NEWS & VIEWS RESEARCH This new understanding will compel space physicists to re-evaluate their concept of radiation-belt dynamics and its finer complexities. The results also shed light on the nature of radiation-belt dynamics in other planetary systems9, such as those of Jupiter, Neptune and Uranus, because these planets all have a fast rotation period and significant tilt between the magnetic moment and axis of rotation (unlike Saturn). We can look forward to testing the
model using observations for these systems from future missions. ■ Drew L. Turner is in the Department of Earth, Planetary, and Space Sciences, University of California, Los Angeles, Los Angeles, California 90095-1567, USA. e-mail: [email protected] 1. Van Allen, J. A. & Frank, L. A. Nature 183, 430–434 (1959).
2. Vernov, S. N. & Chudukov, A. E. in Proc. Moscow Cosmic Ray Conf. Vol. 3 (ed. Syrovatsky, S. I.) 19–29 (Int. Un. Pure Appl. Phys., Moscow, 1960). 3. Horne, R. B. Nature Phys. 3, 590–591 (2007). 4. Baker, D. N. Science 297, 1486–1487 (2002). 5. Ukhorskiy, A. Y. et al. Nature 507, 338–340 (2014). 6. Mitchell, D. G. et al. Space Sci. Rev. 179, 263–308 (2013). 7. Mauk, B. H. et al. Space Sci. Rev. 179, 3–27 (2013). 8. Sauvaud, J.-A. et al. J. Geophys. Res. Space Phys. 118, 1723–1736 (2013). 9. Mauk, B. H. & Fox, N. J. J. Geophys. Res. 115, A12220 (2010).
G E NETICS
Closing the distance on obesity culprits Genetic variation in a non-protein-coding region of the gene FTO is implicated in obesity. A study finds evidence that, rather than affecting FTO itself, variations in this region influence expression of a distant gene, IRX3. See Letter p.371 D AV I D U . G O R K I N & B I N G R E N
G
enome-wide association studies have identified more than 75 locations in the human genome at which changes in DNA sequence are linked to obesity and traits closely related to the condition, such as body mass index. In these studies, single nucleotide changes in a non-protein-coding region (an intron) of the gene FTO often have the strongest association with obesity1–3. It is generally thought that this association arises because of a genetic defect that alters the function or expression level of FTO, which encodes an enzyme known to be involved in the control of body weight and metabolism in mice4,5. However, evidence of a direct link between the single nucleotide changes and alteration of FTO function or expression level has been lacking. In this issue, Smemo et al.6 (page 371) present compelling evidence that the association between obesity and FTO actually involves another gene called IRX3, which encodes a transcription factor involved in multiple developmental processes. IRX3 is located a long way — roughly 500 kilobases — from FTO’s first intron, in which the single nucleotide changes (also known as single nucleotide polymorphisms, or SNPs) associated with obesity are located. Despite previous research7 suggesting that long-range enhancer sequences in FTO’s first intron might regulate the expression of IRX3, attention has continued to focus on FTO, partly owing to a lack of more-definitive evidence linking these enhancers to IRX3 expression. Now, Smemo and colleagues have confirmed and expanded on this link. Verifying a functional relationship between an enhancer sequence and a distant target gene requires a demonstration that the enhancer
interacts physically with the target gene’s promoter in the cell nucleus (a promoter is a DNA sequence immediately adjacent to the beginning of a gene that is involved in regulating transcription). Smemo and colleagues investigated long-range interactions between FTO and IRX3 using a technique called chromatin conformation capture, which measures how frequently different regions of the genome interact8. The authors found that the promoter of IRX3 physically interacts with the first intron of FTO (Fig. 1). This interaction was found in mouse and zebrafish embryos, adult mouse brains and human cell lines, suggesting that interaction between these two regulatory regions is an evolutionarily conserved feature of genome organization. The authors also found that sequences in the first intron of FTO show enhancer activity in several of the tissues in which IRX3 is expressed, and that the promoter of IRX3 alone cannot account for the gene’s observed expression pattern, indicating that IRX3 relies on long-range regulatory input. Smemo and co-workers reasoned that, if the Enhancer
association between obesity and FTO does result from genetic alteration of an IRX3 enhancer, then the same SNPs linked with obesity should also be associated with changes in IRX3 expression. To investigate this, the authors examined IRX3 expression in 153 human brain samples. Obesity-linked SNPs were associated with IRX3 expression in these samples, but not with expression of FTO, directly linking these variants to IRX3 regulation. In a final, but crucial, set of experiments, Smemo et al. found that mice lacking a functional copy of Irx3 have significantly lower body weight than control animals, along with a higher base metabolic rate, less body fat and a predisposition to form brown over white adipose tissue (the latter being more likely to accumulate in obese individuals). This clearly demonstrates a previously unappreciated role for Irx3 in controlling body weight. Furthermore, the authors report that these same traits are also seen in mice when a ‘dominantnegative’ mutant form of Irx3, which interferes with the function of normal Irx3, is expressed in the hypothalamus, a region of the brain that has a key role in regulating food intake and metabolism. These data indicate that control of body weight relies specifically on Irx3 activity in the hypothalamus. Smemo and colleagues’ data suggest a model in which a particular genetic variant (or variants) in the first intron of FTO disrupts an enhancer of IRX3, thus altering IRX3 expression and, in turn, influencing body weight. However, important questions remain. First, what is the true functional variant (or variants) that causes the association between this region
FTO gene
500 kb Promoter IRX3 gene
Figure 1 | Long-range control of gene expression. Smemo et al.6 have demonstrated that a non-protein-coding region of the gene FTO, which has been linked to obesity, physically interacts with the promoter sequence required for expression of the IRX3 gene, located around 500 kilobases (kb) away. The authors find that sequences within this non-protein-coding region of FTO act as enhancer elements, regulating expression of the distant IRX3. 2 0 M A RC H 2 0 1 4 | VO L 5 0 7 | NAT U R E | 3 0 9
© 2014 Macmillan Publishers Limited. All rights reserved
RESEARCH NEWS & VIEWS and obesity? Although many SNPs identified in this region have been associated with obesity, it is likely that these associations reflect a single genetic defect in the region. Without pinpointing this defect, it will be difficult to determine whether the genetic mechanism involves disrupted regulation of FTO, IRX3 or perhaps both. Second, what tissues are most relevant to this association? The current study does an admirable job of examining appropriate tissues wherever possible, but there are missing links. For example, the authors observed that loss of Irx3 function in the hypothalamus causes changes in body weight in mice, but the human brain samples were from the cerebellum. Additional studies are needed to answer these and other questions about the connection between obesity, FTO and IRX3. The implications of Smemo and co-workers’ study extend far beyond obesity. SNPs associated with other human traits frequently occur at or near transcriptional enhancers9, and linear genomic distance is often an unreliable predictor of enhancer–promoter interactions10,11. The connection between IRX3 and FTO is particularly instructive because the enhancers of one gene reside within an intron of the other. However, this is not an isolated case. For example, an enhancer in an intron of the gene LMBR1 regulates the developmental gene SHH located more than 1 megabase away, and mutations in this enhancer can cause limb malformations owing to altered SHH expression12. Similarly, an enhancer within an intron of the gene HERC2 contains a SNP that influences human eye, hair and skin colour by modulating the expression of a neighbouring gene called OCA2 (ref. 13). Through their study, Smemo et al. provide an excellent example of how detailed functional analyses, particularly those that link enhancers to their target genes, can help to evaluate the biological consequences of variation in non-coding sequences. ■ David U. Gorkin and Bing Ren are at the Ludwig Institute for Cancer Research, La Jolla, California 92093, USA. B.R. is also in the Department of Cellular and Molecular Medicine, University of California, La Jolla, USA. e-mails: [email protected]; [email protected] Frayling, T. M. et al. Science 316, 889–894 (2007). Scuteri, A. et al. PLoS Genet. 3, e115 (2007). Dina, C. et al. Nature Genet. 39, 724–726 (2007). Fischer, J. et al. Nature 458, 894–898 (2009). Church, C. et al. Nature Genet. 42, 1086–1092 (2010). Smemo, S. et al. Nature 507, 371–375 (2014). Ragvin, A. et al. Proc. Natl Acad. Sci. USA 107, 775–780 (2010). 8. van de Werken, H. J. G. et al. Nature Methods 9, 969–972 (2012). 9. Maurano, M. T. et al. Science 337, 1190–1195 (2012). 10. Sanyal, A., Lajoie, B. R., Jain, G. & Dekker, J. Nature 489, 109–113 (2012). 11. Jin, F. et al. Nature 503, 290–294 (2013). 12. Lettice, L. A. et al. Hum. Mol. Genet. 12, 1725–1735 (2003). 13. Visser, M., Kayser, M. & Palstra, R.-J. Genome Res. 22, 446–455 (2012). 1. 2. 3. 4. 5. 6. 7.
This article was published online on 12 March 2014.
TEC H N O LO GY
Photonics illuminates the future of radar The first implementation of a fully photonics-based coherent radar system shows how photonic methods for radio-frequency signal generation and measurement may facilitate the development of software-defined radar systems. See Letter p.341 JASON D. MCKINNEY
F
or well over a decade, there has been intense pursuit of photonic techniques for the synthesis and processing of broadband radio-frequency signals in applications ranging from wireless communications to radar. Such work is motivated by one main challenge: the lack of electronic systems capable of directly generating, processing and digitizing signals that have high central frequencies and large bandwidths while maintaining signal fidelity (minimal spurious-signal content and low noise levels). That challenge is sure to remain, given the escalating interest in higher centre frequencies and greater signal agility for software-defined radio and radar architectures — those in which the desired signal can be rapidly changed under software control. Such signal agility could offer, for example, increased radar resolution. On page 341 of this issue, Ghelfi et al.1 describe the first field demonstration of a coherent radar system based on photonic techniques. Their work shows that such techniques may indeed provide capability for next-generation radar systems. Coherent radar systems2 use both the amplitude and phase (frequency) of the radar signal that is reflected from a given target (the radar return) to provide range and velocity data for the target. In such a system, a radar waveform of low centre frequency is designed — that is, its bandwidth is chosen — to give the desired range resolution. This waveform is then shifted to a higher centre frequency by multiplication with a stable, continuouswave radio-frequency (RF) signal (carrier), and subsequently amplified and transmitted to the target. On reaching the radar receiver, the waveform is shifted to a lower, intermediate frequency, again through multiplication with a stable RF signal, and processed to extract the target’s range and velocity. Information on range is acquired from the time of arrival of the radar return. The range resolution is determined by the waveform’s bandwidth-limited duration, and improves as this duration decreases. The need for increased resolution requires the use of higher carrier frequencies, which are necessary to obtain waveforms of shorter duration. Velocity data are obtained by comparing the frequency
3 1 0 | NAT U R E | VO L 5 0 7 | 2 0 M A RC H 2 0 1 4
© 2014 Macmillan Publishers Limited. All rights reserved
of the return waveform against a stable, continuous-wave reference signal of the same frequency as that of the original radar waveform. For a moving target, the return waveform will be shifted in frequency relative to its original frequency owing to the Doppler effect (at acoustic frequencies, this effect is analogous to the way in which the perceived pitch of a
Radar transmission
Radar return Photonics-based RF generator
Radar transceiver
MLL
Photonics-based ADC
Digital-signal processor
Figure 1 | A photonics-based radar system. At the heart of the radar transmitter–receiver (transceiver) implemented by Ghelfi et al.1 is a mode-locked laser (MLL). This laser is connected by optical fibres (blue arrows) to a photonics-based radio-frequency (RF) generator, in which the laser output is first optically modulated and then converted to electronic form to obtain a radar signal. The MLL is also connected to a photonics-based analog-to-digital converter (ADC). The generator’s output is connected to an antenna by an RF cable (left red arrow) and transmitted towards a target. The signal reflected from the target (radar return) is collected by the antenna and directed by means of the RF cable (right red arrow) to the ADC. The ADC uses a train of pulses from the MLL to optically measure the amplitude of the reflected signal at discrete instances in time with high precision (optical sampling). The resulting optical samples are converted to digital electronic form and transmitted (black arrow) to the digital-signal processor of a computer. (Graphic adapted from Fig. 2 of the paper1.)
model using observations for these systems from future missions. ■ Drew L. Turner is in the Department of Earth, Planetary, and Space Sciences, University of California, Los Angeles, Los Angeles, California 90095-1567, USA. e-mail: [email protected] 1. Van Allen, J. A. & Frank, L. A. Nature 183, 430–434 (1959).
2. Vernov, S. N. & Chudukov, A. E. in Proc. Moscow Cosmic Ray Conf. Vol. 3 (ed. Syrovatsky, S. I.) 19–29 (Int. Un. Pure Appl. Phys., Moscow, 1960). 3. Horne, R. B. Nature Phys. 3, 590–591 (2007). 4. Baker, D. N. Science 297, 1486–1487 (2002). 5. Ukhorskiy, A. Y. et al. Nature 507, 338–340 (2014). 6. Mitchell, D. G. et al. Space Sci. Rev. 179, 263–308 (2013). 7. Mauk, B. H. et al. Space Sci. Rev. 179, 3–27 (2013). 8. Sauvaud, J.-A. et al. J. Geophys. Res. Space Phys. 118, 1723–1736 (2013). 9. Mauk, B. H. & Fox, N. J. J. Geophys. Res. 115, A12220 (2010).
G E NETICS
Closing the distance on obesity culprits Genetic variation in a non-protein-coding region of the gene FTO is implicated in obesity. A study finds evidence that, rather than affecting FTO itself, variations in this region influence expression of a distant gene, IRX3. See Letter p.371 D AV I D U . G O R K I N & B I N G R E N
G
enome-wide association studies have identified more than 75 locations in the human genome at which changes in DNA sequence are linked to obesity and traits closely related to the condition, such as body mass index. In these studies, single nucleotide changes in a non-protein-coding region (an intron) of the gene FTO often have the strongest association with obesity1–3. It is generally thought that this association arises because of a genetic defect that alters the function or expression level of FTO, which encodes an enzyme known to be involved in the control of body weight and metabolism in mice4,5. However, evidence of a direct link between the single nucleotide changes and alteration of FTO function or expression level has been lacking. In this issue, Smemo et al.6 (page 371) present compelling evidence that the association between obesity and FTO actually involves another gene called IRX3, which encodes a transcription factor involved in multiple developmental processes. IRX3 is located a long way — roughly 500 kilobases — from FTO’s first intron, in which the single nucleotide changes (also known as single nucleotide polymorphisms, or SNPs) associated with obesity are located. Despite previous research7 suggesting that long-range enhancer sequences in FTO’s first intron might regulate the expression of IRX3, attention has continued to focus on FTO, partly owing to a lack of more-definitive evidence linking these enhancers to IRX3 expression. Now, Smemo and colleagues have confirmed and expanded on this link. Verifying a functional relationship between an enhancer sequence and a distant target gene requires a demonstration that the enhancer
interacts physically with the target gene’s promoter in the cell nucleus (a promoter is a DNA sequence immediately adjacent to the beginning of a gene that is involved in regulating transcription). Smemo and colleagues investigated long-range interactions between FTO and IRX3 using a technique called chromatin conformation capture, which measures how frequently different regions of the genome interact8. The authors found that the promoter of IRX3 physically interacts with the first intron of FTO (Fig. 1). This interaction was found in mouse and zebrafish embryos, adult mouse brains and human cell lines, suggesting that interaction between these two regulatory regions is an evolutionarily conserved feature of genome organization. The authors also found that sequences in the first intron of FTO show enhancer activity in several of the tissues in which IRX3 is expressed, and that the promoter of IRX3 alone cannot account for the gene’s observed expression pattern, indicating that IRX3 relies on long-range regulatory input. Smemo and co-workers reasoned that, if the Enhancer
association between obesity and FTO does result from genetic alteration of an IRX3 enhancer, then the same SNPs linked with obesity should also be associated with changes in IRX3 expression. To investigate this, the authors examined IRX3 expression in 153 human brain samples. Obesity-linked SNPs were associated with IRX3 expression in these samples, but not with expression of FTO, directly linking these variants to IRX3 regulation. In a final, but crucial, set of experiments, Smemo et al. found that mice lacking a functional copy of Irx3 have significantly lower body weight than control animals, along with a higher base metabolic rate, less body fat and a predisposition to form brown over white adipose tissue (the latter being more likely to accumulate in obese individuals). This clearly demonstrates a previously unappreciated role for Irx3 in controlling body weight. Furthermore, the authors report that these same traits are also seen in mice when a ‘dominantnegative’ mutant form of Irx3, which interferes with the function of normal Irx3, is expressed in the hypothalamus, a region of the brain that has a key role in regulating food intake and metabolism. These data indicate that control of body weight relies specifically on Irx3 activity in the hypothalamus. Smemo and colleagues’ data suggest a model in which a particular genetic variant (or variants) in the first intron of FTO disrupts an enhancer of IRX3, thus altering IRX3 expression and, in turn, influencing body weight. However, important questions remain. First, what is the true functional variant (or variants) that causes the association between this region
FTO gene
500 kb Promoter IRX3 gene
Figure 1 | Long-range control of gene expression. Smemo et al.6 have demonstrated that a non-protein-coding region of the gene FTO, which has been linked to obesity, physically interacts with the promoter sequence required for expression of the IRX3 gene, located around 500 kilobases (kb) away. The authors find that sequences within this non-protein-coding region of FTO act as enhancer elements, regulating expression of the distant IRX3. 2 0 M A RC H 2 0 1 4 | VO L 5 0 7 | NAT U R E | 3 0 9
© 2014 Macmillan Publishers Limited. All rights reserved
RESEARCH NEWS & VIEWS and obesity? Although many SNPs identified in this region have been associated with obesity, it is likely that these associations reflect a single genetic defect in the region. Without pinpointing this defect, it will be difficult to determine whether the genetic mechanism involves disrupted regulation of FTO, IRX3 or perhaps both. Second, what tissues are most relevant to this association? The current study does an admirable job of examining appropriate tissues wherever possible, but there are missing links. For example, the authors observed that loss of Irx3 function in the hypothalamus causes changes in body weight in mice, but the human brain samples were from the cerebellum. Additional studies are needed to answer these and other questions about the connection between obesity, FTO and IRX3. The implications of Smemo and co-workers’ study extend far beyond obesity. SNPs associated with other human traits frequently occur at or near transcriptional enhancers9, and linear genomic distance is often an unreliable predictor of enhancer–promoter interactions10,11. The connection between IRX3 and FTO is particularly instructive because the enhancers of one gene reside within an intron of the other. However, this is not an isolated case. For example, an enhancer in an intron of the gene LMBR1 regulates the developmental gene SHH located more than 1 megabase away, and mutations in this enhancer can cause limb malformations owing to altered SHH expression12. Similarly, an enhancer within an intron of the gene HERC2 contains a SNP that influences human eye, hair and skin colour by modulating the expression of a neighbouring gene called OCA2 (ref. 13). Through their study, Smemo et al. provide an excellent example of how detailed functional analyses, particularly those that link enhancers to their target genes, can help to evaluate the biological consequences of variation in non-coding sequences. ■ David U. Gorkin and Bing Ren are at the Ludwig Institute for Cancer Research, La Jolla, California 92093, USA. B.R. is also in the Department of Cellular and Molecular Medicine, University of California, La Jolla, USA. e-mails: [email protected]; [email protected] Frayling, T. M. et al. Science 316, 889–894 (2007). Scuteri, A. et al. PLoS Genet. 3, e115 (2007). Dina, C. et al. Nature Genet. 39, 724–726 (2007). Fischer, J. et al. Nature 458, 894–898 (2009). Church, C. et al. Nature Genet. 42, 1086–1092 (2010). Smemo, S. et al. Nature 507, 371–375 (2014). Ragvin, A. et al. Proc. Natl Acad. Sci. USA 107, 775–780 (2010). 8. van de Werken, H. J. G. et al. Nature Methods 9, 969–972 (2012). 9. Maurano, M. T. et al. Science 337, 1190–1195 (2012). 10. Sanyal, A., Lajoie, B. R., Jain, G. & Dekker, J. Nature 489, 109–113 (2012). 11. Jin, F. et al. Nature 503, 290–294 (2013). 12. Lettice, L. A. et al. Hum. Mol. Genet. 12, 1725–1735 (2003). 13. Visser, M., Kayser, M. & Palstra, R.-J. Genome Res. 22, 446–455 (2012). 1. 2. 3. 4. 5. 6. 7.
This article was published online on 12 March 2014.
TEC H N O LO GY
Photonics illuminates the future of radar The first implementation of a fully photonics-based coherent radar system shows how photonic methods for radio-frequency signal generation and measurement may facilitate the development of software-defined radar systems. See Letter p.341 JASON D. MCKINNEY
F
or well over a decade, there has been intense pursuit of photonic techniques for the synthesis and processing of broadband radio-frequency signals in applications ranging from wireless communications to radar. Such work is motivated by one main challenge: the lack of electronic systems capable of directly generating, processing and digitizing signals that have high central frequencies and large bandwidths while maintaining signal fidelity (minimal spurious-signal content and low noise levels). That challenge is sure to remain, given the escalating interest in higher centre frequencies and greater signal agility for software-defined radio and radar architectures — those in which the desired signal can be rapidly changed under software control. Such signal agility could offer, for example, increased radar resolution. On page 341 of this issue, Ghelfi et al.1 describe the first field demonstration of a coherent radar system based on photonic techniques. Their work shows that such techniques may indeed provide capability for next-generation radar systems. Coherent radar systems2 use both the amplitude and phase (frequency) of the radar signal that is reflected from a given target (the radar return) to provide range and velocity data for the target. In such a system, a radar waveform of low centre frequency is designed — that is, its bandwidth is chosen — to give the desired range resolution. This waveform is then shifted to a higher centre frequency by multiplication with a stable, continuouswave radio-frequency (RF) signal (carrier), and subsequently amplified and transmitted to the target. On reaching the radar receiver, the waveform is shifted to a lower, intermediate frequency, again through multiplication with a stable RF signal, and processed to extract the target’s range and velocity. Information on range is acquired from the time of arrival of the radar return. The range resolution is determined by the waveform’s bandwidth-limited duration, and improves as this duration decreases. The need for increased resolution requires the use of higher carrier frequencies, which are necessary to obtain waveforms of shorter duration. Velocity data are obtained by comparing the frequency
3 1 0 | NAT U R E | VO L 5 0 7 | 2 0 M A RC H 2 0 1 4
© 2014 Macmillan Publishers Limited. All rights reserved
of the return waveform against a stable, continuous-wave reference signal of the same frequency as that of the original radar waveform. For a moving target, the return waveform will be shifted in frequency relative to its original frequency owing to the Doppler effect (at acoustic frequencies, this effect is analogous to the way in which the perceived pitch of a
Radar transmission
Radar return Photonics-based RF generator
Radar transceiver
MLL
Photonics-based ADC
Digital-signal processor
Figure 1 | A photonics-based radar system. At the heart of the radar transmitter–receiver (transceiver) implemented by Ghelfi et al.1 is a mode-locked laser (MLL). This laser is connected by optical fibres (blue arrows) to a photonics-based radio-frequency (RF) generator, in which the laser output is first optically modulated and then converted to electronic form to obtain a radar signal. The MLL is also connected to a photonics-based analog-to-digital converter (ADC). The generator’s output is connected to an antenna by an RF cable (left red arrow) and transmitted towards a target. The signal reflected from the target (radar return) is collected by the antenna and directed by means of the RF cable (right red arrow) to the ADC. The ADC uses a train of pulses from the MLL to optically measure the amplitude of the reflected signal at discrete instances in time with high precision (optical sampling). The resulting optical samples are converted to digital electronic form and transmitted (black arrow) to the digital-signal processor of a computer. (Graphic adapted from Fig. 2 of the paper1.)
