NEWS & VIEWS

In addition, mixing between mantle components can generate a range of basalt isotope
compositions more varied than that seen in
the mantle.
Second, can depleted material really impartdistinctive helium-isotope signals into OIBs?
Both helium and uranium are strongly concentrated into mantle melts. This means that,
although low U/3He ratios may be left behindduring melting, there is very little helium left atall, especially if large amounts of melting occur.
The helium-isotope signature of the depletedmaterial is likely to be hidden by that of various
other mantle components, such as subductedmaterial and surrounding, less depleted bulk
mantle that clearly also contribute to the sourceof OIBs. Furthermore, other signals that would
characterize the depleted regions of mantle
suggested by Parman1 as the origin of OIBs,
including neodymium, lead and hafnium isotopes, are typically not found in OIBs.
Third, how would such a mantle work?
Mantle domains now seen in ocean islands
would have been generated throughout
Earth’s history, and so must have been stored
where mixing would not destroy them. This isa particular problem for the largest hotspotsof Hawaii and Iceland, which have the lowest
4
He/3He ratios and so would need a source as
old as 4 billion years. Although it is tempting
to picture separate blobs circulating in the
mantle like raisins in a pudding, these would
probably be destroyed by mixing7. And questions of how this material can be preferentiallyincorporated into plumes beneath oceanislands would remain. Even more perplexing,
how can individual locations such as Hawaii
and Iceland have basalts derived from a rangeof these sources, as is implied by the spread ofhelium data within these regions?
Overall, the picture suggested by Parman
provides an elegant explanation for a fundamental characteristic of ocean-island rocks.
Although there are still considerable reasons
to be sceptical, the many points of correspondence between peaks in zircon ages in
the crust and helium isotopes in the mantle
seem to be more than a coincidence. If thisobservation survives further scrutiny and datacollection, it will certainly be important forunderstanding some of the most distinctive
volcanic features on Earth.
■
Don Porcelli is in the Department of Earth
Sciences, University of Oxford, Parks Road,
Oxford OX1 3PR, UK.
e-mail: don.porcelli@earth.ox.ac.uk
1. Parman, S. W. Nature 446, 900–903 (2007).
2. Graham, D. W., Lupton, F., Albarède, F. & Condomines, M.
Nature 347, 545–548 (1990).
3. Parman, S. W., Kurz, M. D., Hart, S. R. & Grove, T. L. Nature
437, 1140–1143 (2005).
4. Heber, V. S., Brooker, R. A., Kelley, S. P. & Wood, B. J.
Geochim. Cosmochim. Acta 71, 1041–1061 (2007).
5. Condie, K. C. Earth Planet. Sci. Lett. 163, 97–108(1998).
6. Kemp, A. I. S., Hawkesworth, C. J., Paterson, B. A. & Kinny,
P. D. Nature 439, 580–583 (2006).
7. van Keken, P. E., Hauri, E. H. & Ballentine, C. J. Annu. Rev.
Earth Planet. Sci. 30, 493–525 (2002).

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NATURE|Vol 446|19 April 2007

RNA SILENCING

Genomic defence with a slice of pi
Phillip D. Zamore
In fruit flies, a few very large genes generate the small RNAs that silenceparasitic DNA elements. These RNAs might also participate in an
amplification circuit that increases their potency.
Nearly half of the human genome and a thirdof the fruit fly’s consists of selfish elements
called transposons, ‘jumping genes’ that
insert themselves into new locations, mutating other genes and damaging chromosomes.
These molecular parasites include simple
nucleotide repeats and virus-like elementsthat have colonized genomes throughout
evolution. In response, animals have evolved
complex mechanisms to silence transposons.
The fruit fly Drosophila melanogaster silences
its transposons by a mechanism that uses small
RNA ‘guides’. Reporting in Cell1 and Science2,
two research groups propose an unanticipatedexplanation for the production and amplification of these small, silencing RNAs.
The best known silencing pathway guided
by small RNAs is RNA interference (RNAi),
in which small interfering RNAs (siRNAs)
trigger an immune response that defends
plants and animals against viruses by destroying complementary RNA sequences3,4. The
siRNAs bind to members of the Argonautefamily of proteins — molecular ‘scissors’ that
use the small RNA guide to bind to and cut asecond RNA molecule, the ‘target’. The use of
RNA guides rather than protein antibodies is a
key difference between the sequence-based
RNAi defence pathway and our adaptive
immune responses, which recognize viralproteins. The enzyme Dicer produces siRNAs
by cutting long, double-stranded RNA into
smaller pieces about 21 nucleotides long. One
strand of each siRNA is then loaded onto an
Argonaute protein, generating a RNA–protein
complex that binds to a viral RNA target bybase-pairing and cuts it.
Like viruses, transposons are parasites, but,unlike viruses, they are primarily transmitted
by inheritance, rather than through infection. To produce enzymes that facilitate their
jumping to a new location in the genome,transposons must first be copied into mRNA.
The evolution of small-RNA-guided silencing mechanisms, which prevent copying oftransposons into RNA sequences, allows
higher organisms to defend their genes against
transposons.
In some higher organisms, the RNAi pathway provides a crucial defence mechanism
against transposons5–7. But for fruit flies the
genome is guarded by the Piwi-associatedinterfering RNA (piRNA) pathway8. At theheart of this pathway lies a specialized set of
Argonaute proteins produced in the germ cells.
Flies have five Argonaute proteins: Ago1, whichuses small RNAs called microRNAs to regulate
gene expression; Ago2, which uses siRNAs tofight viral infection; and three closely related
Piwi proteins — Piwi, Aubergine and Argonaute3 (Ago3) — which use piRNAs to silencetransposons and other parasitic DNAs. In
flies, piRNAs are also called repeat-associatedsiRNAs, or rasiRNAs.
The Hannon1 and Siomi2 laboratories separately set out to identify small RNAs boundto each of the three fly Piwi proteins, in thehope that their sequences would reveal how
rasiRNAs are made and function. Their findings are simply spectacular, suggesting that
rasiRNAs arise from a small number of trigger
loci — huge ‘genes’ that produce small RNAs
against many selfish genetic elements — andthat they are amplified through reciprocal
cycles of cleavage by pairs of Piwi proteins(Fig. 1, overleaf).
To identify the RNAs bound to the three
Drosophila Piwi proteins, each laboratory used
antibodies to purify Piwi, Aubergine and Ago3
from the fly’s ovaries, along with their associated rasiRNAs. Hannon and colleagues1 identified 60,691 different rasiRNAs. It is difficult to
pinpoint the site of origin of any one rasiRNAto a single genomic location, because nearly
identical copies of specific transposons litterthe entire genome. However, the set of rasiRNAsequences identified by these authors was solarge that around 12,000 could be assigned tounique sites. These sites formed just 142 clusters, with a single cluster on the right arm ofchromosome 2 comprising about 21% of all
the unique rasiRNAs.
Another cluster corresponded to a genetic
locus called flamenco on the X chromosome,which was previously shown to repress thejumping of the gypsy, Idefix and ZAM transposons. Since its discovery9, flamenco has poseda puzzle because no protein-encoding generesides at this locus. The new results indicatethat flamenco, instead of producing a protein,is the source of rasiRNAs that target multiple
types of transposon. These rasiRNAs may
come from an enormous precursor RNA molecule, as mutations lying at the beginning of thelocus disrupt flamenco-derived rasiRNAs some
168,000 nucleotides away. Loss of flamencofunction activates transposons, such as gypsy,
that lie within it, although most gypsy transposons reside outside this locus. However, it
has no effect on transposons that are not foundin flamenco. Thus, flamenco seems to have
evolved as a master regulator of gypsy, IdefixNEWS & VIEWS

NATURE|Vol 446|19 April 2007ab
Aubergine-associated piRNA
5’
piRNA
cluster3’23

1 2 3 4 5 6 7 8 910

U
A

25

3’

5’

10 9 8 7 6 5 4 3 2 1

Ago3-associated piRNA

Figure 1 | piRNA-mediated silencing of transposons. a, A few trigger loci generate piRNAs,
which target transposons (yellow) elsewhere in the genome and prevent their transcription.
b, Complementary binding of Aubergine- and Ago3-associated piRNA sequences results in theiramplification, ensuring efficient silencing of transposons.

and ZAM transposons and is the primary, if
not the sole, source of rasiRNAs against theseselfish elements.
Most rasiRNAs correspond to the antisense strand of transposons and can therefore
bind to, and presumably destroy, the RNAtranscripts of transposons1,8. These antisense
rasiRNAs bind to Piwi and Aubergine. The two
new papers1,2 report that the small RNAs boundto Ago3 are nearly all of the sense orientation.
Of the 353 Ago3-associated rasiRNAs identified by Siomi’s group2, the first 10 nucleotidesof 16 sequences could be paired with rasiRNAs
bound to Aubergine. And more than 11,200(48%) of the Ago3-associated sense rasiRNAs
identified by Hannon’s group1 could form
an offset couple with at least one antisense
rasiRNA.
A 10-nucleotide offset between the beginning of a small RNA guide and a second RNA
molecule has a special meaning. Argonaute
proteins cut target RNAs by measuring 10
nucleotides from the beginning of their RNA
guide to the site of cleavage on their target.
Such a pairing scheme suggests that the starting
nucleotide of each antisense rasiRNA is definedby a cut that is guided by a corresponding sense
rasiRNA. Reinforcing this view, nearly all theantisense rasiRNAs begin with the nucleotide
U, whereas the sense rasiRNAs show no bias forbeginning with U, A, C or G. Instead, the tenth
nucleotide of the sense rasiRNAs was almost
always A, which would allow it to pair with thefirst nucleotide — U — of an Aubergine- or
Piwi-bound antisense rasiRNA (Fig. 1b).
Imagine, then, that a mother fly protects
her offspring by providing her developing
eggs with some of her Aubergine- and Piwibound antisense rasiRNAs. These could thengenerate sense rasiRNAs by cleaving the RNAtranscripts of transposons, thereby simultaneously silencing them and initiating a cycle ofrasiRNA amplification. The sense rasiRNAs
bound to Ago3 would then cleave the long,antisense transcripts produced by master regulatory loci such as flamenco, producing new
antisense rasiRNAs that would bind to Aubergine or Piwi. If antisense transcripts from master regulatory loci are generally more abundant
than sense transcripts from transposons — areasonable assumption as transposons are normally silenced — then the pool of rasiRNAs
would, as observed, be disproportionately
antisense.
Of course, the model proposed by theseauthors1,2 only explains how the start of eachrasiRNA is defined. How the 3ʹ end of therasiRNA is made remains to be discovered.
And what of piRNAs in humans? piRNAs wererecently discovered in immature mouse, rat andhuman sperm cells10, and in zebrafish testes

and ovaries11, although they were mostly not
associated with transposon sequences. What
piRNAs do in mammalian sperm is unknown,but, like fly piRNAs, they derive from large
genomic clusters. And like fly piRNAs8, they
do not seem to be made by Dicer. Perhaps all
piRNAs are made and amplified by reciprocal
cycles of Piwi-catalysed slicing of sense andantisense transcripts. Stay tuned for further
detailed sequence analyses.
■
Phillip D. Zamore is in the Department ofBiochemistry and Molecular Pharmacology,
University of Massachusetts Medical School,
Worcester, Massachusetts 01605, USA.
e-mail: phillip.zamore@umassmed.edu
1. Brennecke, J. et al. Cell 128, 1089–1103 (2007).
2. Gunawardane, L. S. et al. Science 315, 1587–1590(2007).
3. Fire, A. et al. Nature 391, 806–811 (1998).
4. Hamilton, A. J. & Baulcombe, D. C. Science 286, 950–952(1999).
5. Ketting, R. F., Haverkamp, T. H., van Luenen, H. G. &Plasterk, R. H. Cell 99, 133–141 (1999).
6. Tabara, H. et al. Cell 99, 123–132 (1999).
7. Djikeng, A., Shi, H., Tschudi, C. & Ullu, E. RNA 7, 1522–1530(2001).
8. Vagin, V. V. et al. Science 313, 320–324 (2006).
9. Prud’homme, N., Gans, M., Masson, M., Terzian, C. &Bucheton, A. Genetics 139, 697–711 (1995).
10. Kim, V. N. Genes Dev. 20, 1993–1997 (2006).
11. Houwing, S. et al. Cell 129, 69–82 (2007).

NEUROBIOLOGY

Feeling right about doing right
Deborah Talmi and Chris FrithReason and emotion come into conflict in making all kinds of judgements.
Results of work with brain-damaged patients constitute one line ofevidence that the emotional component is not to be dismissed.
In resolving moral dilemmas, should emotion
be our guide? This is a question prompted byvarious research avenues, including work
described in the paper by Koenigs et al.1 on
page 908 of this issue.
In a typical moral dilemma, we have tochoose between the lesser of two evils. Causing the death of one person is bad, but causing
the death of five people is even worse. So, if you
are on a runaway trolley with no other options,many people say that it is better to switch to
the left fork in the track, resulting in the deathof one person, than to carry on along the rightfork and kill five. But what if there was no fork
in the track and the only way to stop the trolley
killing five people was to throw a large person,
who happens to be standing next to you, under
the wheels? From a utilitarian point of view thedilemma is the same: should we sacrifice one
person for the sake of five? But, given this version of the dilemma, most people will choose
not to throw their companion to his death.
Why the difference?
There is increasing evidence that there isa strong emotional component to our moral

intuitions, and that this determines, to a large
degree, how we make moral judgements2.
Thus the benefit from sacrificing a single life
for the greater good must be pitted against theemotional aversion associated with the takingof life, particularly when we are face-to-facewith our victim. Measurement of brain activity
while people are presented with these dilemmas confirm this intuition: the moral dilemma
involving throwing our companion onto thetrack elicits more activity in emotion-processing regions of the brain than the standard runaway-trolley problem (see ref. 3 for a review).
The implication of these ideas is that people
with impaired emotional responses will havealtered moral intuitions. Koenigs and his colleagues1 have tested this hypothesis with agroup of patients with damage to part of thebrain called the ventral medial prefrontal cortex (VMPFC). As is typical after such damage,the autonomic nervous system in these patients
showed reduced responses to emotionallycharged pictures and, according to their spouses,
the patients showed reduced feelings of empathy and guilt. When confronted with moral
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