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perspective to that provided by the past
50 years of field observations of wild chimpanzees. They also demonstrate that the array of
approaches used to reconstruct human evolution is applicable to chimpanzees, aiding the
study of primate archaeology12. Clearly, the
process of exploring the fine-grained history
of non-human animal behaviour has only just
begun. n
1. Whiten, A. et al. Nature 399, 682–685 (1999).
2. Whiten, A., Horner, V. & de Waal, F. B. M. Nature 437,
737–740 (2005).
3. Biro, D. et al. Anim. Cogn. 6, 213–223 (2003).
4. Langergraber, K. E. et al. J. Hum. Evol. http://dx.doi.
org/10.1016/j.jhevol.2013.12.005 (2014).
5. Manson, J. H. et al. Curr. Anthropol. 32, 369–390
(1991).
6. Prüfer, K. et al. Nature 486, 527–531 (2012).
7. Luncz, L. V. & Boesch, C. Am. J. Primatol. http://
dx.doi.org/10.1002/ajp.22259 (2014).
8. Stout, D., Semaw, S., Rogers, M. J. & Cauche, D.
J. Hum. Evol. 58, 474–491 (2010).
9. Haslam, M. Antiquity 86, 299–315 (2012).
10. Gruber, T. et al. J. Comp. Psychol. 126, 446–457 (2012).
11. Verschuren, D., Laird, K. R. & Cumming, B. Nature
403, 410–414 (2000).
12. Haslam, M. et al. Nature 460, 339–344 (2009).
Michael Haslam is in the Research Laboratory
for Archaeology and the History of Art,
University of Oxford, Oxford OX1 3QY, UK.
e-mail: [email protected]
GENETICS
Up and down in
Down’s syndrome
A comparison of identical human twins, only one of whom has Down’s syndrome,
reveals a genome-wide flattening of gene-expression levels in the affected
individual. SEE ARTICLE P.345
B E N J A M I N D . P O P E & D AV I D M . G I L B E R T
syndrome, and raises the possibility that an
extra copy of any chromosome can disrupt
general gene regulation.
The discovery was made possible by an
elegantly controlled experiment that compared
a set of twins derived from the same fertilized
egg (monozygotic, or ‘identical’, twins) in
which one twin had an extra chromosome 21
and the other did not, owing to chromosomesegregation errors that occurred before the
twinning event3. This unusual circumstance
allowed the effects of the extra chromosome 21 to be studied in isolation. Although
gene expression has been extensively studied
in individuals with Down’s syndrome, the
genome-wide effect discovered by Letourneau
et al. had gone undetected because, as they
show, natural variation among individuals
D
own’s syndrome occurs when humans
have an extra copy of chromosome 21 (ref. 1), a situation referred
to as trisomy 21. Because each chromosome
contains a distinct set of genes that serve as
blueprints for the expression of cellular components, it has been presumed for decades
that the condition is mainly caused by an
overabundance of the products of chromosome 21 genes. But on page 345 of this issue,
Letourneau et al.2 report a case of Down’s
syndrome that is associated with altered gene
expression across every chromosome, not just
chromosome 21. This observation implies
that the expression of any number of genes on
any chromosome may contribute to Down’s
Control
Down’s syndrome
Transcription level
oldest sampled community, the Sonso group
in the Budongo Forest, at more than 2,500
years ago, may pre-date the Roman Empire, the
Classic Maya and the Chinese Han Dynasty.
On this evidence, the Sonso chimpanzees
could be considered to have one of the world’s
oldest continuous cultures. However, the techniques and results presented by Langergraber
et al. offer significant potential beyond simply
estimating the time of community-founding
events.
Chimpanzee cultural differences are maintained through social learning, in which group
members conform to observed behaviour,
either during their juvenile development3 or as
newly immigrant females7. Although females
act as an important cultural vector, bringing
new behaviours into a group when they arrive,
it is possible that the resident males act as a
brake on the speed at which cultural variation
accrues. Without such a conservative mechanism, cultural differences between groups
would be eroded with each passing generation,
and the pattern we observe today would not
have emerged. A similar mechanism was probably in place among early human ancestors, if
stasis in the development of flaked-stone technology over its first million years is a guide8.
Hypothetically, in the absence of a conservative tendency, longer-lived groups should
accrue more cultural idiosyncrasies. But the
new genetic data cast doubt on that hypothesis. For example, the Kanyawara and Ngogo
groups in Kibale National Park are located
less than 20 kilometres apart, and have similar
numbers of observed cultural variants, yet the
TMRCA estimates are more than 1,700 years
for the former and close to 450 years for the
latter. Once similar genetic data are available
for other sites and subspecies, it will be possible
to assess more clearly whether there is a pattern to how quickly a new community reaches
a certain level of cultural complexity. We may
also be able to estimate age ranges for the origin of behaviours shared by communities in a
specific region, such as stone-tool use by West
African chimpanzees9.
The availability of dated communities also
allows us to look more closely at the reasons
for their founding. For example, fluctuation
in African forest sizes through time probably
influences chimpanzee community dynamics10. Keeping error margins in mind, it is
interesting that for the five chimpanzee groups
with a TMRCA of less than 1,000 years, these
dates all coincide with periods of East African
drought11. Do droughts promote chimpanzee
group fission, as forests fragment and food
scarcity increases? The same factors might
also negatively affect the retention of cultural
knowledge related to the exploitation of particular insect or nut species, creating a complex
temporal link between genetic and cultural
evolution.
Genetic dates such as those provided by
Langergraber et al. open up a complementary
Increased transcription
in repressed domains
Decreased transcription
in transcribed domains
Length along chromosome
Figure 1 | Flattened gene expression. Letourneau et al.2 show that genomic domains that are normally
associated with low or high levels of gene expression are respectively up- or downregulated in a person
with Down’s syndrome, compared with their identical twin who does not have the condition. The result is
a genome-wide flattening of gene expression.
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© 2014 Macmillan Publishers Limited. All rights reserved
RESEARCH NEWS & VIEWS
is strong enough to mask the effect.
Importantly, the authors found that the
altered gene expression followed a consistent
pattern, with increased and decreased geneexpression levels alternating across large
chromosomal segments. The discovery of
these up- and downregulated segments, which
Letourneau et al. call gene expression dysregulation domains (GEDDs), supports mounting
evidence that chromosomes contain functional domains that may help to provide cells
with access to the genetic information at the
appropriate place and time. The positions of
the GEDDs align with chromosome domains
defined by other structural and functional
properties, such as domains that associate with
nuclear lamina proteins (lamina-associated
domains; LADs4) or that are replicated at different times during the DNA-synthesis phase
of the cell-division cycle5. These findings
strengthen the idea that chromosome functions reflect underlying structural domains.
The authors also report the presence of
GEDDs in mice that carry an extra piece of
chromosome 16 (the mouse counterpart to
most of human chromosome 21) and that
show several features of Down’s syndrome6.
The GEDDs were observed throughout the
mouse genome at positions corresponding
to their locations on human chromosomes.
Furthermore, the authors demonstrate that
the domains were largely preserved after the
human twins’ cells were artificially reprogrammed to a developmental state resembling
that of embryonic stem cells (induced pluripotent stem cells)7. The authors understandably focus on the similarities between GEDDs
before and after this reprogramming. However, the differences that they observed may
correspond to the changes in replication timing, or perhaps lamina association, that occur
during reprogramming5.
Intriguingly, Letourneau and colleagues
show that GEDDs with increased expression
corresponded to otherwise repressed genomic
domains, whereas GEDDs with decreased
expression corresponded to domains normally
characterized by active transcription (Fig. 1).
This means that there is a diminished difference between expressed and repressed genes in
people with Down’s syndrome, suggesting that
the extra chromosome 21 interferes with the
cell’s ability to regulate transcriptional output.
The authors made several attempts to
understand the mechanism behind GEDDs,
but they found no significant changes in LADs
or in patterns of DNA methylation — a modification that affects gene-transcription rates.
They did find that levels of trimethylation at
amino-acid residue lysine 4 on histone H3 correlated well with the transcriptional changes
seen in GEDDs (histones are proteins around
which DNA is wound in the nucleus, forming a complex called chromatin), but this is to
be expected because such post-translational
histone modification tracks with expressed
genes8. The results of the authors’ investigation
of chromatin accessibility within GEDDs (the
accessibility of chromatin to gene-transcription
machinery also regulates expression levels)
were difficult to interpret.
So how could the addition of a single, relatively small chromosome — chromosome 21 is
the smallest human chromosome and accounts
for less than 2% of the genome — dampen
transcriptional differences across the genome?
Two kinds of mechanism seem most plausible. First, and perhaps most simply, it is possible that the increased dosage of one or more
genes on chromosome 21 is responsible. For
example, human chromosome 21 and mouse
chromosome 16 carry the HMGN1 gene, the
product of which competes9 with histone H1
for access to the linker DNA between nucleosomes, the repeating units of chromatin.
Because H1 is associated with less-accessible
chromatin, an increase in dosage of HMGN1
would be consistent with an increase in global
chromatin accessibility. Increased access to
normally inaccessible chromatin would be
expected to dilute the activity of factors that
switch on genes in other parts of the genome,
or release factors that repress genes in active
regions, or both, with the net effect of flattening gene-expression levels genome-wide. An
obvious experiment would be to examine the
effect of controlled overexpression of HMGN1
on global transcription levels.
A second, much less defined possibility is
that the phenomenon described by Letourneau
et al. results from the extra DNA content, for
example by sequestering factors that regulate
expression10. This hypothetical mechanism
need not be specific to chromosome 21
and could be explored further by comparing monozygotic twins that differ in other
trisomies. Although less common, most
other trisomies do cause some of the clinical features of Down’s syndrome, and extra
copies of larger chromosomes are associated
with more-extreme effects11. Sex chromosomes, which are much more benign in a
trisomic context, are the exception11.
Letourneau and colleagues have used a set
of well-controlled, carefully performed and
reproducible experiments to report a provocative new phenomenon. Their findings raise
more questions than they answer, and open the
door to exciting further research. n
Benjamin D. Pope and David M. Gilbert
are in the Department of Biological Science,
Florida State University, Tallahassee,
Florida 32306, USA.
e-mails: [email protected]; [email protected]
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2. Letourneau, A. et al. Nature 508, 345–350 (2014).
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2086–2093 (2008).
4. Guelen, L. et al. Nature 453, 948–951 (2008).
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ORGANIC CHEMISTRY
Catalysis marches on
A fresh take on an established chemical reaction has solved a long-standing
problem in organic synthesis: how to prepare single mirror-image isomers of
groups known as isolated quaternary stereocentres. SEE ARTICLE P.340
J A M E S P. M O R K E N
T
he production of a wide array of
compounds, ranging from polymers to
liquid crystals to human therapeutics,
depends on stereoselective synthesis, which
enables three-dimensional control over the
isomer of the product that forms. Not surprisingly, the more stereoselective reactions
that chemists have in their toolbox, the more
efficiently they can construct these materials.
One tool that is not well developed is a method
for the stereoselective construction of quaternary stereocentres — in which a carbon atom
is bonded to the carbon atoms of four other
distinct appendages — at positions that are
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remote from any other groups in a molecule. In
this issue, Sigman and colleagues1 (page 340)
describe a process that accomplishes just that.
The handedness, or chirality, of enzymes,
proteins, nucleic acids and carbohydrates
results in distinct binding sites that often
accommodate one mirror-image form (enantiomer) of a small-molecule substrate better
than the other. Preparing effective inhibitors
of biological processes is therefore dependent
on our ability to selectively make one enantiomeric form of a small molecule. Such selectivity
is the goal of asymmetric organic synthesis. A
central dogma in this area is that optimum efficiency results from catalytic asymmetric reactions, in which the handedness of the catalyst