[MUSIC] We are the paradoxical ape.
Bipedal, naked, large brain.
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. [MUSIC]
Ancient DNA analysis began
almost 40 years ago with
the technological advances associated with PCR,
and we're immediately applied to
questions about human population history.
One of the pioneers of
ancient DNA research was Svante Paabo,
who just won the Nobel Prize in Medicine and Physiology,
"For his discoveries concerning the genomes
of extinct hominins and human evolution."
In 1997, Svante Paabo led the first ancient DNA study of
a Neanderthal to try to assess
the relationship between Neanderthals and modern humans.
In this study, which I was part of,
we used ancient DNA methods to retrieve
a portion of mitochondrial DNA.
The mitochondrial DNA genome,
which is only inherited from your mother,
it really surprisingly,
I guess, suggested that Neanderthals and modern humans
were not related to each other in terms of interbreeding.
This was a major debate at the time.
However, as I said,
the mitochondrial DNA genome
is really a very small portion of
our genome and it's unlike the rest of
our genome in that we inherit it only from our mothers.
In 2010, the first study of
the full Neanderthal genome was published also
from Svante's lab, and this,
along with subsequent genome sequences
from additional Neanderthals
as well as another archaic human known as a Denisovan,
showed us that there was in fact
interbreeding among archaic and modern humans.
Here you can see that with
the blue arrows in the diagram,
and each of these shows at least one admixture event.
When you look at this,
what you can see is that there
were multiple cases of admixture
at different points in time among different hominins.
We see evidence of admixture between
early anatomically modern humans
and Neanderthals even prior
to the major expansion
of anatomically modern humans out of
Africa 50-70,000 years ago.
This is likely something that
happened during climatic periods
when the Sahara was
greener and that facilitated expansions,
little movements out of Africa and
interactions between separated groups.
Those were likely in the Middle East.
We see evidence of that archaeologically.
The genome data now support that,
that gene flow occurred.
In addition, we see insights into
the timing and number of admixture events.
We also see from the genome data,
which includes some really high-quality genomes,
what variation there was in the population,
what genetic variation and
what adaptations we can make
inferences about those as well.
From the variation, or actually rather
the limited amount of variation found in archaic humans,
we can infer that they had fairly small populations.
We also see evidence of inbreeding.
We can also compare the genomes of modern humans today to
see how much DNA we inherited from archaic humans.
What we see is that non-Africans have
about 1 to 5 percent archaic human ancestry,
that is from Neanderthals or Denisovans.
The distribution of this ancestry is not even.
It's not even geographically when we look at
populations from different places, for example,
people in Southeast Asia,
Island Southeast Asia in particular,
and Australia and the
Philippines have more Denisovan ancestry.
It's also not even across our genome.
I'll talk a little bit more about that in a minute.
Some of the archaic alleles that we
have in modern humans appear to be adaptive.
Examples have included alleles related to immunity,
skin pigmentation, and high altitude adaptation.
Now, evolution, which is the change in
allele frequencies from generation
to generation, hasn't stopped.
Ancient DNA analysis have
also shown us that the forces of evolution,
including selection,
gene flow or migration and genetic drift,
have been important during the Holocene as well.
Particularly related to the major shift in
subsistence from hunting and gathering to agriculture.
What questions remain and how will
additional ancient DNA data
build on the initial findings related to human evolution?
First, we can think about this in terms of
who, when, where questions.
Were there additional admixture events
with other groups of archaic humans?
If so, where and when?
We have limited data from Australia,
Southeast Asia, and Africa, in particular.
For example, we know as I mentioned,
that people in Ireland, Southeast Asia,
and Australia have more Denisovan ancestry
and you can see that
here on the map but we
don't actually have Denisovan DNA
from that region, from actual bones.
What we do know from looking at
modern human DNA with Denisovan admixture is
that there's likely
a different source population in terms
of the Denisovan population
that contributed to that ancestry.
It's likely a different source of population
compared with the individuals who lived
at Denisova Cave or that contributed to
Denisovan ancestry to the people
who live in mainland Asia today.
We can also use sedimentary DNA analyses and analyses of
ancient proteins in places where there are
no bones or there only tiny bone fragments.
This can be particularly useful in places
where we have a very complex stratigraphy.
For example, at Denisova Cave,
which is where we get the term Denisovan,
you can see this very complex stratigraphy and in
these different occupation layers using
these sedimentary DNA and
mass spectroscopy protein analyses,
we can infer whether Denisovan or Neanderthals or
even both were living in the cave at that time.
That's a really exciting feature to
be used at sites like Denisova Cave and elsewhere.
In addition, ancient proteins actually
preserve better than ancient DNA and
so these data can help
push identifications back in time and place.
We can also use
both the sedimentary DNA and the ancient proteins
to identify what animals these individuals were hunting.
As I said, in terms of identifying who
occupied the cave at certain time periods,
we can see what stone tools were they using
and then link potentially
Denisovans to other sites where we don't have DNA or
protein preservation and get a better sense of
their distribution both in time and space.
I think ideally these methods will be used in
combination with other archaeological analyses
and really let us put together a picture of a site.
For example the used areas,
If people butchered in one area
and maybe slept in a different area.
Help us identify both plant and
animal resources that they use and even show us
the biological relationships among individuals within
a group so that we can make
inferences about social organization.
In terms of what questions remain and how
additional ancient DNA data can build upon this,
we can also think about the legacy of
archaic admixture in modern humans today.
A number of really fascinating questions
remain one of which is,
why do we have so little Neanderthal
and Denisovan ancestry today?
Now, part of the reason is
that anatomically modern humans in a sense,
swamped out the smaller populations
of archaic humans over time.
But there's also evidence that some of this archaic DNA
may have been deleterious or slightly deleterious.
Analyses of additional individuals
who lived soon after admixture events,
as well as computer modeling can give us a better sense
of how quickly archaic DNA was lost.
In other words, a sense of the cost,
if there was one of archaic DNA in our own genomes.
We can look at the so-called ancient DNA,
or archaic DNA deserts in our genome.
This map here shows
a distribution of Neanderthal ancestry.
This is taken from a hundreds of genomes of
Europeans in East Asian genomes,
the regions that are Neanderthal or have
been found in East Asian genomes to have
neanderthal alleles are in red and
in blue are those
that have been discovered in European genomes.
One of the things we see several places where in
neither group is there
any Neanderthal ancestry so these white areas.
These are so-called archaic or Neanderthal deserts
in terms of the DNA in our genome.
We might ask why,
is that by chance?
Or is there something there that is
important for being a modern human and if so what is it?
What does it do and how does it
contribute to our phenotypes today?
Functional analyses may help us
figure out what these differences are
between modern humans and
archaic human gene variants in these regions.
We can also think,
what have we gained in terms
of alleles from archaic humans?
What is the adaptive legacy?
Neanderthals and Denisovans lived in
Eurasia far longer than we have,
and thus likely adapted to the environment.
We've identified some variants that affect
specific genotypes or specific phenotypes.
What we know is very largely
biased by the phenotype data that we have,
which is mostly medical in nature in
terms of having a real sense
of the distribution linked to clear genomic variance.
We also have a poor sense of more complex phenotypes,
which are really most
of the phenotypes we tend to think about.
The phenotype genotype data that we do have
is primarily from European populations.
We don't really have comparative data
yet for Denisovan variants,
which are mostly found in people from, as I said,
Islands of East Asia in particular.
Much of the variation that we do have is
likely to be regulatory in
nature or affect regulatory regions of our genome and
there are ways to infer gene regulation
specifically because methylation changes
or we can infer methylation patterns
which help turn genes on and
off based on damaged patterns
that we see in the ancient DNA.
This was done in a study by Gokhman et al to look at what
regulatory regions were methylated particularly
differently between archaic humans and modern humans.
Really interestingly, one of the regions
that was found to be very
different was associated with the face and
vocal tract in anatomically modern humans
compared with archaic humans.
This is an area where further work to tease out
these signatures and what they
mean will be very interesting.
I think we can look forward to
many exciting insights into
anthropogeny from ancient DNA research.
While I have focused on
the questions related to archaic humans,
there's also many interesting projects using ancient DNA
to understand human population history in the Holocene,
as well as the process of
domestication and the evolution of human pathogens.
I think we will have
a lot of really fascinating findings in the future.
I would like to thank not
just the organizers of this symposium,
but also the members of my laboratory and
the funding agencies who
have funded our research in the past.
Thank you very much [MUSIC]