Lecture on the evolutionary impact of malaria on humans

I like sometimes to say
that everything I know about human genetics
I learned from malaria and there’s some
real truth to that. For one thing I first
learned human genetics from Frank Livingstone,
Frank was an anthropologist who specialized in understanding
the role of malaria in human adaptation
and evolution. He worked in West Africa
to uncover the mechanics of the famous sickle cell allele
and how it resists malaria, he also focused on the
way that allele interacts with other genes that
have adapted to malaria and he was one of the leaders in understanding how different
genes contribute to adaptation to this very important trait. So from that standpoint I
really did learn at the knee of somebody who was
focused on malaria as a factor on human evolution. But the other way in which
that’s true is that malaria and its effects on humans
have imposed selection in many different patterns
so that when we look at the different patterns of
selection that have resulted from malaria and patterns
of chance evolution that have resulted
from malaria in humans. We’re really looking at
the text book in the way that humans can respond
to selection and evolutionary forces. Mutation, genetic
drift, natural selection and migration are all
incredibly important in the way that they interact to give
rise to today’s pattern of malaria adaptations. So understanding how malaria has
affected us is really a good way of understanding how human
evolution more generally has happened. Now to talk about malaria
first I want to introduce you to the malaria parasite, malaria
is not caused by a bacterium and it’s not caused by a virus,
it’s caused by a protozoan and that protozoan single celled
organism has a very complex life cycle. Now most people probably
know that malaria is spread by mosquitoes so a mosquito
bites an infected person, draws in that person’s blood
and that blood is infected by the protozoan, the parasite. That parasite has life cycles
that it begins to unfold within the mosquito’s gut. As it draws in your blood it’s
drawing in if you’re infected from malaria it’s
drawing in gametocytes, male and female cells that have
sex inside of the mosquito’s gut and give rise to eggs, oocytes. Those oocytes go through a
stag within the mosquito’s gut and develop into
spores, sporicides. Those sporozoites are
then possibly infectious to other people who are
bitten by the mosquito. So mosquito who has
these sporozoites in its gut comes along,
it bites another human and there’s a blood exchange, the sporozoites enter
the human’s blood from there they take root in
the liver and malaria goes through a life stage within the
liver of an infected individual. The malaria parasite breeds,
becomes more and more common and ultimately when it’s come to being common enough
it bursts into the blood. In the blood it affects red
blood cells, it’s at that stage that malaria can be transmitted
to another mosquito and passed on to another individual. Its one single celled
organism that goes through this complex series
of very distinct life stages and each of those
contributes to its trickiness as a parasite it’s very
difficult for our immune systems to deal with these
different phases that malaria goes through. It’s in the liver
for a while but just as your body is beginning
to notice it, it bursts into blood cells
and it’s in your blood cells for a while and as your
body begins resist it it’s transmitted to another
individual. That cycle of being infected, going through an asymptomatic
phase that can last a week or two suddenly having
fevers that knock you down because you’re blood
cells are going through cycles of being destroyed
by these parasites and having mosquitoes
bite you and transmitted to another individual, that is a
very complex life cycle and one that makes it hard
for us to fight. Well, malaria has become
an important disease killer in populations across
the tropical world. It remains very important
today in tropical Africa, in tropical Southeast Asia
and to a certain extent in the tropical Americas. It has been important
historically in a much broader area
into the subtropical and temperate regions of
Europe, of west Asia, south Asia and of the Americas including
the American south during the 18th and 19th centuries. Malaria has had a very wide
geographic distribution that’s had a huge effect on
human populations. But what most people
don’t know is that malaria as a human parasite
is relatively recent. Okay, malaria that
infects humans around the world today
occurs in multiple forms, each of these forms is a
different species of malaria, the two major species of
malaria are falciparum malaria and vivax malaria. Falciparum is the most
virulent of these, it causes the most severe
symptoms and it’s most common in tropical Africa
although it also occurs in tropical Asia including
south Asia and Southeast Asia. Vivax malaria is often
associated with Asia, it’s most common in
south and Southeast Asia but it also occurs
widely in tropical Africa. These two parasites have
different histories, falciparum malaria is closely
related to the chimpanzee and gorilla versions of
malaria, the reichenowi malaria. It probably has come into humans
within the last 5,000 years, it’s in other words a
very recent immigrant into human populations. Vivax malaria is a little older
it’s come into human populations within apparently the
last 40,000 years but both of those are actually
very recent, malaria parasites have infected
primates for millions of years and through most of
human evolution it looks like we were not effected by the malaria parasites
that exist now. The two that are major in
human populations are recent immigrants, that being
said we have lots of very, very strong genetic adaptations
to these two forms of malaria, the most famous of these
is the sickle cell trait. Sickle cell trait is a
trait in which you look at red blood cells under a
microscope they have a slight tendency to become
elongated, sort of oval shaped, at an extreme those ovals
deform into the shape of a crescent moon
or a sickle shape. The sickle cell anemia, the
disorder that’s a result of the sickle cell allele is
something that effects people when they have two
copies of the allele that in one copy creates
a sickle cell trait. The sickle cell trait
is adapted to malaria, people that carry one copy of
this gene have a resistance to falciparum malaria that
people who have no copies of this gene don’t have. In other words one
copy is advantage, causes you to survive
more from malaria, causes you to have a better
survival in a malarial area. Two copies of the allele however
are bad, if you have two copies of it your blood cells form this
sickle shaped form very commonly and that form has trouble
getting through the capillaries of your blood, it’s
filtered out by your liver, you have an inability to
create enough blood cells to maintain normal metabolism and without advanced medical
care you’re very unlikely to survive into your
teenage years. So sickle cell anemia is a
very serious genetic disorder, it’s one that occurs in
people who have ancestry from the populations where the
sickle cell trait is common and that’s principally
populations of west and central Africa just
below the Sahara Desert, a major malaria belt. The sickle cell trait is also
relatively common in Pakistan and some nearby areas
of south Asia and in the Persian golf area
there is both the allele that causes sickle cell in
south Asia and the allele that causes sickle
cell in Africa combined because that area of the world
has a history of Arab trading with both of those areas. So we have sickle cell in a
very characteristic distribution that’s coincident with
the malaria distribution in those two areas of the
world and sickle cell seems to adapt people to malaria. It’s a famous example
because it invokes a balance, people who have two copies of the sickle allele have
the disadvantage but people who have no copies of it
also have a disadvantage, the balanced polymorphism
one copy of the sickle allele and one copy of the
normal allele that balance polymorphism
has been retained in human populations for
a few thousand years. Well, that’s a very well
known example and many of you will have heard
of that example before. But it’s far from
the only example and from sickle cell we
can generalize a bit, the sickle cell mutation
is a mutation to a gene called beta globin
and beta globin is one of the essential components
of hemoglobin the molecule in blood cells that
carries oxygen. The way that sickle cell
works is by altering the form of hemoglobin when
it is oxygenated so that the red blood
cell membrane takes on a slightly different
configuration, that different configuration
is more difficult for the malaria parasite to
infect and so malaria has less of an ability to have
catastrophic health impacts on people who carry this one
copy of the sickle trait. But the sickle allele in two
copies has a much larger effect on the geometry of
those blood cells and the consequence they have a
much greater difficulty adopting the normal form. The blood cells have
a greater surface area than would be expected
for their volume, they’re not little [inaudible]
they’re slightly dimpled and that dimpled shape allows
them to conform their way through the small
vessels of your body. If you exaggerate that they
get caught on each other. So the way that they
resist malaria is by altering the geometry of the
surfaces of those blood cells. Other mutations to beta
globin have the same effect, so there’s a condition
called beta thalassemia. Beta thalassemia
is much more common than the sickle cell trait,
beta thalassemia is common in populations around
the Mediterranean and also some populations
of sub Saharan Africa and there are distinct beta
thalassemia mutations that occur in south Asia and the
southeastern Asian populations. Beta thalassemia unlike the
sickle cell trait doesn’t create a slightly different
functional version of beta globin it breaks
beta globin altogether. So that your blood cells
carry a different form of the hemoglobin molecule a
certain percentage of the time. That also interrupts the
malaria parasites ability to effect blood sells but it
does so by breaking a gene, so here we have two
mutations to beta globin, one of which changes the
function of the normal molecule, the other which breaks
the normal molecule. Both of them have been
favored by selection in malarial populations
because malaria is such a severe selective impact
that you’re body would want to do anything to try
to reduce the frequency of your being effected by it. There are other
hemoglobinopathies that are associated
with malaria, hemoglobin C is a
different version of the beta globin molecule
that’s found in West Africa. Hemoglobin E is a different from
that’s found in Southeast Asia, alpha thalassemia is a condition that affects the alpha globin
molecule, the other component of hemoglobin and it’s
also commonly found in malarial areas. The association of these
hemoglobinopathies, these disorders of
hemoglobin with areas where there are malaria was
noticed in the late 1940’s by J.B. S. Haldane a famous
population geneticist. Haldane speculated the
reason why these are found in malarial areas is that they
cause resistance to malaria, that hypothesis was
confirmed as people began to understand the function of
these things and to observe that the way that the malaria
parasite actually affects blood cells. So we see two different
mechanisms of mutation, one of which breaks genes and
one of which changes genes and we see them unfolding
in different populations. I asked Frank Livingstone
one time why is it that these populations all
have different versions of these hemoglobinopathies,
you’d expect that the best one would be found
everywhere, so hemoglobin E for example does not have the
really severe side effects of the sickle cell trait, why is
it that hemoglobin E isn’t found in west Africa where
sickle cell is common. And Frank said to me it
just didn’t happen there and that illustrates a
really important fact about natural selection in human
populations, it has to happen in a population, the mutation
in order to be selected in the population,
not only that it has to survive the first
few generations when it’s initially rare. A mutation that happens
that valuable that doesn’t survive those first
few generations will never be established in a population. A mutation that doesn’t happen
will never be established in a population. Different genetic
strategies have been lit upon in different human population. Different genetic
strategies have been lit upon in different human
populations because of chance, chance has influenced the
way that we’ve adapted to this force, malaria
which is present so broadly in different populations today. We can look beyond hemoglobin because the malaria
parasite has caused dozens of mutational changes to
different human populations. Melanesian ovalocytosis
is another disorder of the blood that’s
common in Papua New Guinea and areas nearby in Melanesia. G6PD deficiency is a very
famous mutational change in North African populations
that’s an adaptation to malaria. t’s a gene that’s
on the x-chromosome and so the deficiency
involved, the inability to create an enzyme that
processes a protein found in the diet that deficiency
is most notable in men but the frequency of this has
risen to very high frequencies in North Africa and is
noticeable in the diet. A allergy to fava beans
is called G6PD…is caused by G6PD deficiency. It’s called favism
and it’s found in Mediterranean populations
where fava beans are consumed and where malaria has
historically been common. Several blood types are
involved in malaria resistance, the famous ABO blood
type is one of them as you know people can be
type A blood, type B blood, type O blood or type AB blood because this gene ABO
has three alleles. O blood has a greater resistance
to malaria and is more common in places that have
a history of malaria. Another blood type
that’s involved in malaria resistance is the
Duffy antigen, Duffy is named after a person named Duffy because unlike the ABO blood
types the Duffy blood types doesn’t usually create a problem
with transfusions but in people that have transfusions many,
many times during the course of their lives sometimes
they’ll raise an antibody to one of the Duffy blood
types and that was true of a person named Duffy in 1950. A hemophiliac who
had gotten blood from many different individuals
and began to display an antigen to a new receptor that people
hadn’t realize occurred on blood cells before. Each blood type is a
receptor that’s on the surface of a blood cell and the
Duffy blood type occurs in three forms, A, B
and O we call them. It’s not the same as
the ABO blood type but because there’s three
we call them A, B and O and functionally they’re
pretty much the same. The O blood type in ABO does
not make the normal product, it makes a knockout product, it’s not making the
normal product that’s on the surface of cells. The O blood type for Duffy,
likewise makes a knockout, it doesn’t create the
normal blood type people who carry Duffy type O are
resistant to vivax malaria and that Duffy O blood
type is very common in sub Saharan Africa, that
occurs in as many as 95 percent of people in some places
south of the Sahara. It’s very rare in other
populations of the word so one reason why vivax
malaria today is less severe in Africa is that the population
has developed a resistance to it and that resistance
was introduced with the Duffy O blood type
as much 30 thousand years ago. So we have an ancient resistance
that’s emerged in a population as a function of the presence
of vivax malaria but that hasn’t yet spread by gene flow
to far off populations where vivax malaria
remains important. So why is it that we
think malaria began to invade human populations
only recently and was absent from them in the distant past. We think this because
of a genetic change to a gene called CMAH, CMAH
is an enzyme that’s necessary for the transformation
of one type of sialic acid into another. The sialic acids are sugar
chains that are found on the surfaces of
most of your cells. One particular type
of sugar chain in glycolyl neuraminic acid
is the infection pathway of plasmodium reichenowi
the malaria parasite that affects chimpanzees
and gorillas. That pass way is present because
the normal action of CMAH which allows the
precursor molecule in aceto neuraminic
acid to be processed into the N glycolyl
neuraminic acid. Well, humans have undergone
a mutation to the CMAH gene that deactivates it, an axon of the gene was removed
during our evolution so that the precursor molecule
has stacked up on the surfaces of our cells and the
glycolyl neuraminic acid that reichenowi uses to invade
cells is not longer produced in big quantities. What that means is that Plasmodium reichenowi
the major parasite of our close relatives
does not affect humans, it doesn’t have the
infection pathway. Now from the genetics
of CMAH it looks like that gene was deactivated
as early as 2 million years ago in our evolution, this must
have been a wonderful event for ancient humans because once that deactivation became common
malaria no longer had a purchase on our population. Where [inaudible] presumably
had the ability to be affected by the malaria parasite
that affect our relatives. Homo did not, that event
may have been as important in our evolution as almost
anything else we could imagine creating an opportunity for our
lineage to expand and evolve through the tropic free
of this ancient malaria. As all good things in
life it was temporary, the reichenowi parasite
developed a way to invade our cells and by doing so it invades today the
sialic acid that we express on ourselves, the
precursor molecule, the acetyl neuraminic acid. It did so by evolving
into falciparum malaria. So we have a new parasite that’s
come into human populations and has learned to
deal with the trick that our ancestors developed
to avoid it that window of opportunity through which
humans evolved and may have had as big an impact on us as
anything else was invisible to us until we could look
at the genetics of malaria and how humans have
adapted to it. But we now understand that
today’s malaria and the effects that it’s begun to
have catastrophically on our population our only
the most recent episode during which our population
has tried to and in some cases succeeded
in resisting malaria. We’re locked in a
cycle of challenge from this ancient parasite, it’s once again found our
population a large population that allows it to spread
throughout the world. Maybe we’ll with technology find
ways to defeat this parasite but at the moment our mechanisms
are the major mechanisms of natural selection, they
include the balancing selection on genes like sickle
cell, the long history of directional selection
on genes like Duffy they include
chance the establishment of different malaria
resistant alleles and different populations and they involve the complete
elimination of malaria through some parts of our
evolution and the reintroduction of malaria as a zoonosis,
an animal derived parasite into our recent populations. Everything I know about human
genetics can pretty much be categorized into those things
and so it’s a great example to understand how human
evolution has unfolded and also some of the invisible
aspects of our evolution that never the less
have a huge impact.

11 thoughts on “Lecture on the evolutionary impact of malaria on humans

  1. Damn! this video was so clear! fantastic, fascinating! thank you so much for sharing this John Hawks, greetings from Argentina!

  2. You do a very good job at presenting information in a clear and concise manner. You are one of the most valuable educators on YouTube. The information in your lessons have immense value to humanity. Thanks again for another great lesson.

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