www.sciencemag.

org SCIENCE VOL 340 17 MAY 2013 799

NEWS&ANALYSIS
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COLD SPRING HARBOR, NEW YORKIn
2010, a girls pinkie bone from Denisova Cave
in Siberia added a new branch to the human
family tree. The bone was so well preserved
that researchers could fully sequence its
genome and glimpse the DNA of archaic peo-
ple now called Denisovans (Science, 28 Janu-
ary 2011, p. 392; 26 August 2011, p. 1084).
Now, researchers have analyzed three more
samples from that same cave using a power-
ful new method that reveals ancient genomes
in brilliant detail. One sample, a Neander-
tal toe bone, has yielded a nearly complete,
high-coverage genome of our closest cousins,
paleogeneticist Svante Pbo from the Max
Planck Institute for Evolutionary Anthropol-
ogy in Leipzig, Germany, reported at a meet-
ing here last week.
*

The analyses paint a complex
picture of mingling among ancient
human groups, Pbo reported. The
data suggest inbreeding in Nean-
dertals, a large Denisovan popula-
tion, and mixing between Deniso-
vans and an even earlier mystery
species. Its wonderful; amazing,
says Eric Lander, director of the
Broad Institute in Cambridge, Mas-
sachusetts. It opens up a vista on
the past world.
Neandertals, the closest known
relatives to modern humans, ranged
across Europe to western Asia
from perhaps 300,000 years ago
until about 30,000 years ago. Their
overlap in time and space with our
ancestors had fueled debate about whether
the two species had interbred. Then, in 2010,
Pbos group published a low-coverage
sequence (1.3 copies on average) of DNA
from three Neandertal bones from Croatia,
which showed interbreeding: About 2% of
the DNA in living people from outside Africa
originally comes from Neandertals (Science,
7 May 2010, pp. 680 and 710).
That rst Neandertal sequence was a huge
accomplishment, as Neandertal DNA made
up just a few percent of the DNA in the fos-
sils, the rest being bacterial and other con-
taminants. Since then, the Leipzig group has
found ways to zero in on human genetic mate-
rial and to get more from degraded ancient
DNA by using a sequencing method that
starts with single, rather than double, strands
of DNA. The approach provided a startlingly
detailed view of the Denisovan pinkie bone
(Science, 31 August 2012, p. 1028).
But this powerful technique had yet to be
applied to Neandertals. So Pbo was thrilled
when the DNA in the sample taken from the
toe bone proved to be 60% Neandertal. The
researchers were able to sequence each base
50 times over, on averageenough cover-
age to ensure the sequence is correct. This
approach also provided low coverage of the
genome from another fossil, a Neandertal
babys rib, more than 50,000 years old, from a
cave in Russias Caucasus region between the
Caspian and Black seas.
In a 10 p.m. talk to a full house, Pbo
offered some surprising results from the toe
bone. For long stretches, the DNA from each
parental chromosome is closely matched,
strongly suggesting that this Neandertal was
the offspring of two first cousins, he said.
Comparing the data with those from the fos-
sils from Croatia and the Caucasus showed
that these populations were fairly separated
from one another. The group also compared
the chunks of Neandertal DNA found in liv-
ing people with each of these three Nean-
dertal samples. The closest match was with
the Caucasus population, suggesting that
interbreeding with our ancestors most likely
occurred closer to that region.
From the detailed genomes of both Nean-
dertals and Denisovans, Pbo and Montgom-
ery Slatkin of the University of California,
Berkeley, estimated that 17% of the Deniso-
van DNA was from the local Neandertals. And
the comparison revealed another surprise:
Four percent of the Denisovan genome comes
from yet another, more ancient, human
something unknown, Pbo reported. Get-
ting better coverage and more genomes, you
can start to see the networks of interactions
in a world long ago, says David Kingsley, an
evolutionary biologist at Stanford University
in Palo Alto, California.
With all the interbreeding, its more a net-
work than a tree, points out Carles Lalueza-
Fox, a paleogeneticist from the Institute of
Evolutionary Biology in Barcelona, Spain.
Pbo hesitates to call Denisovans a distinct
species, and the picture is getting more com-
plicated with each new genome.
Pbos team also deciphered additional
Denisovan DNA, both nuclear and mitochon-
drial, from two teeth found in different layers in
Denisova Cave. The nuclear DNA conrmed
that both teeth are Denisovan. But, surpris-
ingly, one tooth showed more than 80 mito-
chondrial DNA differences from
both the other tooth and the pinkie
bone. These Denisovans, who lived
in the same cave at different times,
were as genetically diverse as two
living humans from different conti-
nents and more diverse than Nean-
dertals from throughout their range,
says Susanna Sawyer from Pbos
lab. Such diversity implies that the
Denisovans were a relatively
large population that at some
point may have outnumbered
Neandertals, Pbo said.
In addition, the genomes
are clarifying genetic changes
that underlie our own evolu-
tion. We will be able to know
all the changes that are ances-
tral, Lalueza-Fox says. Pbo and his col-
leagues have lined up the chimp, modern
human, Neandertal, and Denisovan genomes
to see whats unique to our species. The cat-
alog includes 31,000 single-base changes,
which led to 96 protein changes, and more
than 3000 changes in regulatory regions, as
well as 125 small insertions and deletions,
Pbo reported.
Peter Sudmant from the University of
Washington, Seattle has already begun scan-
ning the Neandertal genome for uniquely
human duplications and deletions. Its some-
thing we thought we would never be able to
do, he says. Adds Kingsley: It will take
a long time to gure out the real causative
events and gure out what traits they control,
but its a nite list.
ELIZABETH PENNISI
More Genomes From Denisova Cave
Show Mixing of Early Human Groups
HUMAN EVOLUTI ON
A cave for all people. Denisova Cave in
Siberia yielded a Neandertal toe bone (inset) as
well as fossils of a new group of humans called
the Denisovans.
*The Biology of Genomes, 7 to 11 May.
Published by AAAS

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