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NEWSFOCUS
Kissing cousins
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The long-awaited sequence of the Neandertal genome suggests
that modern humans and Neandertals interbred tens of thousands
of years ago, perhaps in the Middle East

680

7 MAY 2010

Online

VOL 328 SCIENCE www
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org
Published by AAAS

CREDIT: TOMISLAV MARICIC

IT’S THE MYSTERY OF MOUNT CARMEL
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Then, perhaps as early as 80,000 years ago, members
of another species reached and occupied the
caves: heavy-bodied Neandertals, who were
escaping a cold spell in Europe and moving
south into the Middle East
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Some claim
that the anatomy of fossils shows that Neandertals, our closest cousins, did mate with
modern humans, either in the Middle East or
in Europe
...

And the genetic evidence from ancient bones
showed no sign that Neandertals had swapped
genes with our ancestors—until now
...
Neandertals did coexist with modresearchers presents their first detailed anal- ern humans in Europe from 30,000 to
ysis of the draft sequence of the Neandertal 45,000 years ago, and perhaps in the Middle
genome, which now includes more than 3 bil- East as early as 80,000 years ago (see map,
lion nucleotides collected from the bones of p
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But there was no sign of admixthree female Neandertals who lived in Croa- ture in the complete Neandertal mitochontia more than 38,000 years ago
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866)
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org
that there was no interbreeding
Special online
that both Europeans and Asians
that led to viable offspring
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But Afri- Neandertal genome
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This suggests that
David Reich of Harvard Medical
early modern humans interbred with Nean- School in Boston
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The evi- be more similar to European DNA than to
dence showing interbreeding is “incontrovert- African DNA, he thought, “Ah, it’s probably
ible,” says paleoanthropologist John Hawks of just a statistical fluke
...

was not involved in the work
...
”
in different labs to confirm the result
...
sciencemag
...

“In a sense, the Neandertals are then not
altogether extinct,” says lead author Svante
Pääbo, a paleogeneticist at the Max Planck
Institute for Evolutionary Anthropology in
Leipzig, Germany, who was surprised to
find he was part Neandertal
...
”
The team also used the Neandertal DNA
like a probe to find the genes that make
us modern
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84% identical, the researchers identified regions that
have changed or evolved since our ancestors
and Neandertals diverged sometime between
270,000 and 440,000 years ago—their new,
slightly younger estimate of the split
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“This is a
groundbreaking study!” enthuses evolutionary geneticist Hendrik Poinar of McMaster
University in Hamilton, Canada
...
”

confident now because three different ways
of analyzing the data all come to this conclusion of admixture,” says Pääbo
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“It’s not a pure Out-of-Africa
replacement model—2% interbreeding is
not trivial,” says paleoanthropologist Chris
Stringer of the Natural History Museum
in London, one of the chief architects of a
similar model
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“It’s replacement with leakage
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3-fold coverage of the
Neandertal genome is a remarkable technical
feat, one-third of the genome is still murky
...
723), the team describes
and successfully tests a new method for filling in gaps in the rough draft of the genome
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First, they
compiled the Neandertal genome using DNA
from the limb bones of three female Neandertals who lived in Vindija Cave in Croatia from 38,000 to 44,000 years ago; they
confirmed parts of the genome with much
smaller amounts of DNA from Neandertals
who lived in Spain, Germany, and Russia
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Then they compared
the new, derived genetic variants in Neandertals to those in the complete genomes of
five living humans, including a San from
Southern Africa, a Yoruba from West Africa,
a Papua New Guinean, one Han Chinese,
and one French European
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When they compared a Neandertal with a European and an
Asian, they found that the Neandertal always
shared the same amount of derived (or more
recently evolved) SNPs with each of them
...
sciencemag
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Researchers carefully
worked with DNA from three Neandertals’ bones (left) in Vindija Cave, Croatia,
where the fossils were found (right)
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Archaeological data suggest that Neandertals and early modern humans may have
overlapped early in the Middle East and later in Europe
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“We’ve shown that Neandertals are significantly more closely related
to non-Africans than Africans on average,”
says Reich
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But sequencing additional
Africans would be a good idea, says Reich
...
At
first, “we were baffled that this affinity with

www
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org SCIENCE VOL 328
Published by AAAS

Neandertals was not only in Europe and West
Asia [where it was most expected], but also
in Papua New Guinea” where Neandertals
never set foot, says Pääbo
...
Using the published
genome of an African American from the
Human Genome Project, they compared
large regions of African and European
ancestry in this single genome to Neandertal regions
...


7 MAY 2010

681

Finally, population geneticist Rasmus
Nielsen of the University of California
(UC), Berkeley, scanned the human genome
for “ancient” genomic segments—those
that might predate the time when modern humans arose, about 200,000 years
ago
...
He identified 13 “old” variants as possibly coming
from Neandertals or other archaic ancestors, because they were missing from the
genomes of 23 African Americans (used as
proxies for Africans)
...
“There are places in
the genome where we can say this section
is really, really likely to be from a Neandertal,” says Reich
...
If a
few Neandertals interbred with members
of a small population of modern humans,
Neandertal gene variants might persist in
subsequent generations of modern humans
if the interbred population expanded rapidly,

thereby spreading Neandertal DNA widely
...
Although each group may
have occupied the caves intermittently,
some say they may have overlapped for up
to 10,000 years
...
The two species
had much in common: Both lived in caves,
used similar toolkits (although Neandertals
may have made better spear points), and
hunted the same fallow deer and gazelles
...
sciencemag
...
sciencemag
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So once the idea of sequencing the Neandertal genome became more than a glimmer in a
paleogeneticist’s eye, some have asked, “Could
we, should we, would we, bring this extinct
human species back to life?” After all, biologists
are trying to bring back the woolly mammoth by
cloning
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Could we do it? Robert Lanza laughed at the
thought
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But cloning Neandertals is fantasy, says Lanza
...

The Neandertal genome sequence reported
on page 710 (and see main text, p
...
Because the isolated DNA
was in pieces typically about 50 bases long,
there are many missing stretches, particularly
repetitive regions
...
Jurassic Park aside, recon-

CREDIT: M
...

Even if scientists had the complete genome,
it wouldn’t be enough
...
Chemical modifications to the
genome, the way chromosomes arrange in the
nucleus, and maternal components in the egg all
play a role in translating a genetic blueprint into
a viable individual
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None of that
information is even available for Neandertals
...
One cell
provides a nucleus (with DNA inside), and one
is an egg cell, most often of the same species,
whose DNA has been removed
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“If you have just got DNA, you
are asking an enormous amount of the oocyte
that you are going to put the DNA into,” explains
Ian Wilmut, who cloned Dolly the sheep and
now works at the University of Edinburgh in the
United Kingdom
...
”
That leads to the next problem: What species’ egg would play host to this DNA? The
obvious candidate would be a modern human
egg, but they are notoriously fickle and don’t
take well to nuclear transfer, even of modern
human DNA
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“[Cloning] works very poorly
...

Molecular geneticist George Church of Harvard University has proposed another approach:
modify the DNA in a human cell line to resemble the Neandertal
...
P
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“We always
predicted low-level mixing,” because some
Neandertals in the Middle East, such as a
female skeleton at Tabun, look less robust
than Neandertals in Asia and Europe
...

Finally, the researchers cannot rule out
the possibility that what they see as “Neandertal” motifs are really ancient genetic

Computer Kid Makes Good
Late 2007 was a real low point for Richard “Ed”
Green and colleagues at the Max Planck Institute for Evolutionary Anthropology in Leipzig,
Germany
...
They knew going in that most
of the DNA in fossil bone is bacterial, with only
a small percentage of Neandertal DNA
...
“We
were in kind of an awkward situation of having
announced to the world we were going to do it,
and we were left with no concrete plan of how
to do it,” Green recalls
...
”
Their fears increased when they discovered that
their first million bases of Neandertal sequence
were contaminated with modern human DNA
...
He and colleagues developed methods
to control contamination by putting bar codes
on all DNA coming from the fossils (Science,
13 February 2009, p
...
They cut down on
the amount of DNA to be deciphered by cutting up much of the bacterial DNA so that the
sequencing reactions ignored it
...

“Many people here have been able to say they
‘saved the Neandertal genome project,’ ” he
notes
...

“Ed brought the quantitative and algorithmic horsepower needed to interpret the
Neandertal data,” says David Haussler of
the University of California (UC), Santa Cruz,
where Green now works as an assistant professor
...
”
That computational horsepower is what
landed Green the job of shepherding
the Neandertal genome
...
Richard Green overcame
obstacles to sequencing Neandertal DNA
...
sciencemag
...
Pääbo and the sequencing
company 454 Life Sciences in Branford, Connecticut, had just sequenced cave bear and
mammoth DNA and were puzzling over the
results: There was so much microbial sequence,
it was hard to detect mammalian DNA
...

“This was really the first large-scale snapshot of what the universe of [ancient] DNA
looked like when it came out of a bone,” Green
recalls
...
’ It was obvious that this was a once-in-alifetime opportunity
...
“He is
able to design ways to analyze a whole genome
under circumstances that are nonstandard,”
says Pääbo
...
He was “very patient
in terms of helping and training others,” says
Pääbo
...
” The job required long hours at the lab,
but Green says he didn’t mind because the Max
Planck facilities were “maximally comfortable,”
complete with Ping-Pong table, sauna, barbecue grill, and even a resting room
...
Now that he’s settled in at
UC Santa Cruz, Green expects to switch gears
again
...
“Ed is an
incredibly skilled bioinformatician,” says Pääbo
...
”

7 MAY 2010

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Neandertal genome sequence and is about to
join Church’s lab
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But there’s
on the order of a million differences between
the Neandertal and human genomes, and the
more changes needed, the greater the risk of
introducing errors
...
What species would that
mother belong to? Again, the obvious choice
is a human, but no one knows whether a modern woman’s biochemistry would be compatible with that of a Neandertal fetus
...

Once cloning works well in a variety of animals and stem cell–derived organs become
commonplace, “I think the resistance to it will
disappear,” he says
...
“We do not—and
should not—create human beings just to satisfy our scientific curiosity,” says Pääbo, pointing out that Neandertals are a species of human,
so cloning them raises many of the same ethical
issues as cloning a modern human
...
With a Neandertal, “all of these safety issues would apply,
only writ large,” says Wilmut
...

“Not even for medical purposes are we thinking about creating a [modern] human being
...
Although all early modern populations, including in Africa, interbred, that
gene flow was not complete enough to pass
these Neandertal motifs to all Africans
...

To date, the genomic data don’t support interbreeding in the time and place
when everyone most expected it: between
45,000 and about 30,000 years ago in
Europe
...
But such late European mixing cannot explain the current findings, in which
Asians and Europeans are equally similar
to Neandertals
...

In some ways, it is surprising that there
isn’t more evidence of interbreeding, now
that researchers know it was biologically
possible
...

“Was it a cultural barrier?”
Modern motifs
The Neandertal genome also gives researchers a powerful new tool to fish for genes that
have evolved recently in our lineage, after we
split from Neandertals
...
They found 78
684

Protein important for the beating of the sperm
flagellum

Different paths
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new nucleotide substitutions that change the
protein-coding capacity of genes and that
are present in most humans today; just five
genes had more than one such substitution
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“Only 78 substitutions in the
last 300,000 years!” says Poinar
...
”
But the mutations they’ve found so far
“are all very interesting, precisely because
there are so few,” says Pääbo, whose team
is trying to identify their function
...
Several of these
newly evolved modern human genes encode
proteins expressed in the skin, sweat glands,
and inner sheaths of hair roots, as well as
skin pigmentation
...
Pääbo speculates that these changes “reflect that skin
physiology has changed but how, of course,
we don’t know yet
...
Specifically, they have
identified 15 regions containing between
one and 12 genes
...
Changes in this gene
may have affected energy metabolism in
modern humans
...
One gene,
RUNX2, is associated with a disease that
leads a spectrum of developmental abnormalities, including misshapen clavicles and
a bell-shaped rib cage
...
But precisely how
all these genetic differences are expressed
physiologically is the next frontier
...
Are there regions that
are functionally significant?” says Tishkoff
...

His own group is already working
on such functional studies
...
Such studies may eventually
offer clues about why Neandertals went
extinct—and our ancestors didn’t
...
“It is why we
were so successful that we replaced all the
others
...
“This is the real
appeal of this project: What will the genome
of the Neandertal tell us about functional
differences between the two [species],” says
Poinar
...
sciencemag
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, SCIENCE 328 5979 (7 MAY 2010)

SPAG17

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delayed closure of cranial sutures, malformed clavicles,
bell-shaped rib cage, and dental abnormalities



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