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August 2011, Week 4

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Fri, 26 Aug 2011 22:29:29 -0400
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Did Sex With Neanderthals and Denisovans Shape Our
Immune Systems? The Jury's Still Out

by Ed Yong
August 25, 2011
http://blogs.discovermagazine.com/notrocketscience/2011/08/25/did-sex-with-neanderthals-and-denisovans-shape-our-immune-systems-the-jury%E2%80%99s-still-out/

The Neanderthals may be extinct, but they live on inside
us. Last year, two landmark studies from Svante Paabo
and David Reich showed that everyone outside of Africa
can trace 1-4 percent of their genomes to Neanderthal
ancestors. On top of that, people from the Pacific
Islands of Melanesia owe 5-7 percent of their genomes to
another group of extinct humans - the Denisovans, known
only from a finger bone and a tooth. These ancient
groups stand among our ancestors, their legacy embedded
in our DNA.

Paabo and Reich's studies clearly showed that early
modern humans must have bred with other ancient groups
as they left Africa and swept around the world. But
while they proved that Neanderthal and Denisovan genes
are still around, they said little about what these
genes are doing. Are they random stowaways or did they
bestow important adaptations?

When I spoke to Reich about this earlier this year, he
was starting to sift through the data. "To a first
approximation, they are random," he said. "It's possible
that modern humans could have used the Neanderthal or
Denisovan material to adapt to their environment, but we
don't have evidence for that." However, palaeontologist
Chris Stringer offered an intriguing suggestion: "If
Denisovans were in South-East Asia long-term, they would
have evolved immunities and defences to some of the
diseases there, like different forms of malaria. That's
something modern humans could have picked up that
would've been useful."

He might have been right. Laurent Abi-Rached from
Stanford University has just published a new study
suggesting that our immune system owes a debt to our
ancestors' trysts with Neanderthals and Denisovans.

Abi-Rached looked at a set of three diverse immune
system genes called HLA-A, HLA-B and HLA-C. These help
our cells recognise and respond to a wide variety of
invasive threats like viruses and bacteria. And because
we such threats are legion, the HLA genes are
exceptionally diverse. For each of the three, there are
thousands of different versions, or alleles.

Abi-Rached thinks that we inherited several of these
alleles from Denisovans, for they are far more common in
Asia and Melanesia than in other parts of the world such
as Africa. For example, a version of HLA-A known as A*11
is found in 50-60 percent of people in China and Papua
New Guinea, but it is supposedly absent in Africans.
Abi-Rached thinks that these variants entered the human
genome after our ancestors bred with Denisovans
somewhere in ancient Asia. These incoming genes provided
an advantage in those areas, probably against local
infections, and they gradually became more common.

Neanderthals also made their mark. Again, some of the
HLA versions carried by the three individuals whose
genomes have been sequenced are still around today. They
are common in Europe and Asia, and absent in Africa. All
in all, Abi-Rached thinks that Europeans gained over
half of their HLA-A variants from having sex with other
groups of ancient humans. Asians gained over 70 percent
of their HLA-A variants in this way, and Papua New
Guineans 95 percent.

It is a big claim, but David Reich is not convinced. "It
is well known that present-day frequencies of genetic
variants provide a very poor clue to the geographic
place where those variants arose," he says. John Hawks
from the University of Wisconsin makes a similar point.
For example, he notes that A*11, which Abi-Rached
describes as "absent from Africa" is actually found in
the region, albeit very rarely. "This is difficult to
interpret," he writes on his blog. "If it has any tiny
disadvantage against malaria, for instance, its rarity
in Africa is easily explained as a function of recent
evolution, while its presence almost everywhere outside
Africa would be no surprise even if there were never any
interbreeding."

Hawks argues that the presence of variants like A*11 in
Denisovans and modern Asians could be coincidence. Both
of them could have inherited A*11 from a common
ancestor, a possibility that Abi-Rached discounted.
Hawks argues that all of the major HLA alleles are much
older than the origins of modern humans, or than the
split between Neanderthals and Denisovans. To truly show
that Asians inherited A*11 from Denisovans, Abi-Rached
would need to show that there are changes in the allele
that are common to these groups, but are absent
elsewhere in the world.

There are other inconsistencies in the paper. Abi-Rached
says that humans picked up a version of HLA-B called
B*73 from Denisovans, somewhere in western Asia. But
Reich failed to find any evidence of Denisovan genes in
people outside of southeast Asia and Melanesia. Paabo
notes that the allele could have come from Neanderthals,
who were certainly around in Western Asia.

Despite these misgivings, both Paabo and Reich are
excited to see other scientists expand upon their work.
Paabo says, "I think it is really great that they have
used the two genomes to look at new and exciting things.
This is of course exactly why we sequenced the genomes."
Regardless of whether Abi-Rached is right about the
immune system genes, his study is a sign that groups
around the world are starting to interrogate the genes
of our ancient relatives for clues about our own
evolution. And that is certainly a step in the right
direction.

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