Huntington's disease is a fatal neurodegenerative disorder that is caused by CAG-CAA repeat expansion, encoding polyglutamine, in the huntingtin (HTT) gene. Current age-of-clinical-onset prediction ...models for Huntington's disease are based on polyglutamine length and explain only a proportion of the variability in age of onset observed between patients. These length-based assays do not interrogate the underlying genetic variation, because known genetic variants in this region do not alter the protein coding sequence. Given that individuals with identical repeat lengths can present with Huntington's disease decades apart, the search for genetic modifiers of clinical age of onset has become an active area of research.
Results from three independent genetic studies of Huntington's disease have shown that glutamine-encoding CAA variants that interrupt DNA CAG repeat tracts, but do not alter polyglutamine length or polyglutamine homogeneity, are associated with substantial differences in age of onset of Huntington's disease in carriers. A variant that results in the loss of CAA interruption is associated with early onset and is particularly relevant to individuals that carry alleles in the reduced penetrance range (ie, CAG 36–39). Approximately a third of clinically manifesting carriers of reduced penetrance alleles, defined by current diagnostics, carry this variant. Somatic repeat instability, modified by interrupted CAG tracts, is the most probable cause mediating this effect. This relationship is supported by genome-wide screens for disease modifiers, which have revealed the importance of DNA-repair genes in Huntington's disease (ie, FAN1, LIG1, MLH1, MSH3, PMS1, and PMS2).
Focus needs to be placed on refining our understanding of the effect of the loss-of-interruption and duplication-of-interruption variants and other interrupting sequence variants on age of onset, and assessing their effect in disease-relevant brain tissues, as well as in diverse population groups, such as individuals from Africa and Asia. Diagnostic tests should be augmented or updated, since current tests do not assess the underlying DNA sequence variation, especially when assessing individuals that carry alleles in the reduced penetrance range. Future studies should explore somatic repeat instability and DNA repair as new therapeutic targets to modify age of onset in Huntington's disease and in other repeat-mediated disorders. Disease-modifying therapies could potentially be developed by therapeutically targeting these processes. Promising approaches include therapeutically targeting the expanded repeat or directly perturbing key DNA-repair genes (eg, with antisense oligonucleotides or small molecules). Targeting the CAG repeat directly with naphthyridine-azaquinolone, a compound that induces contractions, and altering the expression of MSH3, represent two viable therapeutic strategies. However, as a first step, the capability of such novel therapeutic approaches to delay clinical onset in animal models should be assessed.
Abstract
Populating the exoplanet mass–radius diagram in order to identify the underlying relationship that governs planet composition is driving an interdisciplinary effort within the exoplanet ...community. The discovery of hot super-Earths—a high-temperature, short-period subset of the super-Earth planet population—has presented many unresolved questions concerning the formation, evolution, and composition of rocky planets. We report the discovery of a transiting, ultra-short-period hot super-Earth orbiting
TOI-1075
(TIC
351601843)
, a nearby (
d
= 61.4 pc) late-K/early-M-dwarf star, using data from the Transiting Exoplanet Survey Satellite. The newly discovered planet has a radius of 1.791
−
0.081
+
0.116
R
⊕
and an orbital period of 0.605 day (14.5 hr). We precisely measure the planet mass to be 9.95
−
1.30
+
1.36
M
⊕
using radial velocity measurements obtained with the Planet Finder Spectrograph mounted on the Magellan II telescope. Our radial velocity data also show a long-term trend, suggesting an additional planet in the system. While TOI-1075 b is expected to have a substantial H/He atmosphere given its size relative to the radius gap, its high density (
9.32
−
1.85
+
2.05
g cm
−3
) is likely inconsistent with this possibility. We explore TOI-1075 b’s location relative to the M-dwarf radius valley, evaluate the planet’s prospects for atmospheric characterization, and discuss potential planet formation mechanisms. Studying the TOI-1075 system in the broader context of ultra-short-period planetary systems is necessary for testing planet formation and evolution theories and density-enhancing mechanisms and for future atmospheric and surface characterization studies via emission spectroscopy with the JWST.
Root production influences carbon and nutrient cycles and subsidizes soil biodiversity. However, the long‐term dynamics and drivers of belowground production are poorly understood for most ...ecosystems. In drylands, fire, eutrophication, and precipitation regimes could affect not only root production but also how roots track interannual variability in climate.
We manipulated the intra‐annual precipitation regime, soil nitrogen, and fire in four common Chihuahuan Desert ecosystem types (three grasslands and one shrubland) in New Mexico, USA, where the 100‐year record indicates both long‐term drying and increasing interannual variability in aridity. First, we evaluated how root production tracked aridity over 10–17 years using climate sensitivity functions, which quantify long‐term, nonlinear relationships between biological processes and climate. Next, we determined the degree to which perturbations by fire, nitrogen addition or intra‐annual rainfall altered the sensitivity of root production to both mean and interannual variability in aridity.
All ecosystems had nonlinear climate sensitivities that predicted declines in production with increases in the interannual variance of aridity. However, root production was the most sensitive to aridity in Chihuahuan Desert shrubland, with reduced production under drier and more variable aridity.
Among the perturbations, only fire altered the sensitivity of root production to aridity. Root production was more than twice as sensitive to declines with aridity following prescribed fire than in unburned conditions. Neither the intra‐annual seasonal rainfall regime nor chronic nitrogen fertilization altered the sensitivity of roots to aridity.
Synthesis. Our results yield new insight into how dryland plant roots respond to climate change. Our comparison of dryland ecosystems of the northern Chihuahuan Desert predicted that root production in shrublands would be more sensitive to future climates that are drier and more variable than root production in dry grasslands. Field manipulations revealed that fire could amplify the climate sensitivity of dry grassland root production, but in contrast, the climate sensitivity of root production was largely resistant to changes in the seasonal rainfall regime or increased soil fertilization.
These results yield new insight into how dryland plant roots respond to climate change. The comparison of dryland ecosystems of the northern Chihuahuan Desert predicted that root production in shrublands would be more sensitive to future climates that are drier and more variable than root production in dry grasslands. Field manipulations revealed that fire could amplify the climate sensitivity of dry grassland root production, but in contrast, the climate sensitivity of root production was largely resistant to changes in the seasonal rainfall regime or increased soil fertilization.
Primary productivity response to climatic drivers varies temporally, indicating state-dependent interactions between climate and productivity. Previous studies primarily employed equation-based ...approaches to clarify this relationship, ignoring the state-dependent nature of ecological dynamics. Here, using 40 y of climate and productivity data from 48 grassland sites across Mongolia, we applied an equation-free, nonlinear time-series analysis to reveal sensitivity patterns of productivity to climate change and variability and clarify underlying mechanisms. We showed that productivity responded positively to annual precipitation in mesic regions but negatively in arid regions, with the opposite pattern observed for annual mean temperature. Furthermore, productivity responded negatively to decreasing annual aridity that integrated precipitation and temperature across Mongolia. Productivity responded negatively to interannual variability in precipitation and aridity in mesic regions but positively in arid regions. Overall, interannual temperature variability enhanced productivity. These response patterns are largely unrecognized; however, two mechanisms are inferable. First, time-delayed climate effects modify annual productivity responses to annual climate conditions. Notably, our results suggest that the sensitivity of annual productivity to increasing annual precipitation and decreasing annual aridity can even be negative when the negative time-delayed effects of annual precipitation and aridity on productivity prevail across time. Second, the proportion of plant species resistant to water and temperature stresses at a site determines the sensitivity of productivity to climate variability. Thus, we highlight the importance of nonlinear, state-dependent sensitivity of productivity to climate change and variability, accurately forecasting potential biosphere feedback to the climate system.
Genomic research has evolved from seeking to understand the fundamentals of the human genetic code to examining the ways in which this code varies among people, and then applying this knowledge to ...interventions that are tailored to target the underlying causes of disease.
An array of highly structured domains that function as metabolite-responsive genetic switches has been found to reside within noncoding regions of certain bacterial mRNAs. In response to ...intracellular fluctuations of their target metabolite ligands, these RNA elements exert control over transcription termination or translation initiation. However, for a particular RNA class within the 5' untranslated region (UTR) of the glmS gene, binding of glucosamine-6-phosphate stimulates autocatalytic site-specific cleavage near the 5' of the transcript in vitro, resulting in products with 2'-3' cyclic phosphate and 5' hydroxyl termini. The sequence corresponding to this unique natural ribozyme has been subjected to biochemical and structural scrutiny; however, the mechanism by which self-cleavage imparts control over gene expression has yet to be examined. We demonstrate herein that metabolite-induced self-cleavage specifically targets the downstream transcript for intracellular degradation. This degradation pathway relies on action of RNase J1, a widespread ribonuclease that has been proposed to be a functional homolog to the well-studied Escherichia coli RNase E protein. Whereas RNase E only poorly degrades RNA transcripts containing a 5' hydroxyl group, RNase J1 specifically degrades such transcripts in vivo. These findings elucidate key features of the mechanism for genetic control by a natural ribozyme and suggest that there may be fundamental biochemical differences in RNA degradation machinery between E. coli and other bacteria.
Interannual variability in precipitation has increased globally as climate warming intensifies. The increased variability impacts both terrestrial plant production and carbon (C) sequestration. ...However, mechanisms driving these changes are largely unknown. Here, we examined mechanisms underlying the response of aboveground net primary production (ANPP) to interannual precipitation variability in global drylands with mean annual precipitation (MAP) <500 mm year−1, using a combined approach of data synthesis and process‐based modeling. We found a hump‐shaped response of ANPP to precipitation variability along the MAP gradient. The response was positive when MAP < ~300 mm year−1 and negative when MAP was higher than this threshold, with a positive peak at 140 mm year−1. Transpiration and subsoil water content mirrored the response of ANPP to precipitation variability; evaporation responded negatively and water loss through runoff and drainage responded positively to precipitation variability. Mean annual temperature, soil type, and plant physiological traits all altered the magnitude but not the pattern of the response of ANPP to precipitation variability along the MAP gradient. By extrapolating to global drylands (<500 mm year−1 MAP), we estimated that ANPP would increase by 15.2 ± 6.0 Tg C year−1 in arid and hyper‐arid lands and decrease by 2.1 ± 0.5 Tg C year−1 in dry sub‐humid lands under future changes in interannual precipitation variability. Thus, increases in precipitation variability will enhance primary production in many drylands in the future.
Both observational data and modeling analyses showed that the effect of interannual precipitation variability on aboveground net primary production was positive when mean annual precipitation <~300 mm year−1 and negative when mean annual precipitation was higher than this threshold. Modeling analyses also showed that the positive effect peaked at 140 mm year−1. Transpiration and subsoil water content mirrored the response of aboveground net primary production to precipitation variability; evaporation responded negatively and water loss through runoff and drainage responded positively to precipitation variability.
Temporal fluctuations in plant species coexistence are key to understanding ecosystem state transitions and long-term maintenance of species diversity. Although plant microbiomes can alter plant ...competition in short-term experiments, their relevance to natural temporal patterns in plant communities is unresolved. In a semiarid grassland, the frequency and magnitude of change in plant species composition through time varied from relatively static to highly dynamic among patches across the landscape. We field tested whether these alternative successional trajectories correlated with alternative plant–soil interactions. In temporally stable patches, we found negative plant–soil feedbacks, where plants grew worse with conspecific than heterospecific soil biota—a mechanism that maintains stability in mathematical models. In contrast, feedbacks in temporally dynamic patches were neutral to positive. Importantly, the magnitude of feedbacks depended on plant frequency, enabling plant species to increase in cover when rare, which theory predicts will promote long-term, stable coexistence. Although our study does not determine the direction of causality, our results reveal a novel link between plant—microbe interactions and temporal stability of plant species coexistence and help to explain 20+ yr of plant abundance dynamics at the patch-to-landscape scales.
Huntington disease (HD) is caused by a CAG repeat expansion in the huntingtin (HTT) gene. Although the length of this repeat is inversely correlated with age of onset (AOO), it does not fully explain ...the variability in AOO. We assessed the sequence downstream of the CAG repeat in HTT reference: (CAG)n-CAA-CAG, since variants within this region have been previously described, but no study of AOO has been performed. These analyses identified a variant that results in complete loss of interrupting (LOI) adenine nucleotides in this region (CAG)n-CAG-CAG. Analysis of multiple HD pedigrees showed that this LOI variant is associated with dramatically earlier AOO (average of 25 years) despite the same polyglutamine length as in individuals with the interrupting penultimate CAA codon. This LOI allele is particularly frequent in persons with reduced penetrance alleles who manifest with HD and increases the likelihood of presenting clinically with HD with a CAG of 36–39 repeats. Further, we show that the LOI variant is associated with increased somatic repeat instability, highlighting this as a significant driver of this effect. These findings indicate that the number of uninterrupted CAG repeats, which is lengthened by the LOI, is the most significant contributor to AOO of HD and is more significant than polyglutamine length, which is not altered in these individuals. In addition, we identified another variant in this region, where the CAA-CAG sequence is duplicated, which was associated with later AOO. Identification of these cis-acting modifiers have potentially important implications for genetic counselling in HD-affected families.
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