...this versatile
approach
promises to be
an important
resource for
studying the
sequence
determinants of
gene regulation
across diverse
species.
A new computational tool can predict
gene regulatory elements from
diverse taxonomic groups and types
of expression data.
existing methods for predicting
regulatory elements are limited to
specific species or to particular types
of element and expression data -- this
is because they rely on underlying
assumptions about the relationship
between elements and expression patterns.
elemento and colleagues developed
a method -- FIRe (Finding
Informative Regulatory elements)
-- that dispenses with such assumptions,
instead directly quantifying the
relationship between gene expression
levels and potential regulatory motifs
using information theory
The authors tested their approach
on gene clusters derived from existing
Saccharomyces cerevisiae microarray
data, using FIRe to identify
short sequence motifs that are highly
informative about gene expression.
FIRe predicted 17 dNA motifs from
promoter regions and 6 RNA motifs
from 3 uTRs; 14 of these matched
known yeast regulatory elements,
indicating that the approach works
well. Further validation came from
conservation of the predicted motifs
in a closely related yeast species, and
from the fact that the target genes
of a particular motif generally have
related functions.
unlike existing methods, large
numbers of false positives are not a
problem for FIRe: rates were found
to be zero or close to zero across a
range of genomes and data types
-- an important advantage, especially
for application to larger genomes.
elemento and colleagues applied
and validated their method for
different types of expression data
from other species including fruitfly,
worm, mouse and human. Their
predictions included sequence
motifs from the malaria parasite
Plasmodium falciparum, which is
inaccessible using other methods
A major goal for gene therapy is to
correct genetic defects in patientderived
stem cells, which could be
put back into the patient to alleviate
disease symptoms. However, the most
widely used approach involves the
genomic insertion of a transgene,
which -- owing to the non-specific
nature of insertion -- runs the risk of
harmful side-effects. Advances using
site-specific DNA-cutting enzymes
are now showing promise for safer
forms of gene therapy.
Zinc-finger nucleases (ZFNs)
are engineered DNA editing
enzymes that consist of a DNA
binding zinc-finger domain and the
nuclease domain of a restriction
endonuclease. These enzymes
produce double-stranded breaks,
which can be targeted to a site of
choice by altering the zinc-finger
DNA binding specificity. ZFNs have
been used previously to correct point
mutations by inducing homologous
recombination that brings about gene
conversion from a donor DNA.
This approach avoids the insertion
of new material into the genome.
However, it requires the efficient
delivery of three different constructs
-- two ZFNs (as the enzymes act as
heterodimers) and the donor DNA
-- and current systems for delivery into
clinically relevant target cells are highly
inefficient. To overcome this problem,
Lombardo and colleagues used an
integrase-defective lentiviral vector
(IDLV), which can infect most primary
cells and deliver transgenes efficiently,
but doesn't integrate into the host
genome. For three human cell types,
the authors showed that delivery of the
necessary constructs using three IDLVs
resulted in the desired gene editing
outcome. For the different cell types, a
variable but significant proportion of
cells showed gene correction. In cases
in which an endogenous gene was
edited, there was normal expression of
the gene product.
gene THeRAPy
Gene editors deliver
The availability of Neanderthal
genomic sequence data is allowing
us to date key events in our own
evolution.
So far, only one gene has been
convincingly associated with human
language and speech -- forkhead box
P2 (FOXP2). Despite being a highly
conserved gene, the human and
chimapanzee versions differ at two
positions in exon 7, and these
substitutions have been implicated in
our unique ability for speech.
Krause et al. found both
substitutions in two Spanish
Neanderthal samples. Further, they
concluded that, for both substitutions,
at least one of the individuals was
homozygous for the derived allele that
is predominant in modern populations.
Next, the authors analysed the
Neanderthal samples for evidence of
a selective sweep close to exon 7
of FOXP2 that, from modern human
genetic diversity data, was previously
proposed to have occurred within the
past 200,000 years. Seven
polymorphic regions from the intronic
region upstream of exon 7 were
successfully amplified from the
Neanderthal samples and, for six of
these, all products from both
Neanderthals represented the derived
allele. These results suggest that the
selective sweep in the FOXP2 region
began before the split from the
human­Neanderthal common
ancestor, which existed 300,000 to
400,000 years ago -- much earlier
than previously thought.
So, Neanderthal sequences can
provide a useful tool to investigate our
own evolution, making the extreme
care that must be taken when
retrieving genetic information from
ancient samples worthwhile.
Carrie Patis
oRiginAL ReseARcH PAPeR Krause, J. et al.
The derived FOXP2 variant of modern humans
was shared with Neandertals. Curr. Biol. 17,
1908­1912 (2006)
genomics
Decoding the regulatory genome
evoLUTion
neanderthals
help to tell
our story
research highlights
908 | deCemBeR 2007 | vOLume 8 www.nature.com/reviews/genetics
 2007 Nature Publishing Group