THIS WEEK

Inside the brain

of a Neanderthal
The first look at which genes
were switched on and off in our
extinct cousins is allowing us to
peer into their minds

Sara Reardon, Chicago

BONES. That is all the passing

millennia have left us of the
Neanderthals and the more
elusive Denisovans. Until recently,
the main insights gleaned from
these bones have been physical:
what our cousins might have
looked like, for instance, and how
they moved. But cutting-edge
genetic science is changing that.
We can now see, for the first
time, which genes are switched
on in humans but were not in
Neanderthals and Denisovans,
and vice versa. The findings

The approach could offer

unprecedented insight
into the mental abilities of
extinct hominin species

PA/AP Photo/Frank Franklin II

point to subtle differences

between our brain structure
and function, and theirs.
The research, presented last
week at the Society for Molecular
Biology and Evolution meeting
in Chicago, reveals that after our
ancestors split from Neanderthals
and Denisovans, they evolved
differences in genes connected
with cognitive abilities. Many
of those genes are associated
with mental disorders in
modern humans.
Working out which genes are
switched on or not involves
looking at the epigenome, or the
chemical methyl tags attached
to genes. Genomes, in contrast,
show only the basic sequence of
genes. Liran Carmel at the Hebrew
University of Jerusalem, Svante
Pbo of the Max Planck Institute
for Evolutionary Anthropology in
Leipzig, Germany, and colleagues
analysed the epigenomes of
Neanderthals and Denisovans and
compared them with those of
modern humans (see Whats
good about decay, top right).
Altered methylation patterns
are frequently associated with
disease, particularly cancer and
mental disorders. So Carmels
approach has the potential to give
Dem bones got something to say us unprecedented insight into the
6 | NewScientist | 20 July 2013

In this section
n Levitation by sound, page 10
n Chimps have more experimental sex than us, page 12
n Which twin is the lawbreaker? page 18

mental abilities and behaviour

of extinct hominin species: if a
gene causes a mental disorder in
humans, then variations in its
sequence or expression pattern
in another species could tell us
something about their mental
abilities. This just puts us into
a whole different realm, says
Sarah Tishkoff at the University
of Pennsylvania in Philadelphia,
who was not involved in the study.
Carmel and colleagues found
that about 99 per cent of the
epigenome was identical across
the three species. But zooming
in on about 700 regions that
varied threw up some intriguing
patterns. In more than 200
of these, Neanderthals and
Denisovans shared the same
methylation pattern while
humans had the opposite,
suggesting these differences are
key to our uniquely human traits.
Many of the genes in these
regions play big roles in immunity,
metabolism and, when they
misfire, disease. Preliminary
findings suggest that more than
half of the disease-linked human
genes identified are associated
with psychiatric and neurological
conditions.
The findings complement
previous studies. In 2012, Pbos
team sequenced the Denisovan
genome and found that humans
have eight key gene variants not
shared with Neanderthals or
Denisovans that allow neurons to
project further across the brain
and connect with one another.

They may have allowed our direct

ancestors brains to become more
complex.
Taken together, the studies
suggest that changes both in
genetic sequences and in pattern
of activation of the genes were
crucial in enabling our ancestors
to develop larger, more complex
brains.
That may have helped give us
our cognitive edge. For instance,
genes and gene-expression
patterns that conferred greater
abilities in communication and
social interaction, or changes
in cognition, would have been
evolutionarily advantageous
for humans, says Tishkoff.
But if the genes that power our
supersmart brains misfire, they
can lead to altered mental states:
in humans, changes in the eight
gene variants identified by Pbo
have been linked to autism.
That doesnt necessarily mean
Neanderthals and Denisovans had
autism-like traits, says Tishkoff,
as neurological conditions are
complex and involve many genes.
And after all, our extinct relatives
fared well for tens of thousands
of years.
But the findings do suggest
that their brains were wired
differently. We have very little
information about the culture
and cognitive abilities of
Neanderthals, says Khaitovich,
and this is where the epigenome
might come in useful.
Archaeologist Richard Klein of
Stanford University in California

evolving away from chimps

In an ideal world, we would be able
to compare which genes are switched
on in our brainswith those in the
brains of Neanderthals and other
species. But all we have left of our
extinct cousins are bones.
So Soojin Yi of the Georgia
Institute of Technology in Atlanta
and colleagues went further back
in evolutionary time and instead
compared the patterns of gene
activation, or epigenome, in chimps

and humans in the prefrontal cortex.

This brain area is highly developed in
humans and is the seat of our unique
cognitive abilities. The idea was that
this would give some insight into
changes that happened after our
ancestors split from those of chimps,
several million years ago.
In the epigenomic regions that
differ between species, the human
brain contains almost five times as
many genes that are linked to

Whats good about decay

The decay of DNA is one of the
toughest hurdles in sequencing
ancient genomes. But it has turned
out to be a boon for those studying
ancient epigenomes, such as
Liran Carmel and colleagues at the
Hebrew University of Jerusalem
(see main story).
DNA and RNA have five building
blocks: adenine, cytosine, thymine,
guanine and uracil. Over thousands
of years, cytosine with a methyl
tag degrades into thymine, while
unmethylated cytosine becomes
uracil. In 2009, Adrian Briggs,
then at the Max Planck Institute
for Evolutionary Anthropology in
Leipzig, Germany, and colleagues
invented a method for ancient-

genome sequencing that

distinguishes original thymines
in DNA from degraded cytosines,
making it possible to indirectly
study the epigenomes which
genes were switched on and off as a
result of methylation in the bones
of Neanderthals (Nucleic Acids
Research, doi.org/ffqscd).
Comparing the epigenomes
of extinct animals could give us
insight into key changes in the first
mammals, says Philipp Khaitovich
of the Chinese Academy of Sciences
in Shanghai, such as when female
mammals began methylating an
entire X chromosome to inactivate
it, which prevents a gene overdose
in her offspring.

hopes that the Neanderthal and

neurological disorders (see
Denisovan epigenomes, along
Evolving away from chimps,
with their genome sequences,
below left).
might start to tell us why humans
As revealing as this new
outcompeted their cousins and
technique is, it has significant
spread around the world.
limitations. Each tissue in the
An interesting next step might
body has its own methylation
be to analyse the epigenome of a
chimpanzee, says Soojin Yi of the The epigenome might
startto tell us why
Georgia Institute of Technology
humans outcompeted
in Atlanta, who was not involved
their Neanderthal cousins
in the latest research. This could
reveal some of the mental traits of
the common ancestor of humans pattern, so patterns in the bones
and Neanderthals. Yis lab has
the source of the DNA in all three
already found that the areas of
species may well be different
the genome in which chimp and
from those in the brain.
human methylation patterns
Methylation patterns also differ
in the brain tend to differ are
between individuals, and there are
also those associated with
very few ancient hominins with
DNA available to sequence. The
individuals in this study may not
be representative of their species.
cognitive function as would be
James Noonan of Yale
expected by chance, Yi says. Defects
University says that to prove
in them are connected with problems
that the methylation differences
in the early stages of brain
matter, the team needs to
development. Humans also have 3.5
put the ancient hominin DNA
times as many autism-related genes.
into human cells and see how
So while our brains have become
the cells change. Tishkoff
bigger and more intelligent, it seems
suggests we may be able to
that evolutionary changes have also
neanderthalise a mouse by
made our brains more prone to
inserting genes with Neanderthal
develop neurological conditions,
methylation patterns and
such as autism and schizophrenia.
compare their effect with a
similarly humanised mouse. n
20 July 2013 | NewScientist | 7