black means it’s single copy. So the really important thing is that when you look at this math 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 assembled 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, were the thickness here
represents the amount of duplicated material that has been added at different times
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 based 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 variation that you see is the 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 gene called SRGAP2C. 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 spines, 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 is duplicated
specifically in humans since divergence starting
about 3.2 million year 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 number of synaptic connections. So this is work largely
from Frank Pelo’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, largely by Velon Hutner, that the expression of this gene, if you put it in another organism it will actually increase
the number of cell divisions of these progenitor cells. Such that when neurons are produced, there are more of them ’cause
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 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 gyrophy when they introduce this gene into the mouse. This last example is when we worked with David Housner on, NOTCH2NL. This is a duplicate gene that duplicated 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 a 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 denisovan neanderthal, the biggest difference that exists between us and neanderthal denisova is a large duplication that
has expanded specifically not just in humans, but on
the Homo Sapiens lineage since divergence 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 denisovan neanderthal that we
looked at with Svante Paabo. It contains four genes. Those genes are important in terms of essentially neurotransmitter reuptake. They’re genes important
in terms of recombination. And interestingly, they’re genes 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. And speaking to the last speaker, this is I think quite interesting. Coming back to the disease angle, this duplication which
is Homo Sapien specific, contributes to the second leading cause, at least genetically, of
autism in the human population. In other words, the placement
of these duplicated sequences creates instability that
doesn’t exist or wouldn’t exist in denisovan, 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 sequences 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 not using reads
that are 15, 20, 100,000 base pairs in length. And we can now sequence
and assemble genomes as 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 analyze those genomes, we can now discover structural differences that are actually specific to the 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
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. So we’ve been able to complete that. And what I’m really excited
by 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 exists that we
previously didn’t recognize. We’re also sequencing the genes. Instead of boring them
from the human genomes, we’re actually now have the ability with the same technology
to sequence entire genes from the species and from the tissues of those species that we’re interested in. So the good news is that we
can how build trees like this for a 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 prefunctional
in terms of regulation that actually have been lost on the human lineage since divergence. 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 Frank Pelo as well as Alex Poland
to look at the areas where there’s structural
differences in genes. And look at 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 macaque primary tissue and look for the intersection between genes that have undergone
structural change versus genes that now
show specific differences in expression of the human brain
compared to the other apes. And I won’t go through this diagram other than to say that 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 deletions
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 is more hypothesis. And genes that are
up-regulated 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. Which probably at least, and no geneticist 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
irrefutable at this point. This has accumulated
in a non-random fashion over evolutionary time with over a third of 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 involved 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 a billion dollars to do
for the first human genome in an individual lab, working
on projects to identify the genetic differences
that make us human. Thanks. (crowd applauds) (upbeat music)

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