News: Human evolution: Details of being human.
Ye Old One
doi:10.1038/454021a
http://www.nature.com/news/2008/080702/full/454021a.html
News Feature
Human evolution: Details of being human
A difference in one molecule led physician Ajit Varki to question what
sets humans apart from other apes. Bruce Lieberman meets a man who
sees a big picture in the finer points.
Bruce Lieberman
The human body does not welcome an injection of horse serum. Ajit
Varki discovered this when, as a young San Diego doctor in 1984, he
administered some to a woman with bone-marrow failure. The serum was a
standard treatment intended to stop the woman's T cells from
destroying her bone marrow. But it was also known to prompt a reaction
called 'serum sickness' and, sure enough, the patient broke out in
hives a week after treatment — the result, Varki assumed, of her
immune system's assault on proteins from another species.
Soon after observing his patient's reaction, Varki learned that
proteins weren't the only thing to blame. So were sialic acids, sugars
that carpet the surface of mammalian cells. Some studies had suggested
that the human immune system reacted against one sialic acid called
N-glycolyl neuraminic acid (Neu5Gc) in the horse serum. “How can that
be?” Varki remembers thinking. “How can you have a reaction against
sialic acid? It's everywhere. All mammals have sialic acid.” Varki
wondered whether humans might in fact be the only mammal that lacked
Neu5Gc.
A physician and biochemist by training, Varki had already embarked on
a career in the relatively new field of glycobiology, the study of the
sugar chains that decorate many proteins and lipids inside and outside
the cell. But it was another 14 years before he got the chance to
answer his original question. In 1998, he and his colleagues used
high-performance liquid chromatography to analyse blood samples from
chimps, bonobos, gorillas, orangutans and humans. They found that
humans are indeed the only primates missing Neu5Gc[1] and that human
cells are instead rich in another sialic acid, N-acetyl neuraminic
acid (Neu5Ac).
A career in evolution
These findings started Varki off on a road that led to his becoming
not only a leading glycobiologist but a respected 'honorary'
palaeo-anthropologist. He is one of the co-founders and directors of
the multidisciplinary Center for Academic Research and Training in
Anthropogeny (CARTA) — a research collaboration between the University
of California, San Diego, and the Salk Institute in nearby La Jolla.
The centre was launched in March this year with a US$3-million grant
from the G. Harold & Leila Y. Mathers Foundation, based in New York
state.
The 'Anthropogeny' in the centre's title resurrects a term for the
study of both the evolution and the individual development of human
beings that would have been familiar to earlier generations of
anthropologists. To Varki, the word encapsulates some of the biggest
questions in the study of human origins, such as how, why and when the
human brain evolved its present functions. One of his latest research
projects is a collaboration with Spanish palaeontologist Juan Luis
Arsuaga, of the Complutense University of Madrid, for the biochemical
analysis of 900,000-year-old Homo antecessor fossils from Atapuerca in
northern Spain, some of the oldest hominid bones yet found in Europe.
What Varki is looking for is evidence that Neu5Gc was lost very early
in human evolution. He believes that the fact that humans, and only
humans, have lost Neu5Gc could be implicated in the emergence of
hominid species.
The journey from glycobiologist to director of a multidisciplinary
human origins centre has been fuelled by Varki's insatiable desire for
knowledge. “The guy is just an encyclopaedia,” says glycobiologist
Mark Lehrman at the University of Texas Southwestern Medical Center in
Dallas. “Even though he wasn't trained in anthropology, he's been able
to educate himself in this area and become an authority. It's a
remarkable gift to be able to do that and do it well.”
Varki initially trained as a general medical doctor at the Christian
Medical College in Vellore, India. To pursue a dual medical and
research career, he went to the United States, eventually taking up a
fellowship under Stuart Kornfeld at Washington University in St Louis,
Missouri, in the late 1970s.
Kornfeld was beginning his work on sugar chains, including sialic
acids, and Varki was intrigued by the opportunity to contribute to a
largely unexplored area of biology. In 1982, he set up his own
glycobiology lab at the University of California, San Diego, where he
still works today.
On a molecular level, the difference between Neu5Gc and Neu5Ac is tiny
— a single added oxygen atom perched on one arm distinguishes one from
the other (see graphic). But on a biological level, the difference
could be enormous. “We thought if monkeys and all of our closest
relatives have Neu5Gc and humans don't, then there must be a molecular
basis for that,” Varki says. He subsequently found it in an enzyme
that converts Neu5Ac to Neu5Gc, but which is disabled by mutation in
humans[2].
Selection pressure
Varki's discovery pointed to a definitive difference that set chimps
and humans biochemically apart, says Morris Goodman, an evolutionary
biologist at Wayne State University in Detroit, Michigan. It was one
of the first such differences to be found, and because sialic acids
serve many biological roles, primarily as cell-recognition and
cell-adhesion molecules, it might explain some of the unique aspects
of human biology. “What we're dealing with here is a gene loss that
has an effect throughout the whole body,” says Goodman.
At the time, Varki realized he knew little about human evolution
except what he'd learned as an undergraduate or read in National
Geographic. So he set out to educate himself. He took a short
sabbatical at the Yerkes National Primate Research Center in Atlanta,
Georgia. Reviewing the animals' medical records with a veterinarian,
he learned that the centre had never seen a case of rheumatoid
arthritis or bronchial asthma — common conditions in humans.
Chimpanzees don't get sick from the human malaria parasite, Plasmodium
falciparum. Conversely, humans can't be infected with P. reichenowi,
the malaria parasite that plagues chimpanzees.
“What we're dealing with here is a gene loss that has an effect
throughout the whole body.”
Morris Goodman
In subsequent work, Varki and his team showed that the different
susceptibilities were due to the differences in sialic acids. P.
reichenowi prefers to grab hold of Neu5Gc on chimp red blood cells,
whereas P. falciparum favours Neu5Ac[3]. The researchers hypothesized
that the selection pressure to evade P. reichenowi may have led humans
to lose Neu5Gc and acquire resistance to this parasite — and that this
loss may have helped to fuel the emergence of P. falciparum, which
could gain entry by latching onto Neu5Ac instead. Other discoveries in
Varki's lab — including ten other human-specific genetic changes
affecting sialic acid function — may help to explain uniquely human
vulnerabilities to conditions such as Alzheimer's disease and multiple
sclerosis.
Varki's interest in human evolution soon extended far beyond chimps
and their sugars. “I found he was talking with several people on
campus,” says neuroscientist Fred Gage at the Salk Institute, a
long-time collaborator and friend. “I told him that it wasn't fair
that he would have these one-on-one conversations and not share what
was being talked about,” he jokes.
Reimagining anthropogeny
Gage encouraged Varki to organize a series of informal seminars on
human origins at the university. Between 1998 and 2007, the Project
for Explaining the Origin of Humans drew in anthropologists, primate
biologists, geneticists, immunologists, neuroscientists, linguists and
many others. They discussed topics ranging from the evolution of
language to the differences between humans, Neanderthals and Homo
erectus, the first hominid to leave Africa. Goodman says the
interdisciplinary nature of the series made it extremely important to
the field. “You really had the chance to explore an issue as it
relates to the evolutionary origins of our species,” he says.
Differences in sialic acids between chimps and humans alter
susceptibilities to some diseases.Differences in sialic acids between
chimps and humans alter susceptibilities to some diseases.P.
TWEEDIE/CORBIS
Varki's motivations were partly selfish: “One of my goals, my secret
agenda, was to educate myself,” he admits. “At the last meeting I
asked the people who attended if I could have a bachelor's degree in
anthropogeny.” Varki estimates that he has listened to more than 300
talks on various aspects of this discipline. “The idea is the linguist
needs to talk to the molecular biologist who needs to talk to the
neuroscientist who needs to talk to the psychologist and philosopher
about these issues,” he says. “Most areas of human knowledge are
somewhere relevant.”
CARTA is a successor to the human origins series. Directed by Varki,
Gage, Margaret Schoeninger, a professor of anthropology at the
University of California, San Diego, and Pascal Gagneux, a primate
biologist and Varki's close collaborator, the centre already has some
40 San Diego-based members and more than 100 in the rest of the United
States and elsewhere in the world.
CARTA aims to foster connections between these researchers worldwide,
facilitate access to resources for great-ape research, develop a
peer-reviewed journal and offer courses on human origins. The project
is in some ways comparable to the Leipzig School of Human Origins in
Germany, an interdisciplinary PhD programme run jointly by the Max
Planck Institute for Evolutionary Anthropology in Leipzig and Leipzig
University since 2005. Varki says that CARTA will be more of a virtual
organization and that “the effort should transcend disciplines”,
pointing as an example to his own work on sialic acids, which has
required collaboration between biochemists, palaeontologists and
physicians.
Acid test
Back in the lab, Varki and Gagneux will in the next few months embark
on the preliminary analysis of animal fossils from Atapuerca, to see
if they can detect preserved sialic acids using high-performance
liquid chromatography and mass spectrometry. If so, sialic acids are
likely to be preserved in hominid fossils from the same strata and the
researchers will test those next.
“Palaeontologists are usually seen as people interested in something
that is finished and belongs to the past,” Arsuaga says, “and usually
the idea is missed that we are looking for an explanation of living
humans.” He says he was persuaded to let tests be done on the precious
H. antecessor fossils because “the damage is not big” from current
techniques that drill small amounts of powder from inside the bone.
“Understanding where we came from is very important to
understanding where we're going.”
Ajit Varki
Varki and Gagneux hope that these fossils may help to answer some
grand hypotheses about Neu5Gc and its role in human evolution. They
estimate that the mutation that caused the loss of Neu5Gc first
appeared among human ancestors 2 million to 3 million years ago, which
coincides with the emergence of H. erectus, and they believe that
pathogens such as malaria may have initiated this change. They wonder
whether the change in this ubiquitous sugar could have had other
broad-ranging biological effects that helped create repro-ductive
isolation between those with Neu5Gc and those without, and whether
these effects could have contributed to the emergence of H. erectus,
followed by H. antecessor. “Losing Neu5Gc may have been great for
survival, but it may have forced you to forgo reproduction with a
whole group of your former buddies who didn't undergo this change,”
Gagneux says. If they can show that Arsuaga's H. antecessor fossils
also lack Neu5Gc, this will be yet more evidence in support of their
hypothesis.
If ancient humans can't answer the speciation hypothesis, then perhaps
mice will help. Varki and Gagneux have genetically engineered mice
that lack the Neu5Gc sialic acid that humans are missing and Varki
says that they display subtle human-like features[4]. Compared with
wild-type mice, they have poor hearing, somewhat reminiscent of human
age-related hearing loss, and slower wound healing, as do humans
compared with non-human primates. Further studies should reveal
whether these mice are able to reproduce with wild-type animals that
still have Neu5Gc.
Varki's recent work has brought him back to the immune reaction he
observed nearly 25 years ago. Even though humans don't make Neu5Gc, it
is eaten in animal products that contain it, such as meat and milk.
Varki and Gagneux wonder whether — among meat-eaters at least — Neu5Gc
elicits an immune reaction that might contribute to a whole spectrum
of human-specific diseases that are associated with chronic
inflammation, including heart disease and cancer. Such diseases would
not have been such a problem when humans had shorter life spans.
Food for thought
To test the idea, Gagneux took a trip to a local Whole Foods Market,
loaded up a shopping cart with meat and dairy products and took them
back to the lab for analysis. The researchers found the highest levels
of Neu5Gc in lamb, pork and beef. “We swallowed big bowls of that and
we collected every possible sample we could from ourselves in the
following few weeks to see whether it shows up in our own
glycoproteins,” Gagneux says, “and the answer is yes, it does.” The
team has also found that many people carry antibodies targeted against
the sugar[5].
If their hypothesis holds up, it will illustrate how selection
pressures change: where once selection favoured the loss of Neu5Gc to
protect hominids from pathogens, now its absence could be making
humans susceptible to other diseases. “Once you've lost it, you have
to make do with what you have,” Varki says.
For Varki, who began his professional life observing patients, these
studies have brought him full circle. The molecules that made humans
human may be the same ones that make us uniquely vulnerable to our
most threatening diseases. “In some cases, they would be what I call
the scars of our evolution,” Varki says. “My experience has opened my
mind to the fact that understanding human evolution, where we came
from, is very important to understanding who we are and where we're
going.”
Bruce Lieberman is a freelance science writer based in San Diego.
*
References
1. Muchmore, E. A. et al. Am. J. Phys. Anthropol. 107, 187–198 (1998).
2. Chou, H.-H. et al. Proc. Natl Acad. Sci. USA 95, 11751–11756
(1998).
3. Martin, M. J. et al. Proc. Natl Acad. Sci. USA 102, 12819–12824
(2005).
4. Hedlund, M. et al. Mol. Cell. Biol. 27, 4340–4346 (2007).
5. Tangvoranuntakul, P. et al. Proc. Natl Acad. Sci. USA 100,
12045–12050 (2003).
--
Bob.
Sapient Fridge
One <use...@mcsuk.net> writes
<snip>
>On a molecular level, the difference between Neu5Gc and Neu5Ac is tiny
>— a single added oxygen atom perched on one arm distinguishes one from
>the other (see graphic). But on a biological level, the difference
>could be enormous. “We thought if monkeys and all of our closest
>relatives have Neu5Gc and humans don't, then there must be a molecular
>basis for that,” Varki says. He subsequently found it in an enzyme
>that converts Neu5Ac to Neu5Gc, but which is disabled by mutation in
>humans[2].
>
>
>Selection pressure
>
>Varki's discovery pointed to a definitive difference that set chimps
>and humans biochemically apart, says Morris Goodman, an evolutionary
>biologist at Wayne State University in Detroit, Michigan. It was one
>of the first such differences to be found, and because sialic acids
>serve many biological roles, primarily as cell-recognition and
>cell-adhesion molecules, it might explain some of the unique aspects
>of human biology. “What we're dealing with here is a gene loss that
>has an effect throughout the whole body,” says Goodman.
Oh the irony of it, our DNA lost genes by mutation on the route from
chimp to human!
I have to ask our creationist friends, does this mean that the chimp
genome has more information than ours?
--
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Desertphile
wrote:
> A difference in one molecule led physician Ajit Varki to question what
> sets humans apart from other apes.
A: Digital wrist watches.
--
http://desertphile.org
Desertphile's Desert Soliloquy. WARNING: view with plenty of water
"Why aren't resurrections from the dead noteworthy?" -- Jim Rutz
Desertphile
It would be the common ancestor of Chimpanzees and Humans that had
"more information" than us humans (if an oxygen atom is
"information"). Or more specifically, a portion of the population
of that common ancestory had Neu5Ac, and the rest of that
population had Neu5Gc (which went on the human germ line).
Varki _et_all_ hypothesize that a single mutation (an enzime that
caused the loss of a single atom in a sialic acid) might be the
cause for better reproductive success in the environment that
mutation occurred in (a beneficial mutation that resisted
disease). If that mutation also caused reproductive isolation, it
was a speciation event.
This is very amusing, if valid. It means we not only see a
beneficial mutation occurring 2.5 million years ago, but we also
observe yet another speciation event. Someone should notify Kent
Hovind.
Desertphile
<deser...@invalid-address.net> wrote:
> This is very amusing, if valid. It means we not only see a
> beneficial mutation occurring 2.5 million years ago, but we also
> observe yet another speciation event. Someone should notify Kent
> Hovind.
I must be wrong: the mutation could not be a speciation event
because if it was the mutation could not be passed down to
descendents.
Cj
> On Thu, 03 Jul 2008 22:12:31 -0600, Desertphile
> <deser...@invalid-address.net> wrote:
>
>
>> This is very amusing, if valid. It means we not only see a
>> beneficial mutation occurring 2.5 million years ago, but we also
>> observe yet another speciation event. Someone should notify Kent
>> Hovind.
>
> I must be wrong: the mutation could not be a speciation event
> because if it was the mutation could not be passed down to
> descendents.
>
>
on? (citation?; logic; reason; other)
Cj
Desertphile
Logic and reason.
r norman
<deser...@invalid-address.net> wrote:
>On Fri, 04 Jul 2008 15:52:03 -0400, Cj <C...@mist.net> wrote:
>
>> Desertphile wrote:
>> > On Thu, 03 Jul 2008 22:12:31 -0600, Desertphile
>> > <deser...@invalid-address.net> wrote:
>> >
>> >
>> >> This is very amusing, if valid. It means we not only see a
>> >> beneficial mutation occurring 2.5 million years ago, but we also
>> >> observe yet another speciation event. Someone should notify Kent
>> >> Hovind.
>> >
>> > I must be wrong: the mutation could not be a speciation event
>> > because if it was the mutation could not be passed down to
>> > descendents.
>
>
>> Wow! What an interesting conclusion.... what is the conclusion based
>> on? (citation?; logic; reason; other)
>
>Logic and reason.
Logic and reason that ignores the observed facts on sympatric
speciation in plants by polyploidy.
Logic and reason that also ignores speciation in asexual organisms.
Logic and reason that didn't quite make the grade (or is it the
clade?)
June
I disagree, I think Deserphile is right about THIS mutation. Most of the
context got snipped, here's what Desertphile originally said about
speciation in this instance:
"Varki _et_all_ hypothesize that a single mutation (an enzime that
caused the loss of a single atom in a sialic acid) might be the
cause for better reproductive success in the environment that
mutation occurred in (a beneficial mutation that resisted
disease). If that mutation also caused reproductive isolation, it
was a speciation event.
This is very amusing, if valid. It means we not only see a
beneficial mutation occurring 2.5 million years ago, but we also
observe yet another speciation event. Someone should notify Kent
Hovind."
If a single mutation in a single individual ape caused reproductive
isolation, it couldn't cause a speciation event because that individual
couldn't reproduce, right?
--
My 2¢ ß-}
June
To email me replace 'go' with 'ville' and remove the .spam.jam
Sapient Fridge
writes
I'm not sure but I would guess Desertphile realised that the disabling
of the conversion gene would not stop the bearers of the mutation
interbreeding with the original population, but the mutation would still
spread because of the lower parasite susceptibility.
Interesting the *later* immune sensitivity to Neu5Gc may well be a
speciation event (as in it probably stops interbreeding with earlier
populations) but by the time it happened the entire local population
probably had the mutation already, so the newly acquired immune response
wouldn't make much difference.
It may well have just changed an isolated population from one that could
breed with the original population to one that couldn't, but if it was
isolated in other ways geographical (for example, or by an earlier
speciation event) then there would be no interbreeding anyway so our
species could have quietly separated without anyone noticing.
Sapient Fridge
<deser...@invalid-address.net> writes
>> Oh the irony of it, our DNA lost genes by mutation on the route from
>> chimp to human!
>>
>> I have to ask our creationist friends, does this mean that the chimp
>> genome has more information than ours?
>
>It would be the common ancestor of Chimpanzees and Humans that had
>"more information" than us humans
Routes can go both up and down though. Technically if you were to
enumerate all the mutation from chimp to common ancestor then back down
again to us then you would find that the gene was lost on the way
:-)
(yeah, I'm trying to recover face for my sloppy phrasing, I admit it)
Desertphile
<r_s_norman@_comcast.net> wrote:
> On Fri, 04 Jul 2008 17:54:22 -0600, Desertphile
> <deser...@invalid-address.net> wrote:
>
> >On Fri, 04 Jul 2008 15:52:03 -0400, Cj <C...@mist.net> wrote:
> >
> >> Desertphile wrote:
> >> > On Thu, 03 Jul 2008 22:12:31 -0600, Desertphile
> >> > <deser...@invalid-address.net> wrote:
> >> >
> >> >
> >> >> This is very amusing, if valid. It means we not only see a
> >> >> beneficial mutation occurring 2.5 million years ago, but we also
> >> >> observe yet another speciation event. Someone should notify Kent
> >> >> Hovind.
> >> >
> >> > I must be wrong: the mutation could not be a speciation event
> >> > because if it was the mutation could not be passed down to
> >> > descendents.
> >
> >
> >> Wow! What an interesting conclusion.... what is the conclusion based
> >> on? (citation?; logic; reason; other)
> >Logic and reason.
> Logic and reason that ignores the observed facts on sympatric
> speciation in plants by polyploidy.
Polyploidic plants still reproduce.
> Logic and reason that also ignores speciation in asexual organisms.
Asexual species still reproduce.
> Logic and reason that didn't quite make the grade (or is it the
> clade?)
In this case, logic and reason is enough to conclude that the
mutation alone was not enough to cause the lone individual that
had the mutation to be a new species, given the fact that the
human species still has the mutation.
Desertphile
That is my conclusion. I cheerfully accept other explanations on
why the mutation event did, or could have, cause a new species
which was the ancestor to all humans.
The mutation probably (well, certainly) occurred in a germ cell
(ovum or sperm) that was fertilized and grew into an individual
who had the mutation in all of its cells.
It was like a massive innoculation against many diseases: that
individual apparently was less succepible, or entirely
insucceptible, to many diseases that its peers were dying from.
If that individual was a new species (i.e., the mutation rengered
it incapable of reproducing with its peers), it could not have
been an ancestor of any species.
r norman
<deser...@invalid-address.net> wrote:
Reproductive isolation could occur in the homozygous form but not the
heterozygote. The selective advantage of the mutation would increase
its frequency in the gene pool initially in heterozygotes until the
homozygotes start showing up. By that time, there are sufficient
number to constitute a viable population.
Alternatively reproductive isolation could be incomplete so that there
are some individuals with whom the mutant can interbreed. Or it could
be the case that the mutation occurred in a spermatogonium or
oogonium, the stem cell that produces many sperm or eggs. In that
case, the mutant could have had brothers or sisters all with the same
allele to mate with.
June
OK, that sounds more reasonable. Not complete reproductive isolation,
but partial isolation (but no isolation for the original individual with
the mutation, since all his/her offspring would be heterozygous.) And if
the mutation gave complete immunity to malaria, it would likely spread
quickly.
>
> Alternatively reproductive isolation could be incomplete so that there
> are some individuals with whom the mutant can interbreed.
I'm sure there are more than the heterozygous/homozygous form of
incomplete isolation.
> Or it could
> be the case that the mutation occurred in a spermatogonium or
> oogonium, the stem cell that produces many sperm or eggs. In that
> case, the mutant could have had brothers or sisters all with the same
> allele to mate with.
Wouldn't that cause an extreme genetic bottleneck? A few dozen closely
related individuals interbreeding? My understanding is that homo sap did
go through such a bottleneck, but I thought it was less than 100,000 ya
and that the 'breeding' population was estimated to be several thousand
individuals?
--
My 2Ē ß-}
r norman
Yes you are right. My three scenarios are in decreasing order of
tenability. I was once again deviating from the specific case in hand
to a more general consideration of how a single mutation in a sexually
reproducing species could result in speciation.
In the specific case, the first example -- that reproductive isolation
would only occur in the homozygote -- seems fairly reasonable. I am
not sure whether the mathematics of the second -- partial
reproductive isolation of a phenotypic character -- allows true
speciation in any reasonable breeding population but I am sure there
must be simulations done on this. And, as you suggest, the third --
severe inbreeding -- is an extreme population bottleneck that would
reduce genetic variability in the resulting new species to an
extremely low level.
Ernest Major
<r_s_norman@_comcast.net> writes
against N-glycolyl neuraminic acid (Neu5Gc), but that the reaction
against it is because the immune system hasn't had the opportunity to
learn to identify it as self.
So it does not necessarily follow that there would be any reproductive
problems between individuals with and without the mutation. (Rhesus
factor does cause problems, but there must be plenty of other variants
in the population where mothers don't react to potential fetal antigens.
--
alias Ernest Major