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6| NewScientist | 20 July 2013

BONES. That is all the passingmillennia have left us of the

Neanderthals and the moreelusive Denisovans. Until recentlythe main insights gleaned fromthese bones have been physical:what our cousins might havelooked like, for instance, and howthey moved. But cutting-edgegenetic science is changing that.

We can now see, for the firsttime, which genes are switchedon in humans but were not inNeanderthals and Denisovans,and vice versa. The findings

point to subtle differencesbetween our brain structureand function, and theirs.

The research, presented lastweek at the Society for MolecularBiology and Evolution meetingin Chicago, reveals that after ourancestors split from Neanderthaland Denisovans, they evolveddifferences in genes connectedwith cognitive abilities. Manyof those genes are associatedwith mental disorders inmodern humans.

Working out which genes areswitched on or not involveslooking at the epigenome, or thechemical methyl tags attachedto genes. Genomes, in contrast,show only the basic sequence ofgenes. Liran Carmel at the HebrewUniversity of Jerusalem, Svante

Pbo of the Max Planck Institutefor Evolutionary Anthropology inLeipzig, Germany, and colleaguesanalysed the epigenomes ofNeanderthals and Denisovans ancompared them with those ofmodern humans (see Whatsgood about decay, top right).

Altered methylation patternsare frequently associated withdisease, particularly cancer andmental disorders. So Carmelsapproach has the potential to giveus unprecedented insight into theDem bones got something to say

The first look at which geneswere switched on and off in ourextinct cousins is allowing us topeer into their minds

Inside the brain

of a Neanderthal

Sara Reardon, Chicago

The approach could offerunprecedented insightinto the mental abilities ofextinct hominin species

PA/APPHoTo/FrAnKFrAnKlInI

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20 July 2013 | NewScientist | 7

In ti tin

n Levitation by sound, page 10

n Chimps have more experimental sex than us, page 12

nWhich twin is the lawbreaker? page 18

hopes that the Neanderthal andDenisovan epigenomes, alongwith their genome sequences,might start to tell us why humansoutcompeted their cousins andspread around the world.

An interesting next step mightbe to analyse the epigenome of achimpanzee, says Soojin Yi of theGeorgia Institute of Technologyin Atlanta, who was not involvedin the latest research. This couldreveal some of the mental traits ofthe common ancestor of humansand Neanderthals. Yis lab hasalready found that the areas ofthe genome in which chimp andhuman methylation patternsin the brain tend to differ arealso those associated with

neurological disorders (seeEvolving away from chimps,below left).

As revealing as this newtechnique is, it has significantlimitations. Each tissue in thebody has its own methylation

pattern, so patterns in the bones the source of the DNA in all threespecies may well be differentfrom those in the brain.Methylation patterns also differbetween individuals, and there arevery few ancient hominins withDNA available to sequence. Theindividuals in this study may not

be representative of their species.James Noonan of Yale

University says that to provethat the methylation differencesmatter, the team needs toput the ancient hominin DNAinto human cells and see howthe cells change. Tishkoffsuggests we may be able toneanderthalise a mouse byinserting genes with Neanderthalmethylation patterns andcompare their effect with asimilarly humanised mouse. n

T in ittt t t n ttti Nnt in

In an ideal world, we would be able

to compare which genes are switched

on in our brains with 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

evolvINg away from chImps

cognitive function as would be

expected by chance, Yi says. Defects

in them are connected with problems

in the early stages of brain

development. Humans also have 3.5

times as many autism-related genes.

So while our brains have become

bigger and more intelligent, it seems

that evolutionary changes have also

made our brains more prone to

develop neurological conditions,

such as autism and schizophrenia.

The decay of DNA is one of the

toughest hurdles in sequencing

ancient genomes. But it has turnedout 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.

whaTs good abouT decaymental abilities and behaviourof extinct hominin species: if agene causes a mental disorder inhumans, then variations in its

sequence or expression patternin another species could tell ussomething about their mentalabilities. This just puts us intoa whole different realm, saysSarah Tishkoff at the Universityof Pennsylvania in Philadelphia,who was not involved in the study.

Carmel and colleagues foundthat about 99 per cent of theepigenome was identical acrossthe three species. But zoomingin on about 700 regions thatvaried threw up some intriguing

patterns. In more than 200of these, Neanderthals andDenisovans shared the samemethylation pattern whilehumans had the opposite,suggesting these differences arekey to our uniquely human traits.

Many of the genes in theseregions play big roles in immunity,metabolism and, when theymisfire, disease. Preliminaryfindings suggest that more thanhalf of the disease-linked humangenes identified are associatedwith psychiatric and neurologicalconditions.

The findings complementprevious studies. In 2012, Pbosteam sequenced the Denisovangenome and found that humanshave eight key gene variants notshared with Neanderthals orDenisovans that allow neurons toproject further across the brainand connect with one another.

They may have allowed our directancestors brains to become morecomplex.

Taken together, the studies

suggest that changes both ingenetic sequences and in patternof activation of the genes werecrucial in enabling our ancestorsto develop larger, more complexbrains.

That may have helped give usour cognitive edge. For instance,genes and gene-expressionpatterns that conferred greaterabilities in communication andsocial interaction, or changesin cognition, would have beenevolutionarily advantageous

for humans, says Tishkoff.But if the genes that power our

supersmart brains misfire, theycan lead to altered mental states:in humans, changes in the eightgene variants identified by Pbohave been linked to autism.

That doesnt necessarily meanNeanderthals and Denisovans hadautism-like traits, says Tishkoff,as neurological conditions arecomplex and involve many genes.And after all, our extinct relativesfared well for tens of thousandsof years.

But the findings do suggestthat their brains were wireddifferently. We have very littleinformation about the cultureand cognitive abilities ofNeanderthals, says Khaitovich,and this is where the epigenomemight come in useful.

Archaeologist Richard Klein ofStanford University in California