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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.
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I'll be discussing Human Adaptation to
High Altitude and Aquatic Environments.
I'm sure, for these audience,
a slide like this is
rather familiar where we're looking at
distinct patterns of variation within our species,
and specifically for this talk,
we're looking at how population history or
natural selection impacts the variation we see today.
I am working in a physiology department where we're often
thinking about components and
subcomponents of physiology,
and we really are interested in these systems when
things go awry and result in some disease.
However, on the other side of the coin,
we can look at adaptation to particular environments.
Some examples of that include sickle cell disease,
skin pigmentation, and even lactase persistence,
which we've heard about in previous CARTA symposia.
In these cases, we have some examples of what
we refer to as convergent adaptation
where two different populations,
in this case, of European and African ancestry,
are able to digest milk into adulthood,
and individuals perhaps with a certain skin pigmentation
are maladapted to a particular environment.
These classic approaches in physiology can be very
useful for looking at traits in
human populations as well.
Then thinking about genomics
and the parallels with physiology,
here we're looking at pathways and networks, and again,
we'll pay attention to
these systems when they result in disease.
When we're looking at studies of disease,
we need thousands of cases and thousands of
controls to identify genetic targets.
However, if we're looking at studies of
adaptation within our species,
we can capture enough information from
25 individuals to really
pinpoint some of these genetic factors,
and then we can link those back to the physiology as
in all of those examples I showed you previously.
We can use a lot of
these novel tools to
answer long-standing genetic questions.
There have been many studies completed in populations
throughout the world showing
genetic signatures of selection.
For today, I'll be focusing on high altitude, and
also populations that have
adapted to diving; aquatic environments.
We'll start by discussing some of the work that we've
done in areas near Mount Everest and Machu Picchu.
I've stolen that from our National Geographic Grant,
but really, just going to a lot of these villages
to try to understand adaptations and maladaptations.
Now, high-altitude environs are really one of
the most extreme regions that humans have
occupied and lived out
for thousands and thousands of years.
If we think about populations in
the Tibetan Plateau who have
been there anywhere up to 30-40,000 years,
the Andean Altiplano for
12-14,000 years, or even the Ethiopian Highlands
where people have moved into and out of high altitude and
intermediate altitude regions for
tens of thousands of years.
Each of these populations provide
a natural experiment for
examining the human response to hypoxia.
Now, if we look at
just a snapshot of these different traits,
we can have a sojourner,
somebody who's visiting altitude,
or some of these other highland populations.
If we compare different traits across these groups,
we can see that there's
really a collection of unique traits.
There isn't just one thing that's different,
but really a number of different factors to consider,
and I should point out these could
be adaptive or maladaptive.
Now, one of the traits that's been most
extensively studied is hemoglobin concentration.
If I look at hemoglobin concentration, again,
hemoglobin being the molecule that
transports oxygen throughout the blood,
in male and female Andean individuals,
you can see that the levels of hemoglobin are much
higher at this high altitude, so 4,000 meters.
The range that you would expect to see
here in San Diego or at sea level,
is shown here in red,
but if many of us went up to high altitude,
we would increase our red blood cell production as well.
However, when you look at the Tibetan population,
we see that their hemoglobin concentration is comparable
to what you would expect at sea level
even though they're at 4,000 meters.
Clearly, they have some mechanism to maintain
lower hemoglobin even though they are at high altitude.
Let's start by talking about the populations in Tibet,
4,200 meters above sea level.
We start out with our hypothesis that there would be
certain genes involved in altitude adaptation,
specifically those involved in
hypoxia sensing and response,
and this is the hypoxia-inducible factor pathway.
It controls hundreds and hundreds
of genes within our genome,
and then we perform
two different types of tests for selection.
We generate this list of selection candidate genes and
what we're really interested in is
that overlap of functional candidates,
things that we think might be involved in adaptation, and
those that are showing this really
striking pattern in the genome.
What does that pattern look like?
Well, we refer to it as a selective sweep.
If I took a population, say
from several 100 generations ago and we
looked at their genome and we
lined up a single segment of
their genome here and compared it within the population,
we might see that these black dots
representing the variance that
we have compared to our reference really
don't show a particular pattern.
However, if there is
an individual who has a beneficial variant,
and that variant increases over time, again,
hundreds of generations could
eventually become fixed within the population,
it leaves behind this really
striking pattern in the genome.
We can look at that pattern to find
these incomplete or complete selective sweeps.
Now, I've been showing you cartoons over here,
but really, these are the actual data that
we obtained from Tibetan individuals.
Again, just lining up
their chromosomal segments at these particular regions
revealed that there was in fact a selective sweep at
some of these hypoxia-inducible factor pathway genes.
Hopefully, you can appreciate when I
show the Han Chinese genomes that there is
a very stark contrast and so there is
definitely a signal that we're
seeing in the Tibetan genomes.
Next, we wanted to test whether or not
these genetic markers were
associated with a particular phenotype,
in this case, hemoglobin concentration.
What we found was in fact, that with more copies of
the adaptive region, an individual
tended to have a lower hemoglobin concentration.
Interestingly, we have now been able
to look at whole-genome sequences where before we were
just looking at those single variants or
those flag posts throughout
the genome to pick up those patterns,
but once we look at the whole genome,
we were able to find that in fact,
there were some archaic variants there.
I'm sure many of you have actually done
23andMe and perhaps you know your Neanderthal profile.
I tried to look that up for the fellow speakers,
but I only came across Joanne's.
I don't know who Joanne is,
but she has 300 Neanderthal variants and that's
82 percent more of other 23andMe customers.
What you might also learn about
is your Denisovan profile.
This is another archaic population, and in fact,
there are regions of the Tibetan genome
that are more similar to
this population than any other human population.
What's been interesting to find is that some of
these adaptive genes are within
these regions of archaic introgression,
and in fact, this is one of the regions
that is linked to hemoglobin concentration as well.
Why isn't that there is
relatively lower hemoglobin concentration
in some individuals?
Well, we wanted to look at oxygen utilization,
so we decided to have
our participants complete a VO_2 max study.
This is peak VO_2 on the y-axis and
hemoglobin concentration on the x-axis, and what I
hope you can see is that individuals with
lower hemoglobin concentration tend
to have a higher peak VO_2,
which is a bit counterintuitive,
perhaps for some competitive athletes,
and maybe some people might be interested in how
to better utilize oxygen in certain situations,
and perhaps even for some of
the running that can be done.
But in all of those cases,
it's really just a slight advantage or
a slight increase of
hemoglobin that makes a big difference.
In these highland populations,
it's a different story where we're looking at
a really wide range of
variation and very strong selective pressure.
Here we see lower hemoglobin is
associated with increased exercise capacity.
We were interested in looking at how this relates
to the entire oxygen transport cascade.
Just to remind you,
lower hemoglobin concentration is
associated with adaptive changes in
Tibetan's DNA and increased exercise capacity,
and when we dug a little deeper,
we found that in fact heart and muscle function
as well as ventilation
were very important for this exercise capacity finding.
Then thinking about this breathing or
control of breathing in these populations,
it's been known for a while that
the hypoxic ventilatory response,
this is one of the characteristics I had
shown in the earlier slides,
is really distinct in the Tibetan population.
They appear to maintain
an elevated response compared to others,
including their Andean counterparts.
This is something we're working
on with the original authors of
this study to figure out
if there is in fact a genetic basis to this.
Now let's switch over to talking about
some of the populations in
the Andes that we have studied.
We feel very fortunate that they have
been so interested in working
with our team over the years to
complete a lot of this work to study not only adaptation,
but also maladaptation in this population.
There's something called chronic
mountain sickness that is much
more common among Andeans
compared to Tibetan highlanders.
There are a slew of unfortunate outcomes
that are associated with chronic mountain sickness,
and one of the key differences is
this excessive erythrocytosis or
this overproduction of red blood cells.
Many of those have phenotypes that parallel
those that we see in pulmonary disease.
We think this could be, in fact,
attributed to some of
these differences in the control of breathing.
We have done work with
a number of investigators here at UCSD
and abroad to look at this question
in terms of oxygen saturation and breathing.
We've even done sleep studies at night.
What we find is that the lower saturations
are associated with higher hematocrit
as well as the time spent
below 80 percent oxygen saturation at night.
These things are likely contributing to
some of the maladaptive phenotypes in this population.
Switching gears back to the genetics,
there were a couple of genes that
I've mentioned so far, EPAS1,
which was identified as being introgressed
from the Denisovan population in Tibetans,
and then we found early stage selection of this gene in
Andeans as well as EGLN1.
This gene is associated with the hemoglobin in Tibetans,
and then the variants that we've identified there are at
low frequency or they're completely absent in Andeans.
But there were some recent work
done to show that in fact,
there are variants at this region that are
associated with exercise capacity in this population.
In addition to those
very important genes in the HIF pathway,
we have a number of
other candidates that have come
up in more than one study.
These are all studies based on the Tibetan population,
but when we look in other groups as well,
we can see that there are
additional evidence for targets
of selection in these populations.
Then to take that a step further,
we even see that in high-altitude species,
including deer mice and yak,
and even fruit flies that are studied here at UCSD.
Now we're thinking about some of the work,
not in the mountains,
but actually within the seas.
In our group, we have been able to
look at carboxyhemoglobin levels in elephant seals.
Specifically, this is the work of Michael Tift,
who is a postdoc in the lab and had done
some work at the Scripps Institution of Oceanography.
What he found is that these elephant seals had
carbon monoxide or the carboxyhemoglobin levels
that were comparable to a human cigarette smoker.
These are extremely elevated in that population.
Interestingly, one of the genes that we identified in
Tibetans is this heme oxygenase gene.
This gene is involved in the breakdown of heme,
and it's from the breakdown of heme that
you get carbon monoxide production.
We all have that small amount
of carbon monoxide that we produce.
One of the questions has become whether or
not Tibetans are benefiting
perhaps from these low
to moderate levels of carbon monoxide in their blood.
Now, I have been told that the Tibetans smoke so
much because they say it makes
them feel better at high altitude,
I don't know if that's the case,
but perhaps there is something to carbon monoxide.
There are a lot of studies now
looking at the therapeutic potential of
carbon monoxide and there could be
some interesting clues from these well adapted species.
Additionally, when we look in our Andean highlanders,
so this is Mike using the same exact instrument on one of
our favorite participants in Cerro de Pasco, Peru,
we see that there is, in fact,
a relationship of increased carboxyhemoglobin
with the total hemoglobin increase as well.
Now I have told you about the work in
the highland populations and I want to
focus specifically on Melissa Ilardo's work,
looking at diving populations,
specifically the Bajau in Indonesia.
This work was published just a few years ago in Cell.
Melissa went to Indonesia to collect samples
from this population in
addition to phenotype information.
One of her first questions that she wanted to
ask was whether the Bajau have larger spleens,
because they do very deep dives and
are able to hold their breaths for
extended periods of time.
In other marine mammals,
specifically, they have enlarged spleens which
serve as a reservoir for red blood cells.
What she found, in fact, is that in the Bajau population,
the spleens are quite a bit larger
than what she observed in non-Bajau.
These were neighboring populations who do not have
the same history of diving like the Bajau.
Unlike our study, she actually just took a saliva sample.
She wasn't looking at
hemoglobin concentration or any blood phenotypes,
but from the saliva,
much like 23andMe kit,
she was able to get genomic information.
She looked at some of the markers
scattered across the genome
and identified an interesting signal at the gene PDE10A.
This was among many different
important targets of selection,
but this one in particular
turned out was associated with spleen size.
If you compare the number of adaptive genetic copies for
this particular gene in the context of spleen size,
you could see that with more adaptive copies,
the individual tends to have a larger spleen.
Her work now in animal models is
suggesting that there is some increase in
thyroid hormone that is associated
with the PDE10A association.
A lot of this work that I've told you about,
both by our group and by Melissa,
is really a focus of
a center that we've developed here at UCSD,
so this is the
Center for Physiological Genomics of Low Oxygen.
Again, we're very interested in
looking at natural variation on
the spectrum of adaptive and
maladaptive phenotypes and genotypes,
and hope to continue a lot of this work
even across species in order to
better elucidate some of
the changes that have happened in
human populations in our evolutionary history.
In conclusion, we see that there are a lot of
adaptive factors in Tibetans and Andeans,
some of them are showing up as
the same genes perhaps with
different specific functional markers
that are associated with key phenotypes.
In the Bajau, we do see that there is
an adaptive signature that
is associated with spleen size.
Again, just important to keep in
mind for all of these studies that there are
these unique population histories that
really help shape the variation that we see today.
I would argue being cross-disciplinary in
genomics and physiology that we really
need to integrate across these fields.
With that, I'd like to thank all
of you for your attention,
the participants that have been
involved in all of our studies throughout the world,
in addition to all of the collaborators.
They say that it takes a village,
I say it takes villages all over
the world to make this research happen.
With that, I just want to thank everyone
and hope you enjoy the rest of the symposium.
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