The recessive character of the Cape Verdean mutation raises the prospect of identifying patients who carry two different (milder) FUS mutations. Such a possibility is especially intriguing, because it would reflect a mecha-nism common in complex genetic diseases that obscures the Mendelian patterns of inheritance and consequently complicates the detection of genetic defects.

It could also be that mechanistically differ-ent FUS mutations occur in related neuro-degenerative brain disorders. Frontotemporal lobar degeneration, for example, is a neurode-generative dementia that arises relatively fre-quently in patients with ALS, shares with ALS the characteristic TDP-43 inclusions in motor neurons, and co-occurs in families with ALS more often than expected by chance9. It will be interesting to see if FUS inclusions can be

identified in patients with frontotemporal lobar degeneration, with or without ALS. Although the carriers of the FUS mutations identified so far show no symptoms of the cognitive dys-function characteristic of frontotemporal lobar degeneration, Kwiatkowski and colleagues tissue autopsy analysis1 revealed cytoplasmic FUS inclusions in neurons of the frontal cortex the brain region affected in frontotemporal lobar degeneration.

With both FUS and TDP-43 mutations implicated in ALS, a pattern emerges that links abnormal RNA metabolism with motor-neuron disease. Although the latest findings1,2 are based on an analysis of relatively few patients, they will have a much broader impact, not only by opening up new avenues of research, but also by accelerating efforts to prevent or ameliorate this devastating disease.

Kristel Sleegers and Christine Van Broeckhoven are in the Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, and in the Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp B-2610, Belgium.e-mail: christine.vanbroeckhoven@molgen.vib-ua.be

1. Kwiatkowski, T. J. Jr et al. Science 323, 12051208 (2009).2. Vance, C. et al. Science 323, 12081211 (2009).3. Valdmanis, P. N. & Rouleau, G. A. Neurology 70, 144152

(2008). 4. Rosen, D. R. et al. Nature 362, 5962 (1993).5. Sreedharan, J. et al. Science 319, 16681672 (2008).6. Sapp, P. C. et al. Am. J. Hum. Genet. 73, 397403 (2003).7. Ruddy, D. M. et al. Am. J. Hum. Genet. 73, 390396 (2003).8. Law, W. J. et al. Brief Funct. Genomics Proteomics 5, 814

(2006).9. Neumann, M. et al. Science 314, 130133 (2006). 10. Cironi, L. et al. PLoS ONE 7, e2634 (2008).11. Simpson, C. L. et al. Hum. Mol. Genet. 18, 472481 (2009).

GEOCHEMISTRY

A glacial hangoverLouis A. Derry

The marine geochemical budget of some solutes does not add up. A test case shows that at least part of the reason may lie in the timescale over which continental weathering recovers from glaciations.

On page 493 of this issue, Vance et al.1 describe how they have tackled one of the puzzles in geochemistry: the fact that current tallies of the sources and sinks of certain elements and isotopes in the ocean dont match the observed rates of change. Vance et al. consider the case of strontium isotopes, where the isotopic ratio of 87Sr/86Sr has been evolving at a faster rate than it should, given the known sources and sinks in the oceans. Their conclusion is that the imbalance lies on the river-input side of the equation, and they propose that estimates based on modern river data do not adequately account for the recovery from recent ice ages.

The Quaternary era, which began about 1.8 million years ago, is characterized by cycles between glacial periods of extensive conti-nental ice sheets and the warmer, interglacial states that follow ice-sheet collapse. Over the past million years or so, the frequency of this cycle has been 100,000 years, which implies that processes operating at Earths surface with timescales near that period or longer cannot reach steady state. Many solutes in the ocean have response times that are longer than the ice-age rhythm, and establishing their budgets is complicated by the fact that an assumption of a modern steady state does not apply. Although we cannot measure the past concentrations of ocean solutes, the isotopic compositions of solute elements can be recorded in marine sediments. Many show variations in time that can provide insight into the shifting balance of inputs to the oceans that occur in

response to tectonic or climatic factors. The isotopic composition of strontium has

been of particular interest because its tempo-ral variations primarily reflect the long-term balance between weathering on land, which supplies solutes with high 87Sr/86Sr, and sub-marine hydrothermal activity, whose net effect

is to supply strontium with low 87Sr/86Sr. It has been recognized for some time that the isotopic budget of strontium in the oceans is difficult to balance with the known sources from rivers and input from hydrothermal vents at mid-ocean ridges2. The best estimates of the mod-ern river and mid-ocean-ridge hydrothermal fluxes predict a rate of change in 87Sr/86Sr in sea water that is much faster than observed. Either the flux of 87Sr from rivers has been higher than we think, or the supply of 86Sr from hydrother-mal exchange is underestimated, or perhaps some of both3.

The river data represent a kind of weighted average from many rivers around the world, and it is possible that sampling bias has left us with an incomplete picture of river fluxes. It is also possible that the estimates of modern river

Figure 1 | Earth moving.Glacial action produces huge amounts of crushed and ground rock material, seen here as strips of moraine, that Vance et al.1 argue is subject to enhanced weathering in the early period of glacial retreat.

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fluxes are in fact reasonably good, but that we are living in a time that is not typical of the fluxes averaged over a longer timescale. This is the explanation explored by Vance and col-leagues1: they propose that much of the worlds land surface is suffering from a glacial hang-over, and that geochemical fluxes have not yet recovered from the major perturbation of the last glacialinterglacial transition.

The major glaciations created tremendous volumes of finely ground but chemically fresh sediment, known as loess, which wind and water have by now distributed widely across the planet. Some of the major breadbaskets of the world, including the mid-continent North American and western Russian grain belts, occur on mineral-rich loess soils. But with time, soils become increasingly weath-ered and nutrient-poor, as is the case for many lowland tropical regions. Freshly ground rock material weathers rapidly, but the weather-ing rate declines over time. So, as the great ice sheets retreated, they left vast tracts of the Northern Hemisphere covered in fresh, finely ground rock (Fig. 1) that would have initially weathered fast, and been an excellent source of solutes with high 87Sr/86Sr. But within a few thousand years, weathering rates would have declined noticeably.

Vance and colleagues apply a power law to quantify the relationship between substrate age and weathering rate that seems to satisfy, at least in broad terms, observations from several different environments. They also note that, in recently glaciated environments, not only does the amount of strontium released during weathering of granitic rocks change with time, but so does the isotopic ratio of the strontium released. Initially, breakdown of the mineral biotite releases strontium with a particularly high 87Sr/86Sr ratio, but this effect declines with time4. So, as landscapes recover from gla-ciation, they release less strontium, and that strontium contains proportionally less of the 87Sr isotope, and the landscapes thus become less potent drivers of the marine budget. The time scale of this relaxation is of the order of 10,000 years: although these landscapes have partially recovered from the effects of the last glaciation, they would have been packed a notably bigger punch 5,000 or 10,000 years ago.

Using these time-dependent relationships between soil age, and the amount and isotopic composition of strontium released by weath-ering, Vance et al. then compute the expected impact of the 100,000-year glacialinterglacial cycle on the isotopic budget of strontium in the oceans. Because strontium has a long resi-dence time compared with the climate cyclic-ity, the 87Sr/86Sr ratio does not show significant observable variation at the 100,000-year driv-ing frequency: the damping effect of the long response time is too strong. But the authors do find that they can resolve much of the appar-ent discrepancy between current best estimates of the river and hydrothermal fluxes and the long-term strontium isotopic budget of the

oceans by accounting for variation in both the weathering flux and its isotopic composition on a glacialinterglacial timescale.

The non-steady-state weathering glacial hangover hypothesis has implications for the cycles of other elements including those, such as osmium, that are used as tracers; major salts such as magnesium and calcium; and carbon dioxide. Recognition that the present-day river-flux measurements are inadequate to describe the time-integrated flux to the oceans both complicates and clarifies our understand-ing of important geochemical cycles and how they respond to perturbations.

However, the non-steady-state weathering proposed by Vance et al. could be only part of the story. A source of strontium that is not well quantified is the low-temperature hydro-thermal alteration of the oceanic crust, which occurs away from the axes of mid-ocean ridges. This flux is more widespread than was once thought. But it is difficult to quantify because it is not associated with the obvious chemi-cal plumes of the famous high-temperature (350 C) black smokers along the axes of mid-ocean ridges, where most element exchange between the ocean and Earths crust is believed to take place. There is good evidence that this off-axis flux is important for strontium and perhaps even enough to close the isotopic mass balance5.

It is likely that both the mechanism proposed by Vance et al. and low-temperature alteration of the oceanic crust have a role in creating the apparent imbalance for strontium, but it is too early to reach firm conclusions on the abso-lute importance of each. Further analyses that involve other tracers, such as calcium isotope ratios, and particularly those with response times short enough to be sensitive to glacial cycles, such as silicon and osmium isotope ratios, can provide insight into the problem. But it may be that only a substantial improve-ment in measurement technology will allow us to truly resolve the relative impact of each flux, by providing data on the oh-so-subtle variation of the 87Sr/86Sr ratio at the glacialinterglacial timescale. Louis A. Derry is in the Biogeochemistry and Environmental Biocomplexity Program, Department of Earth and Atmospheric Sciences, Cornell University, Ithaca, New York 14853, USA. e-mail: lad9@cornell. edu

1. Vance, D., Teagle, D. A. H. & Foster, G. L. Nature 458, 493496 (2009).

2. Hodell, D. A., Mead, G. A. & Mueller, P. A. Chem. Geol. 80, 291307 (1990).

3. Galy, A., France-Lanord, C. & Derry, L. A. Geochim. Cosmochim. Acta 63, 19051925 (1999).

4. Blum, J. D. & Erel, Y. Geochim. Cosmochim. Acta 61, 31933204 (1997).

5. Butterfield, D. A., Nelson, B. K., Wheat, C. G., Mottl, M. J. & Roe, K. K. Geochim. Cosmochim. Acta 65, 41414153 (2001).

STRUCTURAL BIOLOGY

Spliceosome subunit revealedCharles C. Query

The spliceosome enzyme binds to RNA transcripts at splice sites and removes intron sequences. The crystal structure of a spliceosome subunit shows how the enzyme recognizes one end of the intron.

Among other defining features, such as the presence of a nuclear membrane separat-ing genetic material from other parts of the cell, all eukaryotes examined to date contain at least one intron (a sequence that is spliced out from RNA transcripts). This is mirrored in all eukaryotic cells by the presence of parts of the spliceosome the multi-component enzyme responsible for excising introns out of RNA and connecting together the remaining sequences (exons) to form a functional mes-senger RNA that can encode proteins. Almost all vertebrate genes contain introns, often in large numbers; variations in RNA splicing can thus generate a great diversity of protein amino-acid sequences.

The spliceosome is therefore implicated in protein evolution and is crucial to the stor-age and retrieval of genetic information in eukaryotes. It consists of five subunits known as small nuclear ribonucleoproteins (snRNPs), each one of which is a complex of a small RNA

and up to dozens of proteins. On page 475 of this issue, Nagai and colleagues1 report the crystal structure of a spliceosomal snRNP called U1, whose core consists of an RNA and ten proteins. U1 snRNP is thought to form the first spliceosomal interaction at the 5 end of the intron and to stimulate the assembly of the rest of the spliceosome (Fig. 1). It was first implicated in splicing on the basis of sequence complementarity between one end of U1 RNA and the 5 boundary of introns2,3. The inter-actions between U1 components revealed by Nagai and colleagues crystal structure not only suggest how the snRNP is assembled, but also hint at how the 5 splice site is recognized.

The authors1 reconstituted U1 snRNP both from genetically modified versions of its con-stituent proteins (expressed in the bacterium Escherichia coli) that lacked various unstruc-tured regions found in the normal proteins, and from RNA produced in vitro, thus obtaining crystals for their study. The Nagai group had

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