Bringing the Genomic Revolution to Comparative Oncology: Human and Dog Cancers.

Dogs are humanity's oldest friend, the first species we domesticated 20,000-40,000 years ago. In this unequaled collaboration, dogs have inadvertently but serendipitously been molded into a potent human cancer model. Unlike many common model species, dogs are raised in the same environment as humans and present with spontaneous tumors with human-like comorbidities, immunocompetency, and heterogeneity. In breast, bladder, blood, and several pediatric cancers, in-depth profiling of dog and human tumors has established the benefits of the dog model. In addition to this clinical and molecular similarity, veterinary studies indicate that domestic dogs have relatively high tumor incidence rates. As a result, there are a plethora of data for analysis, the statistical power of which is bolstered by substantial breed-specific variability. As such, dog tumors provide a unique opportunity to interrogate the molecular factors underpinning cancer and facilitate the modeling of new therapeutic targets. This review discusses the emerging field of comparative oncology, how it complements human and rodent cancer studies, and where challenges remain, given the rapid proliferation of genomic resources. Increasingly, it appears that human's best friend is becoming an irreplaceable component of oncology research.

Local Community Assembly Mechanisms and the Size of Species Pool Jointly Explain the Beta Diversity of Soil Fungi.

Fungi play vital regulatory roles in terrestrial ecosystems. Local community assembly mechanisms, including deterministic and stochastic processes, as well as the size of regional species pools (gamma diversity), typically influence overall soil microbial community beta diversity patterns. However, there is limited evidence supporting their direct and indirect effects on beta diversity of different soil fungal functional groups in forest ecosystems. To address this gap, we collected 1606 soil samples from a 25-ha subtropical forest plot in southern China. Our goal was to determine the direct effects and indirect effects of regional species pools on the beta diversity of soil fungi, specifically arbuscular mycorrhizal (AM), ectomycorrhizal (EcM), plant-pathogenic, and saprotrophic fungi. We quantified the effects of soil properties, mycorrhizal tree abundances, and topographical factors on soil fungal diversity. The beta diversity of plant-pathogenic fungi was predominantly influenced by the size of the species pool. In contrast, the beta diversity of EcM fungi was primarily driven indirectly through community assembly processes. Neither of them had significant effects on the beta diversity of AM and saprotrophic fungi. Our results highlight that the direct and indirect effects of species pools on the beta diversity of soil functional groups of fungi can significantly differ even within a relatively small area. They also demonstrate the independent and combined effects of various factors in regulating the diversities of soil functional groups of fungi. Consequently, it is crucial to study the fungal community not only as a whole but also by considering different functional groups within the community.

Extreme drought impacts have been underestimated in grasslands and shrublands globally.

Climate change is increasing the frequency and severity of short-term (~1 y) drought events-the most common duration of drought-globally. Yet the impact of this intensification of drought on ecosystem functioning remains poorly resolved. This is due in part to the widely disparate approaches ecologists have employed to study drought, variation in the severity and duration of drought studied, and differences among ecosystems in vegetation, edaphic and climatic attributes that can mediate drought impacts. To overcome these problems and better identify the factors that modulate drought responses, we used a coordinated distributed experiment to quantify the impact of short-term drought on grassland and shrubland ecosystems. With a standardized approach, we imposed ~a single year of drought at 100 sites on six continents. Here we show that loss of a foundational ecosystem function-aboveground net primary production (ANPP)-was 60% greater at sites that experienced statistically extreme drought (1-in-100-y event) vs. those sites where drought was nominal (historically more common) in magnitude (35% vs. 21%, respectively). This reduction in a key carbon cycle process with a single year of extreme drought greatly exceeds previously reported losses for grasslands and shrublands. Our global experiment also revealed high variability in drought response but that relative reductions in ANPP were greater in drier ecosystems and those with fewer plant species. Overall, our results demonstrate with unprecedented rigor that the global impacts of projected increases in drought severity have been significantly underestimated and that drier and less diverse sites are likely to be most vulnerable to extreme drought.

Root-centric ß diversity reveals functional homogeneity while phylogenetic heterogeneity in a subtropical forest.

Root-centric studies have revealed fast taxonomic turnover across root neighborhoods, but how such turnover is accompanied by changes in species functions and phylogeny (i.e., ß diversity) remains largely unknown. As ß diversity can reflect the degree of community-wide biotic homogenization, such information is crucial for better inference of below-ground assembly rules, community structuring, and ecosystem processes. We collected 2480 root segments from 625 0-30 cm soil profiles in a subtropical forest in China. Root segments were identified into 138 species with DNA-barcoding with six root morphological and architectural traits measured per species. By using the mean pairwise (Dpw ) and mean nearest neighbor distance (Dnn ) to quantify species ecological differences, we first tested the non-random functional and phylogenetic turnover of root neighborhoods that would lend more support to deterministic over stochastic community assembly processes. Additionally, we examined the distance-decay pattern of ß diversity, and finally partitioned ß diversity into geographical and environmental components to infer their potential drivers of environmental filtering, dispersal limitation, and biotic interactions. We found that functional turnover was often lower than expected given the taxonomic turnover, whereas phylogenetic turnover was often higher than expected. Phylogenetic Dpw (e.g., interfamily species) turnover exhibited a distance-decay pattern, likely reflecting limited dispersal or abiotic filtering that leads to the spatial aggregation of specific plant lineages. Conversely, both functional and phylogenetic Dnn (e.g., intrageneric species) exhibited an inverted distance-decay pattern, likely reflecting strong biotic interactions among spatially and phylogenetically close species leading to phylogenetic and functional divergence. While the spatial distance was generally a better predictor of ß diversity than environmental distance, the joint effect of environmental and spatial distance usually overrode their respective pure effects. These findings suggest that root neighborhood functional homogeneity may somewhat increase forest resilience after disturbance by exhibiting an insurance effect. Likewise, root neighborhood phylogenetic heterogeneity may enhance plant fitness by hindering the transmission of host-specific pathogens through root networks or by promoting interspecific niche complementarity not captured by species functions. Our study highlights the potential role of root-centric ß diversity in mediating community structures and functions largely ignored in previous studies.

Consistent predictors of microbial community composition across spatial scales in grasslands reveal low context-dependency.

Environmental circumstances shaping soil microbial communities have been studied extensively. However, due to disparate study designs, it has been difficult to resolve whether a globally consistent set of predictors exists, or context-dependency prevails. Here, we used a network of 18 grassland sites (11 of those containing regional plant productivity gradients) to examine (i) if similar abiotic or biotic factors predict both large-scale (across sites) and regional-scale (within sites) patterns in bacterial and fungal community composition, and (ii) if microbial community composition differs consistently at two levels of regional plant productivity (low vs. high). Our results revealed that bacteria were associated with particular soil properties (such as base saturation) and both bacteria and fungi were associated with plant community composition across sites and within the majority of sites. Moreover, a discernible microbial community signal emerged, clearly distinguishing high and low-productivity soils across different grasslands independent of their location in the world. Hence, regional productivity differences may be typified by characteristic soil microbial communities across the grassland biome. These results could encourage future research aiming to predict the general effects of global changes on soil microbial community composition in grasslands and to discriminate fertile from infertile systems using generally applicable microbial indicators.

Cytokinin Promotes Jasmonic Acid Accumulation in the Control of Maize Leaf Growth.

Plant organ growth results from the combined activity of cell division and cell expansion. The co-ordination of these two processes depends on the interplay between multiple hormones that determine the final organ size. Using the semidominant Hairy Sheath Frayed1 (Hsf1) maize mutant that hypersignals the perception of cytokinin (CK), we show that CK can reduce leaf size and growth rate by decreasing cell division. Linked to CK hypersignaling, the Hsf1 mutant has an increased jasmonic acid (JA) content, a hormone that can inhibit cell division. The treatment of wild-type seedlings with exogenous JA reduces maize leaf size and growth rate, while JA-deficient maize mutants have increased leaf size and growth rate. Expression analysis revealed the increased transcript accumulation of several JA pathway genes in the Hsf1 leaf growth zone. A transient treatment of growing wild-type maize shoots with exogenous CK also induced the expression of JA biosynthetic genes, although this effect was blocked by the co-treatment with cycloheximide. Together, our results suggest that CK can promote JA accumulation, possibly through the increased expression of specific JA pathway genes.

Equitable machine learning counteracts ancestral bias in precision medicine, improving outcomes for all.

Gold standard genomic datasets severely under-represent non-European populations, leading to inequities and a limited understanding of human disease [1-8]. Therapeutics and outcomes remain hidden because we lack insights that we could gain from analyzing ancestry-unbiased genomic data. To address this significant gap, we present PhyloFrame, the first-ever machine learning method for equitable genomic precision medicine. PhyloFrame corrects for ancestral bias by integrating big data tissue-specific functional interaction networks, global population variation data, and disease-relevant transcriptomic data. Application of PhyloFrame to breast, thyroid, and uterine cancers shows marked improvements in predictive power across all ancestries, less model overfitting, and a higher likelihood of identifying known cancer-related genes. The ability to provide accurate predictions for underrepresented groups, in particular, is substantially increased. These results demonstrate how AI can mitigate ancestral bias in training data and contribute to equitable representation in medical research.

Changes in the Amount and Distribution of Soil Nutrients and Neighbours Have Differential Impacts on Root and Shoot Architecture in Wheat (Triticum aestivum).

Plants exhibit differential behaviours through changes in biomass development and distribution in response to environmental cues, which may impact crops uniquely. We conducted a mesocosm experiment in pots to determine the root and shoot behavioural responses of wheat, T. aestivum. Plants were grown in homogeneous or heterogeneous and heavily or lightly fertilized soil, and alone or with a neighbour of the same or different genetic identity (cultivars: CDC Titanium, Carberry, Glenn, Go Early, and Lillian). Contrary to predictions, wheat did not alter relative reproductive effort in the presence of neighbours, more nutrients, or homogenous soil. Above and below ground, the plants' tendency to use potentially shared space exhibited high levels of plasticity. Above ground, they generally avoided shared, central aerial space when grown with neighbours. Unexpectedly, nutrient amount and distribution also impacted shoots; plants that grew in fertile or homogenous environments increased shared space use. Below ground, plants grown with related neighbours indicated no difference in neighbour avoidance. Those in homogenous soil produced relatively even roots, and plants in heterogeneous treatments produced more roots in nutrient patches. Additionally, less fertile soil resulted in pot-level decreases in root foraging precision. Our findings illustrate that explicit coordination between above- and belowground biomass in wheat may not exist.

Sensitive genetically encoded sensors for population and subcellular imaging of cAMP in vivo.

Cyclic adenosine monophosphate (cAMP) signaling integrates information from diverse G-protein-coupled receptors, such as neuromodulator receptors, to regulate pivotal biological processes in a cellular-specific and subcellular-specific manner. However, in vivo cellular-resolution imaging of cAMP dynamics remains challenging. Here, we screen existing genetically encoded cAMP sensors and further develop the best performer to derive three improved variants, called cAMPFIREs. Compared with their parental sensor, these sensors exhibit up to 10-fold increased sensitivity to cAMP and a cytosolic distribution. cAMPFIREs are compatible with both ratiometric and fluorescence lifetime imaging and can detect cAMP dynamics elicited by norepinephrine at physiologically relevant, nanomolar concentrations. Imaging of cAMPFIREs in awake mice reveals tonic levels of cAMP in cortical neurons that are associated with wakefulness, modulated by opioids, and differentially regulated across subcellular compartments. Furthermore, enforced locomotion elicits neuron-specific, bidirectional cAMP dynamics. cAMPFIREs also function in Drosophila. Overall, cAMPFIREs may have broad applicability for studying intracellular signaling in vivo.

A global inventory of animal diversity measured in different grazing treatments.

Grazing by wild and domesticated grazers occurs within many terrestrial ecosystems worldwide, with positive and negative impacts on biodiversity. Management of grazed lands in support of biological conservation could benefit from a compiled dataset of animal biodiversity within and adjacent to grazed sites. In this database, we have assembled data from the peer-reviewed literature that included all forms of grazing, co-occurring species, and site information. We reviewed 3,489 published articles and found 245 studies in 41 countries that surveyed animal biodiversity co-occurring with grazers. We extracted 16,105 observations of animal surveys for over 1,200 species in all terrestrial ecosystems and on all continents except Antarctica. We then compiled 28 different grazing variables that focus on management systems, assemblages of grazer species, ecosystem characteristics, and survey type. Our database provides the most comprehensive summary of animal biodiversity patterns that co-occur with wild and domesticated grazers. This database could be used in future conservation initiatives and grazing management to enhance the prolonged maintenance of ecosystems and ecosystem services.

Competitive size asymmetry, not intensity, is linked to species loss and gain in a native grassland community.

Competition is often highlighted as a major force influencing plant species diversity. However, there are multiple facets of competition (e.g., strength, intransitivity, and size asymmetry) that may have independent and differential impacts on diversity, making understanding the degree to which competition structures communities difficult. Unfortunately, field-based experiments that decouple multiple facets of competition are lacking, limiting our ability to test theoretical frameworks and reducing understanding of the actual linkages among competition and coexistence. Here, we experimentally manipulate the size structure of local grassland communities to examine the relative impacts of competitive size asymmetry (i.e., competitive advantage based on relative size) and intensity (i.e., mean effect of neighbors on plant growth) on species loss and gain. Increased competitive size asymmetry was associated with increased species loss and decreased species gain, while no relationship was found between competitive intensity and species loss and gain. Furthermore, the probability of loss was not dependent on a species initial size, suggesting that small species may not always be the losers of size-asymmetric interactions. Instead, loss was dependent on species rarity, where loss was higher for rare species. Overall, these results suggest that competitive size asymmetry may be more important for species loss than intensity in some plant communities and demonstrates the importance of decoupling different aspects of competition to better understand their drivers and ecological consequences.

Global urban environmental change drives adaptation in white clover.

Urbanization transforms environments in ways that alter biological evolution. We examined whether urban environmental change drives parallel evolution by sampling 110,019 white clover plants from 6169 populations in 160 cities globally. Plants were assayed for a Mendelian antiherbivore defense that also affects tolerance to abiotic stressors. Urban-rural gradients were associated with the evolution of clines in defense in 47% of cities throughout the world. Variation in the strength of clines was explained by environmental changes in drought stress and vegetation cover that varied among cities. Sequencing 2074 genomes from 26 cities revealed that the evolution of urban-rural clines was best explained by adaptive evolution, but the degree of parallel adaptation varied among cities. Our results demonstrate that urbanization leads to adaptation at a global scale.

Disturbance has lasting effects on functional traits and diversity of grassland plant communities.

Background: Localized disturbances within grasslands alter biological properties and may shift species composition. For example, rare species in established communities may become dominant in successional communities if they exhibit traits well-suited to disturbance conditions. Although the idea that plant species exhibit different trait 'strategies' is well established, it is unclear how ecological selection for specific traits may change as a function of disturbance. Further, there is little data available testing whether disturbances select for single trait-characters within communities (homogenization), or allow multiple trait-types to persist (diversification). We investigated how (a) traits and (b) functional diversity of post-disturbance gap communities compared to those in adjacent undisturbed grasslands, and (c) if altered functional diversity resulted in the homogenization or diversification of functional traits. Methods: Here we emulate the impacts of an extreme disturbance in a native grassland site. We measured plant community composition of twelve paired 50 × 50 cm plots (24 total) in Alberta, Canada. Each pair consisted of one undisturbed plot and one which had all plants terminated 2 years prior. We used species abundances and a local trait database to calculate community weighted means for maximum height, specific leaf area, specific root length, leaf nitrogen percent, and root nitrogen percent. To test the impacts of disturbance on community functional traits, we calculated functional diversity measures and compared them between disturbed and undisturbed communities. Results: Within 2 years, species richness and evenness in disturbed communities had recovered and was equivalent to undisturbed communities. However, disturbed and undisturbed communities had distinct community compositions, resulting in lower functional divergence in disturbed plots. Further, disturbance was linked to increases in community-weighted mean trait values for resource-acquisitive traits, such as specific leaf area, and leaf and root nitrogen. Discussion: Disturbance had lasting effects on the functional traits and diversity of communities, despite traditional biodiversity measures such as richness and evenness recovering within 2 years. The trait space of gap communities shifted compared to undisturbed communities such that gap communities were dominated by traits enhancing resource uptake and growth rates. Overall, these results show that short-term disturbance fundamentally changes the functional character of early-successional communities, even if they superficially appear recovered.

The RppC-AvrRppC NLR-effector interaction mediates the resistance to southern corn rust in maize.

Southern corn rust (SCR), caused by the fungal pathogen Puccinia polysora, is a major threat to maize production worldwide. Efficient breeding and deployment of resistant hybrids are key to achieving durable control of SCR. Here, we report the molecular cloning and characterization of RppC, which encodes an NLR-type immune receptor and is responsible for a major SCR resistance quantitative trait locus. Furthermore, we identified the corresponding avirulence effector, AvrRppC, which is secreted by P. polysora and triggers RppC-mediated resistance. Allelic variation of AvrRppC directly determines the effectiveness of RppC-mediated resistance, indicating that monitoring of AvrRppC variants in the field can guide the rational deployment of RppC-containing hybrids in maize production. Currently, RppC is the most frequently deployed SCR resistance gene in China, and a better understanding of its mode of action is critical for extending its durability.

Host Defense Metabolites Alter the Interactions between a Bark Beetle and its Symbiotic Fungi.

Successful host plant colonization by tree-killing bark beetle-symbiotic fungal complexes depends on host suitability, which is largely determined by host defense metabolites such as monoterpenes. Studies have shown the ability of specific blends of host monoterpenes to influence bark beetles or their fungal symbionts, but how biologically relevant blends of host monoterpenes influence bark beetle-symbiotic fungal interaction is unknown. We tested how interactions between two host species (lodgepole pine or jack pine) and two fungal symbionts of mountain pine beetle (Grosmannia clavigera or Ophiostoma montium) affect the performance of adult female beetles in vitro. Beetles treated with the propagules of G. clavigera or O. montium or not treated (natural fungal load) were introduced into media amended with a blend of the entire monoterpene profile of either host species and beetle performance was compared. Overall, host blends altered beetle performance depending on the fungal species used in the beetle amendment. When beetles were amended with G. clavigera, their performance was superior over beetles amended with O. montium in either host blend. Furthermore, G. clavigera-amended beetles performed better in media amended with host blends than without a host blend; in contrast, O. montium-amended beetles performed better in media without a host blend than with a host blend. Overall, this study showed that host defense metabolites affect host suitability to bark beetles through influencing their fungal symbionts and that different species of fungal symbionts respond differentlly to host defense metabolites.

Positive selection in noncoding genomic regions of vocal learning birds is associated with genes implicated in vocal learning and speech functions in humans.

Vocal learning, the ability to imitate sounds from conspecifics and the environment, is a key component of human spoken language and learned song in three independently evolved avian groups-oscine songbirds, parrots, and hummingbirds. Humans and each of these three bird clades exhibit specialized behavioral, neuroanatomical, and brain gene expression convergence related to vocal learning, speech, and song. To understand the evolutionary basis of vocal learning gene specializations and convergence, we searched for and identified accelerated genomic regions (ARs), a marker of positive selection, specific to vocal learning birds. We found avian vocal learner-specific ARs, and they were enriched in noncoding regions near genes with known speech functions or brain gene expression specializations in humans and vocal learning birds, including FOXP2, NEUROD6, ZEB2, and MEF2C, and near genes with major neurodevelopmental functions, including NR2F1, NRP2, and BCL11B We also found enrichment near the SFARI class S genes associated with syndromic vocal communication forms of autism spectrum disorders. These findings reveal strong candidate noncoding regions near genes for the evolutionary adaptations that distinguish vocal learning species from their close vocal nonlearning relatives and provide further evidence of molecular convergence between birdsong and human spoken language.

Limited evidence of vertical fine-root segregation in a subtropical forest.

Vertical root segregation and the resulting niche partitioning can be a key underpinning of species coexistence. This could result from substantial interspecific variations in root profiles and rooting plasticity in response to soil heterogeneity and neighbours, but they remain largely untested in forest communities. In a diverse forest in subtropical China, we randomly sampled > 4000 root samples from 625 0-30 cm soil profiles. Using morphological and DNA-based methods, we identified 109 woody plant species, determined the degree of vertical fine-root segregation, and examined rooting plasticity in response to soil heterogeneity and neighbour structure. We found no evidence of vertical fine-root segregation among cooccurring species. By contrast, root abundance of different species tended to be positively correlated within soil zones. Underlying these findings was a lack of interspecific variation in fine-root profiles with over 90% of species concentrated in the 0-10 cm soil zone with only one species dominating in the 10-20 cm soil zone. Root profiles exhibited low responsiveness to root neighbours but tended to be shallow in soils with low phosphorus and copper content. These findings suggest that if there is niche differentiation leading to coexistence in this diverse forest, it would be occurring by mechanisms other than vertical fine-root segregation.

Inhibition of CMP-sialic acid transport by endogenous 5-methyl CMP.

Nucleotide-sugar transporters (NSTs) transport nucleotide-sugar conjugates into the Golgi lumen where they are then used in the synthesis of glycans. We previously reported crystal structures of a mammalian NST, the CMP-sialic acid transporter (CST) (Ahuja and Whorton 2019). These structures elucidated many aspects of substrate recognition, selectivity, and transport; however, one fundamental unaddressed question is how the transport activity of NSTs might be physiologically regulated as a means to produce the vast diversity of observed glycan structures. Here, we describe the discovery that an endogenous methylated form of cytidine monophosphate (m5CMP) binds and inhibits CST. The presence of m5CMP in cells results from the degradation of RNA that has had its cytosine bases post-transcriptionally methylated through epigenetic processes. Therefore, this work not only demonstrates that m5CMP represents a novel physiological regulator of CST, but it also establishes a link between epigenetic control of gene expression and regulation of glycosylation.

Long-Term Warming and Nitrogen Addition Have Contrasting Effects on Ecosystem Carbon Exchange in a Desert Steppe.

Desert steppe, a unique ecotone between steppe and desert in Eurasia, is considered highly vulnerable to global change. However, the long-term impact of warming and nitrogen deposition on plant biomass production and ecosystem carbon exchange in a desert steppe remains unknown. A 12-year field experiment was conducted in a Stipa breviflora desert steppe in northern China. A split-design was used, with warming simulated by infrared radiators as the primary factor and N addition as the secondary factor. Our long-term experiment shows that warming did not change net ecosystem exchange (NEE) or total aboveground biomass (TAB) due to contrasting effects on C4 (23.4% increase) and C3 (11.4% decrease) plant biomass. However, nitrogen addition increased TAB by 9.3% and NEE by 26.0% by increasing soil available N content. Thus, the studied desert steppe did not switch from a carbon sink to a carbon source in response to global change and positively responded to nitrogen deposition. Our study indicates that the desert steppe may be resilient to long-term warming by regulating plant species with contrasting photosynthetic types and that nitrogen deposition could increase plant growth and carbon sequestration, providing negative feedback on climate change.

Presence of a dominant native shrub is associated with minor shifts in the function and composition of grassland communities in a northern savannah.

Ecosystems are spatially heterogenous in plant community composition and function. Shrub occurrence in grasslands is a visually striking example of this, and much research has been conducted to understand the functional implications of this pattern. Within savannah ecosystems, the presence of tree and shrub overstories can have significant impacts on the understory herbaceous community. The exact outcomes, however, are likely a function of the spatial arrangement and traits of the overstory species. Here we test whether there are functional linkages between the spatial patterning of a native shrub and the standing biomass, community composition, and overall nutrient cycling of a neighbouring grassland understory communities within the Aspen Parkland of central Alberta, Canada. In a paired grassland-shrub stand study, we found the native shrub, Elaeagnus commutata, has relatively few stand-level impacts on the composition and standing biomass of the ecosystem. One factor contributing to these limited effects may be the overdispersion of shrub stems at fine spatial scales, preventing areas of deep shade. When we looked across a shrub density gradient and incorporated shrub architecture into our analyses, we found these shrub traits had significant associations with species abundance and root biomass in the understory community. These results suggest that stem dispersion patterns, as well as local stand architecture, are influential in determining how shrubs may affect their herbaceous plant understory. Thus, it is important to incorporate shrub spatial and architectural traits when assessing shrub-understory interactions.