Marcelo Nobrega

University of Chicago, Illinois

A human geneticist explores the ways that genes are regulated.

Gene expression is the cellular process that decodes the genetic information in DNA and converts it into proteins. It is regulated at many levels: when messenger RNA is transcribed from DNA; when mRNA is translated into proteins; and at the epigenetic level, when the structure of chromatin, coils of DNA wound around histone proteins, is altered. Although most discussion of gene expression focuses on the regulation of transcription, the other components of the process are also crucial. Yet little is known about how they are integrated.

Work by Tom Misteli at the National Cancer Institute in Bethesda, Maryland, and his team provides a striking example of the integration of seemingly disparate components in gene-expression regulation (R. F. Luco et al. Science 327, 996–1000; 2010). They describe how patterns of alternative splicing of newly made RNA, a key regulatory mechanism, can themselves be regulated by specific chemical modifications in the chromatin. They also found that a given set of modifications to histones predicts patterns of RNA splicing. The authors conservatively estimate that this mechanism occurs in dozens to hundreds of genes in the human genome.

This remarkable study makes a connection between a quintessential transcription-regulation mechanism, histone modification, and a post-transcriptional process, alternative splicing. It shows that chromatin can regulate not only how much of a protein, but also which protein, is made in a cell.

We have seen a surge of intriguing studies suggesting that molecules that were thought to regulate transcription also direct epigenetic modifications, modify alternative-splicing patterns and participate in the intracellular transport of RNA. These findings and the work of Misteli and colleagues provide insight into how the components of gene regulation are integrated.

Nicola Clayton

University of Cambridge, UK

A comparative cognitive scientist considers the effects of high-calorie diets on the brain.

It is well established that an excessive intake of high-calorie foods, unless coupled with plenty of exercise, leads to obesity, which is a growing public-health concern. As a dancer and a scientist, I am well aware of the intimate connection between the body and the brain, and not at all surprised by the recent accumulation of evidence showing that a high-calorie diet leads to a suite of cognitive impairments, particularly in memory. What is striking, however, is how quickly the effects can occur and how selective they are.

Scott Kanoski and Terry Davidson at Purdue University in West Lafayette, Indiana, studied the effects of a high-energy diet on the memory performance of rats trained in a radial-arm maze (S. E. Kanoski and T. L. Davidson J. Exp. Psychol. Anim. Behav. Proc. 36, 313–319; 2010). They found that maintaining rats on a high-energy diet for just 72 hours was sufficient to result in a marked impairment in spatial memory. Deficits in non-spatial memory took much longer to detect, emerging only after 30 days. Spatial skills are therefore particularly vulnerable.

This finding has important implications for our own lifestyle. Clearly, consuming an excessively high-calorie diet can result in marked decreases in cognitive abilities, especially in spatial memory. The fact that this occurs in such a short space of time, prior to any significant gain in body weight, suggests that diet-induced cognitive impairments could contribute to, rather than simply be a consequence of, obesity. So hide the high-calorie foods — if out of sight is out of mind, it might just save your brain!

Ros Rickaby

University of Oxford, UK

A biogeochemist weighs up the climatic influence of carbon dioxide.

Carbon dioxide constitutes a vanishingly small fraction of our atmosphere, but punches well above its weight in terms of greenhouse warming. So just how potent is it?

The geological record provides clues because, over time, Earth has oscillated between greenhouse and icehouse climates. But reconstructing coincident atmospheric CO2 concentrations is notoriously difficult. Modelling and proxy calculations are starting to converge on a single picture of atmospheric CO2 during greenhouse episodes, except for one fly in the ointment: estimates derived from the ratio of carbon isotopes in soil-precipitated carbonates are always higher than those derived from any other source.

Daniel Breecker, now at the University of Texas at Austin, and two co-workers confirm that these estimates are too large (D. O.Breecker et al. Proc. Natl Acad. Sci. USA 107, 576–580; 2010). The numbers relied on measurements of CO2 in soil pores, thought to reflect the growing-season mean. But the creation of soil carbonates is more likely during the driest and warmest parts of the growing season, when the release of CO2 from plant respiration is at a minimum.

To understand the implications of this, think of a gin and tonic. If you have less gin than you thought, you must lower the amount of tonic to get the same tasty ratio. Likewise, because there is less carbon than we thought from plant respiration, we lower our estimate of atmospheric carbon to accord with the observed ratio. The newly calculated values align beautifully with the emerging consensus. A mere 1,000 parts per million by volume (just two and a half times current atmospheric levels and similar to those predicted for AD 2100) is sufficient to induce the hottest greenhouse conditions — such as those of the Mesozoic period 251 million to 65 million years ago. CO2 truly is a heavyweight greenhouse gas.

Petr Svoboda

Institute of Molecular Genetics AS CR, Prague

A molecular biologist explores how new genomic tools can be applied to wild animals.

Some time ago, I learned about a bizarre cancer that is decimating populations of the Tasmanian devil (Sarcophilus harrisii), the carnivorous marsupial popularized by the cartoon character ‘Taz’. Devil facial tumour disease (DFTD) is a rapidly progressive and metastasizing facial cancer caused by a genetically altered cell line that is transmitted between devils by biting.

Studying model organisms in the lab can make the ruthlessness of nature seem distant. But when nature is brought into the lab, one can see the power that modern tools hold for exploring a biological problem — and the limited options available for solving such problems.

Elizabeth Murchison, now at the Wellcome Trust Sanger Institute in Hinxton, UK, and her colleagues performed a comprehensive genomic analysis of the DFTD cells (E. P. Murchison et al. Science 327, 84–87; 2010). They examined not only the nuclear genome, but also that of the mitochondria, cells’ energy-generating organelles. And they performed high-throughput sequencing of RNA molecules, including small RNAs.

Their analysis confirms that DFTD is caused by the transmission of genetically identical cells. The authors also found that DFTD probably originated in Schwann cells, which wrap around neurons, and identified a set of genes that could contribute to DFTD pathology. This is an outstanding example of how next-generation sequencing technologies allow for in-depth analysis of a species that has been difficult to study using other genomic tools.

The data provide diagnostic and monitoring tools that will hopefully help in vaccine development. Until then, Taz’s future lies in the hands of natural selection and conservation efforts that aim to protect healthy animals from DFTD carriers.

Oscar Marin

Institute of Neuroscience, Sant Joan d’Alacant, Spain

A developmental neurobiologist looks at how damage induces cell birth in the adult brain.

The Spanish neuroscientist and 1906 Nobel Laureate Santiago Ramón y Cajal made hundreds of predictions about the organization and function of the nervous system. He was mostly correct, although not where the generation of new neurons in adults was concerned: this he persistently denied. The process is now widely accepted, but I find it fascinating that we have not yet reached consensus on where and when this phenomenon occurs.

Adult neurogenesis has been identified in two brain regions: the olfactory bulb and the hippocampus. Whether it also occurs in the adult neocortex, the region responsible for functions including language and thought, remains highly controversial. So I was intrigued by work by Koji Ohira of Fujita Health University in Toyoake and Takeshi Kaneko of Kyoto University, both in Japan, and their colleagues.

They found a small population of neuronal progenitor or precursor cells in the marginal zone of the adult neocortex (K. Ohira et al. Nature Neurosci. 13, 173–180; 2010). These generate interneurons — cells that modulate and synchronize the activity of principal neurons — that then disperse throughout the neocortex. Although this process is rare in normal circumstances, it is greatly enhanced by ischaemia (restricted blood supply due to damage), the authors show.

The message from Ohira et al. is intriguing and has profound implications. For example, the fact that many of the newborn interneurons express neuropeptide Y, a well-known anti-convulsant and anti-epileptogenic agent, suggests that newly generated neurons might protect the brain from damage. More sophisticated electrophysiological experiments are needed to explain how these interneurons are wired into specific neocortical circuitries and how they modulate neuronal activity.

Marc Vrakking

Max Born Institute for Nonlinear Optics and Short Pulse Spectroscopy, Berlin

A physicist discusses how to visualize a molecule changing shape.

It is the dream of many a chemist to watch a movie of a molecule undergoing structural change. So how can we achieve this? One way is to use the relationship between a molecule’s absorption spectrum and its structure to deduce how the structure changes over time. However, a drawback of this technique is its reliance on prior knowledge of the molecular absorption spectrum.

Faton Krasniqi at the Max Planck Advanced Study Group in Hamburg, Germany, and his co-workers present an alternative idea: using photoelectrons ejected from molecules excited by X-ray free-electron lasers to determine molecular structures that change over time (F. Krasniqi et al. Phys. Rev. A 81, 033411; 2010).

They explain how electrons that are ejected and directly detected without any further interaction with the molecule interfere with electrons that scatter off the surrounding atoms in the molecule, thereby creating holographic patterns. These patterns encode the molecule’s three-dimensional structure. As an example, the researchers present calculations through which they reconstruct the six-membered phenyl ring in a chlorobenzene molecule.

This approach of holographic structure retrieval promises powerful insight into time-dependent molecular dynamics in the next few years. It is an idea that is well founded in earlier experiments at synchrotrons. Many of the required experimental techniques — such as the ability to position molecules in space using moderately intense laser fields — have recently been demonstrated. The Linac Coherent Light Source (LCLS), an X-ray free-electron laser at Stanford University in California, has been up and running since last year. Now it’s showtime!

Aaron Clauset

Santa Fe Institute, New Mexico

A theoretician ponders what physics has to offer ecology.

Many species are concentrated in biodiversity hot spots such as tropical rainforests and coral reefs. But our estimates of how many species these and other ecosystems contain are very rough. Conservation efforts and ecological theories would be better served by a more accurate picture.

Our best guesses come from empirical species–area relationships, which count the number of species observed as a function of geographical area. These relationships show sharp increases at local and continental scales, but slow growth at intermediate scales. Despite decades of study, ecologists have no clear explanation of this pattern’s origins or what causes deviations from it.

James O’Dwyer and Jessica Green at the University of Oregon in Eugene recently developed a spatially explicit stochastic model of species birth, death and dispersal that can be solved mathematically using techniques from quantum field theory (J. P. O’Dwyer and J. L. Green Ecol. Lett. 13, 87–95; 2010). Amazingly, the model predicts a species–area relationship that agrees with decades of empirical data, without including ecologically important factors such as body size, predation, habitat or climate.

The work both solves a long-standing mystery and exemplifies a good null model. Because the model includes only neutral mechanisms (birth, death and dispersal), deviations can be interpreted as evidence of non-neutral, ecologically significant processes. It also shows the value of shifting the focus from small-scale, context-dependent processes to large-scale neutral dynamics, a perspective more common in physics than biology.

The model and its shift in perspective could shed light on the immense, important and increasingly studied world of microbial ecologies, which is even more mysterious than those of rainforests and coral reefs.

James Noonan

Yale University, New Haven, Connecticut

An evolutionary geneticist looks at how small genetic changes can have big evolutionary effects.

Vertebrates are diverse in both form and function. What genetic alterations underlie this diversity? Evolutionary modifications in brain size or limb length, for example, involve changes in the complex developmental processes that give rise to these structures. Work in fish elegantly illustrates how a single genetic change can have profound effects on morphological evolution.

David Kingsley at Stanford University in California and his colleagues focused on threespine sticklebacks (Gasterosteus aculeatus), which exist in both marine and freshwater ecosystems (Y. F. Chan et al. Science 327, 302–305; 2010). Most bear pelvic spines on their underside; however, several freshwater populations have lost these structures.

In previous work, the authors suggested that the gene Pitx1 is involved in pelvic reduction in these fish. Now they show that deletion of a sequence that activates Pitx1 expression in the pelvis is directly responsible for the loss of pelvic spines in sticklebacks. In a simple but powerful experiment, they demonstrate that introducing the Pitx1 gene to these pelvic-reduced fish, under the control of the intact Pitx1 regulatory element, is sufficient to restore pelvic spines.

The Pitx1 regulatory deletion has occurred independently in at least nine stickleback populations. This may be because the Pitx1 regulatory element is in a particularly fragile region of the genome that is prone to deletion. Moreover, population-genetic evidence suggests that this recurrent loss of Pitx1 pelvic expression confers a strong fitness advantage — possibly because insects that prey on sticklebacks can grab onto pelvic spines.

This study illustrates the power of laboratory genetics in understanding evolutionary mechanisms, and by doing so provides a conceptual basis for future functional studies of the evolutionary process.

Jean-Christophe Marine

VIB–Catholic University Leuven, Belgium

A cancer geneticist looks at the link between small RNA molecules and cancer.

My laboratory studies how cancer cells evade the action of tumour-suppressor (TS) genes. For most TS genes, both copies must be lost to facilitate tumour progression. For some, haploinsufficiency — loss of only one copy — may also contribute to carcinogenesis. However, selection generally favours the inactivation of the remaining functional gene copy to accelerate cancer pathogenesis.

Now, an additional class of haploinsufficient TS genes has been identified. Tyler Jacks at the Massachusetts Institute of Technology in Cambridge and his team found that loss of one copy of the gene Dicer1 enhanced tumour formation in a mouse model of lung cancer, but selection strongly disfavoured loss of both copies (M. S. Kumar et al. Genes Dev. 23, 2700–2704; 2009). Publicly available data reveal that in one-third of human tumours only one copy of DICER1 is deleted.

This finding has several profound implications for cancer mechanisms and therapies. Dicer1 codes for an enzyme involved in the generation of microRNAs, short fragments of RNA that silence specific genes. The study provides mechanistic insight into the long-standing observation that microRNAs are often downregulated in human tumours. Perhaps more importantly, the data strongly indicate that Dicer1 — and, by extension, a subset of microRNAs — are in fact required for tumours to survive and/or grow. Further studies aimed at deciphering the dependency of tumours on Dicer1 or microRNAs should therefore lead to exciting therapeutic possibilities.

Meanwhile, this class of TS genes, for which partial loss is advantageous to tumours but complete loss is disadvantageous, must not be overlooked in the ever-growing number of high-resolution analyses of mutations found in cancer.

Kevin Mitchell

Trinity College Dublin

A neurodevelopmental geneticist explores how one mutation can lead to multiple diseases.

Work in psychiatric genetics has revealed that certain deletions or duplications of small chromosomal regions — termed copy-number variants (CNVs) — drastically increase the risk of disorders such as autism and schizophrenia. The findings are contributing to a shift in how we think about the cause of disease: away from a model involving a combination of common gene variants in each individual to one in which single, rare mutations in any of a large number of genes lead to disease in a high proportion of people.

However, it has come as a major surprise that many such mutations increase the risk not just of one disorder but of many — suggesting that primary insults to neural development may manifest themselves differently from one individual to another.

Evan Eichler at the University of Washington in Seattle and his colleagues investigated one possible reason: genetic background effects (S. Girirajan et al. Nature Genet. 42, 203–209; 2010). Previous studies had identified CNVs at a specific location on chromosome 16 in patients with autism or schizophrenia. Eichler et al. found that such mutations are also enriched in patients with developmental delay or cognitive disabilities.

Interestingly, among these cases, the researchers found a sixfold increase in the occurrence of a second CNV in other parts of the genome. Notably, these patients had a different set of symptoms from those with either single CNV alone.

This kind of modifying effect — due to additional, rare mutations in the background — is probably typical in human biology. With a growing understanding of the observable effects of mutations, it will be important and, in the near future, feasible to take each individual’s entire genetic make-up into account when studying the roots of psychiatric disease.