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programs. ♪ [music] ♪ - [Narrator] We are the paradoxical ape:
bipedal, naked large-brained. Lone the master of fire, tools and language, but
still trying to understand ourselves. Aware that death is inevitable, yet filled
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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] ♪ - [Tony] Thank you very much. So I
couldn't have asked for a better introduction for what I'm going to talk to
you about here today. We've heard from several of the previous speakers about the
genetic legacy of interbreeding with Neandertals. But I'm very interested in
understanding what, if anything, is the phenotypic legacy in modern human
populations. Is this Neandertal DNA that remains in us, is it functional and if so,
what function does it have? And so, as we've seen thanks to the pioneering work
of many of these previous speakers, we know that Neandertal DNA remains in
certain modern human populations. And if we look at a schematic of a human
chromosome here, you can think of this as a long string of As, Ts, Cs, and Gs, I've
colored in blue all the locations where we've ever observed someone living today
to have Neandertal DNA in their genome. And if you sort of look across many, many
thousands of European and Asian individuals, you'll see that on average,
around 2% of their genomes are derived from Neandertal interbreeding. As we've
observed, different people will have a different 2%. My 2% is different than Ed's
2% is different than Anne's 2%. And I want you to remember that because this is a
really important feature that we're going to use later to try to understand the
function of these different bits of Neandertal DNA that remain in our genomes.
And some parts of our genome are more likely to retain Neandertal DNA than
others. So in one extreme, we see these Neandertal deserts, like the position here
on the right-hand side, where we've never observed anyone to have Neandertal DNA.
And then on the left-hand side, we have the other extreme where we have up to 60%
of European individuals, if you went out and sequenced a bunch of European people,
would have Neandertal DNA at that location. And so, ultimately this suggests
that Neandertal DNA had an influence on our ancestors after the interbreeding, in
some cases perhaps positive, in other cases perhaps negative. And so for me,
this raised a very big question that I really wanted to answer is, okay so then
what is the phenotypic legacy of this Neandertal interbreeding and the DNA that
remains from it in modern humans? And so, I hope, if you remember nothing else from
my talk, really just two main points. The first is that indeed interbreeding with
Neandertals has left a phenotypic legacy in modern humans. And the way I'm going to
go about trying to show what that legacy has been is using a sort of a new type of
resource that's just becoming available, and that's of large clinical bio banks
with electronic medical records from patients from hospitals linked to genetic
information. And this is a really, really powerful resource for studying the
genetics of disease, but I also think it's a really, really powerful resource for
studying genetics of our recent evolution. And so, if you want to, you can go to
sleep now and just remember those two things and I won't blame you. So,
basically, we got the idea for this project because I collaborate with a big
national consortium called The Electronic Medical Records and Genomics Network. And
what this is, it's a collaboration of about 10 academic hospitals from across
the nation that have electronic medical record systems implemented in their
hospitals and also, genetic information from those patients linked to their
electronic medical records. And so this looks a little something like this where
on the left-hand side we have John Doe's patient records, he's been coming to the
hospital and seeing doctors, let's say, for the last 10 years. And we've got
records of all those events and all the treatments he's received in that
electronic form. And then some day, John comes in to have blood drawn and he says,
"Yeah, actually it'd be okay if you use any leftover material from this blood draw
for basic medical research." And if he's consented to do that, then all that
information is sent through a de-identifying process where all the
identifying information is removed from that electronic medical record, but the
basics of the treatment history are maintained. And then the blood sample is
also passed through and bio-banked and given an ID that links it up to that
anonymized version of the electronic medical record. And now this is really
powerful because it enables us to do genetic association testing on a very
large scale. So what is genetic association testing? Well, let's imagine
we've got a number of patients here for which we have these bio-banked blood
samples. And let's say we're interested in studying something about their genetics.
Well, we can look at these blood samples and see at one given position in their
genome whether or not they have an A, T, C or G. And so in this example, patient one
has an A, patient two has an A and then patient N has a G. And let's say we're
also interested in heart disease and whether or not this particular location in
those patient's genome has any effect on their risk for heart disease. What we can
do is then go look in their electronic medical record and say, "All right, well
has this person ever been treated for heart disease?" And let's say in this case
we find that yes patients one and two have and then patient N has not. And once we
have that information, we can perform statistical tests for association between
these individuals' DNA at that given position in their genome and whether or
not they've ever been treated for heart disease. And so in this simplistic example
we might say that, yes having an A at this location in your genome increases your
risks for heart disease. Now, of course, we don't normally do this on three people,
we do this on tens of thousands of people to try to find significant associations
between regions of our genome and disease. And so now this is all well and good but
let's say we're interested in another disease. Let's say we're interested in
arthritis and the genetic basis for arthritis. Well, if we didn't have this
electronic medical record system, we'd have to go out and collect a whole other
cohort of people that had arthritis and then some match control people that didn't
have arthritis and then genotype them and then test whether or not their genetic
loci had any effect on the risk. But because we have the electronic medical
record system, we can instead just go look in the record and say, "All right, let's
find a new set of cases and controls for arthritis and perform genetic association
tests again on the genetic information we already have." So, that's all well and
good but we're here because we care about human origins and human evolution. So
let's get back to that. How can we use this kind of data to answer this question
about the effects of the Neandertal DNA that remains in modern human populations?
And so what we did was to start with data from this large emerged Electronic Medical
Records and Genomics Network from across the country. We got data for about 28,000
patients from across the country. And we first looked at their genotypes. We first
found genetic information from about 600,000 positions across their genomes.
And so you can think of this as a stream again of about 600,000 As, Ts, Cs and Gs
that we've associated with each one of these patients. And then, what we realized
we could do was use these great, high-quality maps of Neandertal DNA that
remains in modern human populations that you've heard about from Sriram and Josh.
And so we could look at those maps and then intersect them with our own patients
and apply those techniques to our patients' genomes and identify regions
where each patient had Neandertal DNA. And so we could do this for about 1500 of
these positions in these patients' genomes and we can see where some may have
Neandertal DNA and others may not. And then finally, the last piece, as I
indicated before, comes from using this electronic medical record data to define a
set of phenotypes or traits for each of these patients. We can ask for hundreds of
different phenotypes covering the whole spectrum of things you might be treated
for by a doctor whether or not each of these people either had that disease they
were a case, or they were control, or we couldn't really figure it out and we
should leave them out of the analysis. And so then using this matrix of data of
genetic data annotated with Neandertal ancestry and then many, many different
phenotypes, we were able to start testing for the effects of Neandertal DNA on a
much broader scale than really had been possible before. And so before I get into
what we actually find, I'll try to be a good scientist and think about what we
would expect to find before actually running the experiment. And so what did we
expect? Now, as modern humans migrated out of Africa where they first appeared, they
encountered a number of different environments. So they encountered
different climates, you know, different levels of sun exposure, different
temperatures, different sort of seasonal patterns. They also encountered different
animals and plants that led to different diets. And, very importantly, they also
encountered different pathogens. And so it's been proposed that perhaps, by
interbreeding with Neandertals and Denisovans and perhaps other archaic human
forms that had been living in these environments for hundreds of thousands of
years in many cases before anatomically modern human groups ever arrived there,
perhaps there really was some adaptive benefit you could get from, you know,
spending a night with a Neandertal, maybe that was not such a bad trade-off. But
yeah, this is really a hypothesis, this hasn't been shown at all. So under this
hypothesis we might expect that the Neandertal DNA that could have been
adaptive in our modern human populations would have been influencing human traits
that are involved in interactions with the environment. So things like our immune
system, of course, one of the most important, but our skin perhaps, and you
know perhaps also our metabolism or other traits related to our diet. And so, we
also expected that well, we might see some effects on our bone or skeletal structure
because we also know about many important differences, our many very easily
detectable differences between the bones of anatomically modern humans and
Neandertals. So those are some of the things we were expecting as we went into
this analysis. So, what did we find? And now, in doing this analysis, we decided to
split up our data, our 28,000 individuals into two different sets, a discovery
cohort of about 13,500 individuals which we'd run an initial analysis. And then a
replication cohort in which we'd tried to replicate anything that we found in that
first cohort. So in the discovery, I'm going to show you just some of the top
associations we found between Neandertal DNA and potential phenotypes in a European
ancestry anatomically modern human populations. And so, when I saw this I
almost couldn't believe it because what we see at the top, we see osteoporosis, a
bone trait. Then we see hypercoagulable state. So what is that? That's just blood
clotting, your blood's too thick, it clots too much which can lead to all sorts of
problems. Then we see protein-calorie malnutrition, a metabolic trait. And so it
really surprisingly matching sort of what we expected. But before I go too far into
interpreting these, let's talk about that replication analysis I mentioned. So what
we did here is we looked at the other 14,500 individuals we left out of the
initial analysis and tested to see whether we saw a consistent effects in that group.
And so, luckily for four of these top associations I'm telling about, we did see
something consistent, we did see a consistent effect. Unfortunately, the
osteoporosis one that did not replicate there. And I should say just as an aside,
I don't think that necessarily means it's not true but it's sort of notoriously
difficult sometimes to replicate these genetic associations and we're following
that up in some other cohorts. So, let's focus on these four that did replicate. So
first we have this hypercoagulable state association that I already talked a little
bit about. So this means that your blood coagulates very quickly. And this is
actually a very important part of the early immune response. The coagulation
factors, like really some of the first proteins that pathogens interact with when
they come into your body. And so this really fits in with this idea of the
potential immune benefits. And we've looked into the molecular basis for this
association and we've actually been able to show that the Neandertal DNA
nearby...sorry, this Neandertal DNA that is associated with increased coagulation
increases the level of several nearby coagulation factors in your blood. So we
have a very compelling sort of molecular mechanism for how that might be happening.
And now, I'm sure by now you've read the rest of this list and seen one that's sort
of a little bit more difficult to interpret, right? And that's tobacco use
disorder. And so that really just means an addiction to nicotine. And so, I think,
you know, should we be thinking about this? Were Neandertals sitting around
outside of caves smoking? And I want to say unequivocally no. We cannot say this,
we should not say this, we should not think this. This extreme example
highlights a really important point, that the effects of genetic variation in modern
environments may not actually reflect its effects 50,000 years ago against a very
different genetic background in Neandertals or in early human/Neandertal
hybrids. And on top of that, of course, tobacco is a New World plant, they didn't
really have nicotine existing in their environment. But what this does tell us is
that Neandertal DNA in modern humans is influencing a system in our body that is
now, in modern environments, relevant to this trait. And in particular this bit of
Neandertal DNA is very nearby a transporter for a neurotransmitter called
GABA that's involved in all sorts of important processes in the brain and, you
know, even may have a role in circadian processes. So we don't really know what
might have been behind this association. So, now just to move on, I want to tell
you about one more analysis that we did. So in that first set of tests, we were
testing for the effect of one bit of Neandertal DNA with one trait in the human
population. But we wondered, well, what if we looked at all the Neandertal DNA that a
person might or might not have in aggregate, and ask whether or not that
could better predict someone's risk for a disease. And so we did an analysis of
that. And again, we found several very interesting associations that replicated.
And now I think this top one is really fascinating. It's Neandertal DNA. If I
know your Neandertal DNA compliment, I can better predict your risk for actinic
keratosis. And this is a...in case you don't know, this is a skin disease. It's
not terribly serious, it's often seen in fair-skinned people after long-term sun
exposure. And it's caused by malfunctioning of a type of cell in your
skin called keratinocytes. And I find this so fascinating for really several reasons
because keratinocytes, one of their main functions is protecting our skin from UV
radiation. So again, a very important environmental difference between Africa
and other non-African environments. But they're also really intimately involved in
early stage of the immune response, in signaling for the activation of other
immune factors. When we look the patterns of where Neandertal DNA falls in our
genome, we see that many of the Neandertal, high-frequency Neandertal bits
of DNA are nearby genes that are involved in keratin biology. And so this is sort of
taking it to the next step in showing not only is it enriched nearby those genes,
but actually in modern populations, it's having an effect on a phenotype that's
very relevant to keratin. But again here, we'll see there's a second kind of
confusing, or at least more complicated to interpret association that we need to
think about and that's depression. And so again, I really want to be very clear that
this is not what we should be thinking about. Neandertals, we cannot say they
were depressed, we cannot blame them for any depression we have. These are very
complex phenotypes with major environmental components and many of the
genetic components. And the Neandertal influence is really quite modest in the
whole constellation of all the contributions to them. So in conclusion, I
want you to remember that interbreeding with Neandertals has indeed left a
phenotypic legacy in modern humans. And in particular, it's left effects on many
different systems in our bodies: our immune systems, our skin, our metabolism
and in fact, even likely our brains. And so I think largely because of the nature
of the data sets we've been looking at, we found many cases where the Neandertal DNA
has a mildly deleterious effect in modern environments, but again I want to remind
you that's not necessarily true 50,000 years ago when this interbreeding likely
occurred. And so, one of the main challenges going forward is trying to
understand what knowing something about Neandertal DNA in a modern environment can
actually tell us about what was happening back then. And so then, the second point I
wanted you to remember is this was all enabled by using a new type of resource,
these large scale databases of tens or hundreds of thousands of electronic
medical records from patients linked up to genetic information. And so I think just
as the ability to sequence people's DNA at large scale has dramatically changed our
understanding of the genetic basis of human evolution over the past 5 or 10
years thanks to many of the speakers in this symposium, I think that leveraging
these sorts of data and these sorts of projects that are popping up all over the
world will allow us to do the same thing for the phenotypic basis of recent human
evolution. And so with that, I would like to say thank you all very much for
listening and thank all of my collaborators, and yeah. ♪ [music] ♪
