Interspecific competition shapes bird species' distributions along tropical precipitation gradients.

The hypothesis that species' ranges are limited by interspecific competition has motivated decades of debate, but a general answer remains elusive. Here we test this hypothesis for lowland tropical birds by examining species' precipitation niche breadths. We focus on precipitation because it-not temperature-is the dominant climate variable that shapes the biota of the lowland tropics. We used 3.6 million fine-scale citizen science records from eBird to measure species' precipitation niche breadths in 19 different regions across the globe. Consistent with the predictions of the interspecific competition hypothesis, multiple lines of evidence show that species have narrower precipitation niches in regions with more species. This means species inhabit more specialized precipitation niches in species-rich regions. We predict this niche specialization should make tropical species in high diversity regions disproportionately vulnerable to changes in precipitation regimes; preliminary empirical evidence is consistent with this prediction.

A novel role of TRIM28 B box domain in L1 retrotransposition and ORF2p-mediated cDNA synthesis.

The long interspersed element 1 (LINE-1 or L1) integration is affected by many cellular factors through various mechanisms. Some of these factors are required for L1 amplification, while others either suppress or enhance specific steps during L1 propagation. Previously, TRIM28 has been identified to suppress transposable elements, including L1 expression via its canonical role in chromatin remodeling. Here, we report that TRIM28 through its B box domain increases L1 retrotransposition and facilitates shorter cDNA and L1 insert generation in cultured cells. Consistent with the latter, we observe that tumor specific L1 inserts are shorter in endometrial, ovarian, and prostate tumors with higher TRIM28 mRNA expression than in those with lower TRIM28 expression. We determine that three amino acids in the B box domain that are involved in TRIM28 multimerization are critical for its effect on both L1 retrotransposition and cDNA synthesis. We provide evidence that B boxes from the other two members in the Class VI TRIM proteins, TRIM24 and TRIM33, also increase L1 retrotransposition. Our findings could lead to a better understanding of the host/L1 evolutionary arms race in the germline and their interplay during tumorigenesis.

On the predictability of phenotypic divergence in geographic isolation.

Do related populations that are separated by barriers predictably evolve differences from one another over time, or is such divergence idiosyncratic and unpredictable? We test these alternatives by investigating patterns of trait evolution for 54 sister pairs of Andean forest birds that live in similar environments on either side of the arid Marañón Gap, a strong dispersal barrier for humid montane species. We measured divergence in both sexual (song and plumage) and ecological (beak size and beak shape) traits. Sexual traits evolve in a clock-like fashion, with trait divergence positively correlated with genetic distance (r = 0.6-0.7). In contrast, divergence in ecological traits is uncorrelated or only loosely correlated with genetic distance (r = 0.0-0.3). Thus, for geographically isolated Andean montane forest birds that live in similar environments, divergence is predictable in sexual traits, but not for ecological traits. This means that sexual trait divergence occurs independently of adaptive ecological divergence within the mega-diverse tropical Andean avifauna. Last, we show that variation in genetic divergence across a biogeographic barrier is associated with traits that are proxies for species' opportunities for dispersal (low elevation limit and elevational niche breadth), but not with traits that are proxies for species' dispersal abilities (hand-wing index and foraging strata).

Response to comment on "Interspecific competition limits bird species' ranges on tropical mountains".

Xing et al. (1) create new variables and fit models to argue against the hypothesis that interspecific competition shapes species' elevational ranges. However, their key newly created variable is best interpreted as a proxy for the important variable of the interspecific competition hypothesis. Thus, their reanalysis uncovers the patterns we already described that are consistent with the interspecific competition hypothesis.

Zanubrutinib in patients with previously treated B-cell malignancies intolerant of previous Bruton tyrosine kinase inhibitors in the USA: a phase 2, open-label, single-arm study.

BACKGROUND: We hypothesised that zanubrutinib, a highly selective next-generation Bruton tyrosine kinase (BTK) inhibitor, would be a safe and active treatment for patients intolerant of ibrutinib, acalabrutinib, or both. We aimed to assess whether zanubrutinib would prolong treatment duration by minimising treatment-related toxicities and discontinuations in patients with previously treated B-cell malignancies. METHODS: This ongoing, phase 2, multicentre, open-label, single-arm study was done in 20 centres in the USA. Patients aged 18 or older with previously treated B-cell malignancies (chronic lymphocytic leukaemia, small lymphocytic lymphoma, mantle cell lymphoma, Waldenström macroglobulinaemia, or marginal zone lymphoma) who became intolerant of ibrutinib, acalabrutinib, or both, were orally administered zanubrutinib 160 mg twice daily or 320 mg once daily per investigator. The primary endpoint was recurrence and change in severity of ibrutinib or acalabrutinib intolerance events based on investigator-assessed adverse events. Secondary endpoints were investigator-assessed overall response rate; duration of response; disease control rate; and progression-free survival. Analyses included all patients who received any dose of the study drug. This study is registered with ClinicalTrials.gov, NCT04116437. FINDINGS: Between Oct 14, 2019, and Sept 8, 2021, 67 patients (36 [54%] men and 31 [46%] women) who were intolerant of ibrutinib (n=57; cohort 1) or of acalabrutinib or acalabrutinib and ibrutinib (n=10; cohort 2) were enrolled. 63 (94%) patients were White, one (2%) had multiple ethnicities, and three (5%) had unreported or unknown ethnicity. Most intolerance events (81 [70%] of 115 for ibrutinib; 15 [83%] of 18 for acalabrutinib) did not recur with zanubrutinib. Of the recurring events, seven (21%) of 34 ibrutinib intolerance events and two (67%) of three acalabrutinib intolerance events recurred at the same severity with zanubrutinib; 27 (79%) ibrutinib intolerance events and one (33%) acalabrutinib intolerance event recurred at a lower severity with zanubrutinib. No events recurred at higher severity. No grade 4 intolerance events recurred. 64 (96%) of 67 patients had one or more adverse events with zanubrutinib; the most common adverse events were contusion (in 15 [22%] of 67 patients), fatigue (14 [21%]), myalgia (ten [15%]), arthralgia (nine [13%]), and diarrhoea (nine [13%]). Atrial fibrillation occurred in three (4%) patients (all grade 2). Eight (12%) of 67 patients had serious adverse events (anaemia, atrial fibrillation, bronchitis, COVID-19, COVID-19 pneumonia, febrile neutropenia, salmonella gastroenteritis, transfusion reaction, trigeminal nerve disorder, and urinary tract infection). No treatment-related deaths occurred. The median follow-up time was 12·0 months (IQR 8·2-15·6). Among the 64 efficacy-evaluable patients, disease control rate was 93·8% (60; 95% CI 84·8-98·3) and overall response rate was 64·1% (41; 95% CI 51·1-75·7). The median duration of response was not reached; the 12-month event-free duration of response rate was 95·0% (95% CI 69·5-99·3). Similarly, median progression-free survival was not reached; 18-month progression-free survival was 83·8% (95% CI 62·6-93·6). INTERPRETATION: Patients intolerant of previous BTK inhibitors have limited treatment options. These results suggest that zanubrutinib, a safe and viable treatment for patients with B-cell malignancies, might fill that unmet need for those who exhibit intolerance to ibrutinib or acalabrutinib. FUNDING: BeiGene.

Compact Cas9d and HEARO enzymes for genome editing discovered from uncultivated microbes.

Programmable, RNA-guided nucleases are diverse enzymes that have been repurposed for biotechnological applications. However, to further expand the therapeutic application of these tools there is a need for targetable systems that are small enough to be delivered efficiently. Here, we mined an extensive genome-resolved metagenomics database and identified families of uncharacterized RNA-guided, compact nucleases (between 450 and 1,050 aa). We report that Cas9d, a new CRISPR type II subtype, contains Zinc-finger motifs and high arginine content, features that we also found in nucleases related to HEARO effectors. These enzymes exhibit diverse biochemical characteristics and are broadly targetable. We show that natural Cas9d enzymes are capable of genome editing in mammalian cells with >90% efficiency, and further engineered nickase variants into the smallest base editors active in E. coli and human cells. Their small size, broad targeting potential, and translatability suggest that Cas9d and HEARO systems will enable a variety of genome editing applications.

MIRTH: Metabolite Imputation via Rank-Transformation and Harmonization.

Out of the thousands of metabolites in a given specimen, most metabolomics experiments measure only hundreds, with poor overlap across experimental platforms. Here, we describe Metabolite Imputation via Rank-Transformation and Harmonization (MIRTH), a method to impute unmeasured metabolite abundances by jointly modeling metabolite covariation across datasets which have heterogeneous coverage of metabolite features. MIRTH successfully recovers masked metabolite abundances both within single datasets and across multiple, independently-profiled datasets. MIRTH demonstrates that latent information about otherwise unmeasured metabolites is embedded within existing metabolomics data, and can be used to generate novel hypotheses and simplify existing metabolomic workflows.

Interspecific competition limits bird species' ranges in tropical mountains.

Species' geographic ranges are limited by climate and species interactions. Climate is the prevailing explanation for why species live only within narrow elevational ranges in megadiverse biodiverse tropical mountains, but competition can also restrict species' elevational ranges. We test contrasting predictions of these hypotheses by conducting a global comparative test of birds' elevational range sizes within 31 montane regions, using more than 4.4 million citizen science records from eBird to define species' elevational ranges in each region. We find strong support that competition, not climate, is the leading driver of narrow elevational ranges. These results highlight the importance of species interactions in shaping species' ranges in tropical mountains, Earth's hottest biodiversity hotspots.

Responsible agriculture must adapt to the wetland character of mid-latitude peatlands.

Drained, lowland agricultural peatlands are greenhouse gas (GHG) emission hotspots and a large but vulnerable store of irrecoverable carbon. They exhibit soil loss rates of ~2.0 cm yr-1 and are estimated to account for 32% of global cropland emissions while producing only 1.1% of crop kilocalories. Carbon dioxide emissions account for >80% of their terrestrial GHG emissions and are largely controlled by water table depth. Reducing drainage depths is, therefore, essential for responsible peatland management. Peatland restoration can substantially reduce emissions. However, this may conflict with societal needs to maintain productive use, to protect food security and livelihoods. Wetland agriculture strategies will, therefore, be required to adapt agriculture to the wetland character of peatlands, and balance GHG mitigation against productivity, where halting emissions is not immediately possible. Paludiculture may substantially reduce GHG emissions but will not always be viable in the current economic landscape. Reduced drainage intensity systems may deliver partial reductions in the rate of emissions, with smaller modifications to existing systems. These compromise systems may face fewer hurdles to adoption and minimize environmental harm until societal conditions favour strategies that can halt emissions. Wetland agriculture will face agronomic, socio-economic and water management challenges, and careful implementation will be required. Diversity of values and priorities among stakeholders creates the potential for conflict. Successful implementation will require participatory research approaches and co-creation of workable solutions. Policymakers, private sector funders and researchers have key roles to play but adoption risks would fall predominantly on land managers. Development of a robust wetland agriculture paradigm is essential to deliver resilient production systems and wider environmental benefits. The challenge of responsible use presents an opportunity to rethink peatland management and create thriving, innovative and green wetland landscapes for everyone's future benefit, while making a vital contribution to global climate change mitigation.

Genomic and Metabolic Hallmarks of SDH- and FH-deficient Renal Cell Carcinomas.

BACKGROUND: Succinate dehydrogenase-deficient and fumarate hydratase-deficient renal cell carcinomas (SDHRCC and FHRCC) are rare kidney cancers driven by loss of TCA cycle enzymes. OBJECTIVE: To define and compare the genomic and metabolomic hallmarks of SDHRCC and FHRCC. DESIGN, SETTING, AND PARTICIPANTS: We analyzed SDHRCC and FHRCC tumors with either immunohistochemical evidence of loss of protein expression or genomically confirmed biallelic inactivation of SDHA/B/C/D/AF2 or FH. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Somatic alterations were identified using clinical pipelines, with allele-specific copy number alterations (CNAs) identified using FACETS. Mass spectrometry-based metabolomic profiling was performed on available SDHRCC and FHRCC tumors. RESULTS AND LIMITATIONS: Tumors were analyzed for 42 patients (25 FHRCC, 17 SDHRCC). In the germline analysis, 16/17 SDHRCCs harbored a germline alteration in SDHB, whereas only 17/22 FHRCCs had pathogenic germline FH variants. SDHRCCs had a lower mutation burden (p = 0.02) and CNA burden (p = 0.0002) than FHRCCs. All SDHRCCs presented with deletion of chromosome 1p (overlapping SDHB), whereas FHRCCs demonstrated high but not ubiquitous loss of 1q (FH locus). Both SDHRCCs and FHRCCs exhibited significant idiopathic accumulation of the metabolite guanine. FHRCC tumors had elevated levels of urea cycle metabolites (argininosuccinate, citrulline, and fumarate), whereas SDHRCC tumors had elevation of numerous acylcarnitines. These characteristic metabolic changes allowed identification of a previously unrecognized SDH-deficient RCC. CONCLUSIONS: Despite sharing similar genetic etiology, SDHRCC and FHRCC represent distinct molecular entities with unique genetic and metabolic abnormalities. PATIENT SUMMARY: Kidney cancers driven by loss of the gene encoding either the succinate dehydrogenase or fumarate hydratase enzyme are rare. We sought to define and compare the genetic and metabolic features of these cancer entities.

The latitudinal gradient in rates of evolution for bird beaks, a species interaction trait.

Where is evolution fastest? The biotic interactions hypothesis proposes that greater species richness creates more ecological opportunity, driving faster evolution at low latitudes, whereas the 'empty niches' hypothesis proposes that ecological opportunity is greater where diversity is low, spurring faster evolution at high latitudes. We tested these contrasting predictions by analysing rates of beak evolution for a global dataset of 1141 avian sister species. Rates of beak size evolution are similar across latitudes, with some evidence that beak shape evolves faster in the temperate zone, consistent with the empty niches hypothesis. The empty niches hypothesis is further supported by a meta-analysis showing that rates of trait evolution and recent speciation are generally faster in the temperate zone, whereas rates of molecular evolution are slightly faster in the tropics. Our results suggest that drivers of evolutionary diversification are either similar across latitudes or more potent in the temperate zone, thus calling into question multiple hypotheses that invoke faster tropical evolution to explain the latitudinal diversity gradient.

AVONET: morphological, ecological and geographical data for all birds.

Functional traits offer a rich quantitative framework for developing and testing theories in evolutionary biology, ecology and ecosystem science. However, the potential of functional traits to drive theoretical advances and refine models of global change can only be fully realised when species-level information is complete. Here we present the AVONET dataset containing comprehensive functional trait data for all birds, including six ecological variables, 11 continuous morphological traits, and information on range size and location. Raw morphological measurements are presented from 90,020 individuals of 11,009 extant bird species sampled from 181 countries. These data are also summarised as species averages in three taxonomic formats, allowing integration with a global phylogeny, geographical range maps, IUCN Red List data and the eBird citizen science database. The AVONET dataset provides the most detailed picture of continuous trait variation for any major radiation of organisms, offering a global template for testing hypotheses and exploring the evolutionary origins, structure and functioning of biodiversity.

Faster evolution of a premating reproductive barrier is not associated with faster speciation rates in New World passerine birds.

Why are speciation rates so variable across the tree of life? One hypothesis is that this variation is explained by how rapidly reproductive barriers evolve. We tested this hypothesis by conducting a comparative study of the evolution of bird song, a premating barrier to reproduction. Speciation in birds is typically initiated when geographically isolated (allopatric) populations evolve reproductive barriers. We measured the strength of song as a premating barrier between closely related allopatric populations by conducting 2339 field experiments to measure song discrimination for 175 taxon pairs of allopatric or parapatric New World passerine birds, and estimated recent speciation rates from molecular phylogenies. We found evidence that song discrimination is indeed an important reproductive barrier: taxon pairs with high song discrimination in allopatry did not regularly interbreed in parapatry. However, evolutionary rates of song discrimination were not associated with recent speciation rates. Evolutionary rates of song discrimination were also unrelated to latitude or elevation, but species with innate song (suboscines) evolved song discrimination much faster than species with learned song (oscines). We conclude that song is a key premating reproductive barrier in birds, but faster evolution of this reproductive barrier between populations does not consistently result in faster diversification between species.

The formation of avian montane diversity across barriers and along elevational gradients.

Tropical mountains harbor exceptional concentrations of Earth's biodiversity. In topographically complex landscapes, montane species typically inhabit multiple mountainous regions, but are absent in intervening lowland environments. Here we report a comparative analysis of genome-wide DNA polymorphism data for population pairs from eighteen Indo-Pacific bird species from the Moluccan islands of Buru and Seram and from across the island of New Guinea. We test how barrier strength and relative elevational distribution predict population differentiation, rates of historical gene flow, and changes in effective population sizes through time. We find population differentiation to be consistently and positively correlated with barrier strength and a species' altitudinal floor. Additionally, we find that Pleistocene climate oscillations have had a dramatic influence on the demographics of all species but were most pronounced in regions of smaller geographic area. Surprisingly, even the most divergent taxon pairs at the highest elevations experience gene flow across barriers, implying that dispersal between montane regions is important for the formation of montane assemblages.

Analysis of epigenetic features characteristic of L1 loci expressed in human cells.

Only a select few L1 loci in the human genome are expressed in any given cell line or organ, likely to minimize damage done to the genome. The epigenetic features and requirements of expressed L1 loci are currently unknown. Using human cells and comprehensive epigenetic analysis of individual expressed and unexpressed L1 loci, we determined that endogenous L1 transcription depends on a combination of epigenetic factors, including open chromatin, activating histone modifications, and hypomethylation at the L1 promoter. We demonstrate that the L1 promoter seems to require interaction with enhancer elements for optimal function. We utilize epigenetic context to predict the expression status of L1Hs loci that are poorly mappable with RNA-Seq. Our analysis identified a population of 'transitional' L1 loci that likely have greater potential to be activated during the epigenetic dysregulation seen in tumors and during aging because they are the most responsive to targeted CRISPR-mediated delivery of trans-activating domains. We demonstrate that an engineered increase in endogenous L1 mRNA expression increases Alu mobilization. Overall, our findings present the first global and comprehensive analysis of epigenetic status of individual L1 loci based on their expression status and demonstrate the importance of epigenetic context for L1 expression heterogeneity.

Evolutionary conservatism will limit responses to climate change in the tropics.

Rapid species turnover in tropical mountains has fascinated biologists for centuries. A popular explanation for this heightened beta diversity is that climatic stability at low latitudes promotes the evolution of narrow thermal tolerance ranges, leading to local adaptation, evolutionary divergence and parapatric speciation along elevational gradients. However, an emerging consensus from research spanning phylogenetics, biogeography and behavioural ecology is that this process rarely, if ever, occurs. Instead, closely related species typically occupy a similar elevational niche, while species with divergent elevational niches tend to be more distantly related. These results suggest populations have responded to past environmental change not by adapting and diverging in place, but instead by shifting their distributions to tightly track climate over time. We argue that tropical species are likely to respond similarly to ongoing and future climate warming, an inference supported by evidence from recent range shifts. In the absence of widespread in situ adaptation to new climate regimes by tropical taxa, conservation planning should prioritize protecting large swaths of habitat to facilitate movement.

Resource-efficient pooled sequencing expands translational impact in solid tumors.

Intratumoral genetic heterogeneity (ITH) poses a significant challenge to utilizing sequencing for decision making in the management of cancer. Although sequencing of multiple tumor regions can address the pitfalls of ITH, it does so at a significant increase in cost and resource utilization. We propose a pooled multiregional sequencing strategy, whereby DNA aliquots from multiple tumor regions are mixed prior to sequencing, as a cost-effective strategy to boost translational value by addressing ITH while preserving valuable residual tissue for secondary analysis. Focusing on kidney cancer, we demonstrate that DNA pooling from as few as two regions significantly increases mutation detection while reducing clonality misattribution. This leads to an increased fraction of patients identified with therapeutically actionable mutations, improved patient risk stratification, and improved inference of evolutionary trajectories with an accuracy comparable to bona fide multiregional sequencing. The same approach applied to non-small-cell lung cancer data substantially improves tumor mutational burden (TMB) detection. Our findings demonstrate that pooled DNA sequencing strategies are a cost-effective alternative to address intrinsic genetic heterogeneity in clinical settings.

The latitudinal taxonomy gradient.

Emerging large-scale datasets coupled with statistical advances have provided new insights into the processes that generate the latitudinal diversity gradient (LDG). But many of these studies run into an old, if often underappreciated, problem: The interpretation of the data critically depends on the consistent application of criteria to define what constitutes a species. This is particularly pernicious for the LDG because good species have been easier to recognize in temperate than in tropical regions. We provide evidence that this latitudinal taxonomy gradient exists, discuss how this potentially impacts inferences about latitudinal variation in ecoevolutionary processes such as population differentiation and speciation, and provide a roadmap for how to mitigate taxonomic biases in the study of biodiversity patterns.

Montane species track rising temperatures better in the tropics than in the temperate zone.

Many species are responding to global warming by shifting their distributions upslope to higher elevations, but the observed rates of shifts vary considerably among studies. Here, we test the hypothesis that this variation is in part explained by latitude, with tropical species being particularly responsive to warming temperatures. We analyze two independent empirical datasets-shifts in species' elevational ranges, and changes in composition of forest inventory tree plots. Tropical species are tracking rising temperatures 2.1-2.4 times (range shift dataset) and 10 times (tree plot dataset) better than their temperate counterparts. Models predict that for a 100 m upslope shift in temperature isotherm, species at the equator have shifted their elevational ranges 93-96 m upslope, while species at 45° latitude have shifted only 37-42 m upslope. For tree plots, models predict that a 1°C increase in temperature leads to an increase in community temperature index (CTI), a metric of the average temperature optima of tree species within a plot, of 0.56°C at the equator but no change in CTI at 45° latitude (-0.033°C). This latitudinal gradient in temperature tracking suggests that tropical montane communities may be on an "escalator to extinction" as global temperatures continue to rise.