EBP-Colombia and the bioeconomy: Genomics in the service of biodiversity conservation and sustainable development.

The 2016 Peace Agreement has increased access to Colombia's unique ecosystems, which remain understudied and increasingly under threat. The Colombian government has recently announced its National Bioeconomic Strategy (NBS), founded on the sustainable characterization, management, and conservation of the nation's biodiversity as a means to achieve sustainability and peace. Molecular tools will accelerate such endeavors, but capacity remains limited in Colombia. The Earth Biogenome Project's (EBP) objective is to characterize the genomes of all eukaryotic life on Earth through networks of partner institutions focused on sequencing either specific taxa or eukaryotic communities at regional or national scales. Colombia's immense biodiversity and emerging network of stakeholders have inspired the creation of the national partnership "EBP-Colombia." Here, we discuss how this Colombian-driven collaboration between government, academia, and the private sector is integrating research with sustainable, environmentally focused strategies to develop Colombia's postconflict bioeconomy and conserve biological and cultural diversity. EBP-Colombia will accelerate the uptake of technology and promote partnership and exchange of knowledge among Colombian stakeholders and the EBP's global network of experts; assist with conservation strategies to preserve Colombia's vast biological wealth; and promote innovative approaches among public and private institutions in sectors such as agriculture, tourism, recycling, and medicine. EBP-Colombia can thus support Colombia's NBS with the objective of sustainable and inclusive development to address the many social, environmental, and economic challenges, including conflict, inequality, poverty, and low agricultural productivity, and so, offer an alternative model for economic development that similarly placed countries can adopt.

Constraints on the evolution of toxin-resistant Na,K-ATPases have limited dependence on sequence divergence.

A growing body of theoretical and experimental evidence suggests that intramolecular epistasis is a major determinant of rates and patterns of protein evolution and imposes a substantial constraint on the evolution of novel protein functions. Here, we examine the role of intramolecular epistasis in the recurrent evolution of resistance to cardiotonic steroids (CTS) across tetrapods, which occurs via specific amino acid substitutions to the α-subunit family of Na,K-ATPases (ATP1A). After identifying a series of recurrent substitutions at two key sites of ATP1A that are predicted to confer CTS resistance in diverse tetrapods, we then performed protein engineering experiments to test the functional consequences of introducing these substitutions onto divergent species backgrounds. In line with previous results, we find that substitutions at these sites can have substantial background-dependent effects on CTS resistance. Globally, however, these substitutions also have pleiotropic effects that are consistent with additive rather than background-dependent effects. Moreover, the magnitude of a substitution's effect on activity does not depend on the overall extent of ATP1A sequence divergence between species. Our results suggest that epistatic constraints on the evolution of CTS-resistant forms of Na,K-ATPase likely depend on a small number of sites, with little dependence on overall levels of protein divergence. We propose that dependence on a limited number sites may account for the observation of convergent CTS resistance substitutions observed among taxa with highly divergent Na,K-ATPases (See S1 Text for Spanish translation).

Standards recommendations for the Earth BioGenome Project.

A global international initiative, such as the Earth BioGenome Project (EBP), requires both agreement and coordination on standards to ensure that the collective effort generates rapid progress toward its goals. To this end, the EBP initiated five technical standards committees comprising volunteer members from the global genomics scientific community: Sample Collection and Processing, Sequencing and Assembly, Annotation, Analysis, and IT and Informatics. The current versions of the resulting standards documents are available on the EBP website, with the recognition that opportunities, technologies, and challenges may improve or change in the future, requiring flexibility for the EBP to meet its goals. Here, we describe some highlights from the proposed standards, and areas where additional challenges will need to be met.

Impact of 30-day prescribed opioid dose trajectory on fatal overdose risk: A population-based, statewide cohort study.

BACKGROUND: Both increases and decreases in patients' prescribed daily opioid dose have been linked to increased overdose risk, but associations between 30-day dose trajectories and subsequent overdose risk have not been systematically examined. OBJECTIVE: To examine the associations between 30-day prescribed opioid dose trajectories and fatal opioid overdose risk during the subsequent 15 days. DESIGN: Statewide cohort study using linked prescription drug monitoring program and death certificate data. We constructed a multivariable Cox proportional hazards model that accounted for time-varying prescription-, prescriber-, and pharmacy-level factors. PARTICIPANTS: All patients prescribed an opioid analgesic in California from March to December, 2013 (5,326,392 patients). MAIN MEASURES: Dependent variable: fatal drug overdose involving opioids. Primary independent variable: a 16-level variable denoting all possible opioid dose trajectories using the following categories for current and 30-day previously prescribed daily dose: 0-29, 30-59, 60-89, or ≥90 milligram morphine equivalents (MME). KEY RESULTS: Relative to patients prescribed a stable daily dose of 0-29 MME, large (≥2 categories) dose increases and having a previous or current dose ≥60 MME per day were associated with significantly greater 15-day overdose risk. Patients whose dose decreased from ≥90 to 0-29 MME per day had significantly greater overdose risk compared to both patients prescribed a stable daily dose of ≥90 MME (aHR 3.56, 95%CI 2.24-5.67) and to patients prescribed a stable daily dose of 0-29 MME (aHR 7.87, 95%CI 5.49-11.28). Patients prescribed benzodiazepines also had significantly greater overdose risk; being prescribed Z-drugs, carisoprodol, or psychostimulants was not associated with overdose risk. CONCLUSIONS: Large (≥2 categories) 30-day dose increases and decreases were both associated with increased risk of fatal opioid overdose, particularly for patients taking ≥90 MME whose opioids were abruptly stopped. Results align with 2022 CDC guidelines that urge caution when reducing opioid doses for patients taking long-term opioid for chronic pain.

Comparison of record linkage software for deduplicating patient identities in California's Prescription Drug Monitoring Program.

BACKGROUND: To help prevent overdose deaths involving prescription drugs, accurate linkage of prescription drug monitoring program (PDMP) records for individual patients is essential. OBJECTIVES: To compare the accuracy of the linkage program used by California's PDMP against various record linkage programs with respect to accuracy in deduplicating patient identities in the PDMP, with implications for identifying high-risk opioid use and outlier behaviors. RESEARCH DESIGN: We evaluated California's program, Link Plus, LinkSolv, and The Link King on 557 861 PDMP identity records with addresses in two 3-digit zip code areas for patients who filled a controlled substance prescription in 2013. Manual review was performed on a stratified sample of 720 paired records identified as matches by at least one program. MEASURES: We estimated sensitivity and positive predictive value, and computed PDMP patient alerts for the patient entities identified by each program. RESULTS: Sensitivity was 95% for LinkSolv and The Link King, 84% for Link Plus, and 73% for California's program; positive predictive value was ≥93% for all programs. The number of patient entities prompting a PDMP alert was similar among the programs for all alerts except multiple provider episodes (obtaining prescriptions from ≥6 prescribers or ≥6 pharmacies in the last 6 months), which were 10.9%, 26.6%, and 16.9% greater using The Link King, Link Plus, and LinkSolv, respectively, compared to California's program. CONCLUSIONS: PDMPs should assess the accuracy of record linkage algorithms and the impacts of these algorithms on patient safety alerts and develop national best practices for PDMP record linkage.

Epistatic Effects Between Amino Acid Insertions and Substitutions Mediate Toxin resistance of Vertebrate Na+,K+-ATPases.

The recurrent evolution of resistance to cardiotonic steroids (CTS) across diverse animals most frequently involves convergent amino acid substitutions in the H1-H2 extracellular loop of Na+,K+-ATPase (NKA). Previous work revealed that hystricognath rodents (e.g., chinchilla) and pterocliform birds (sandgrouse) have convergently evolved amino acid insertions in the H1-H2 loop, but their functional significance was not known. Using protein engineering, we show that these insertions have distinct effects on CTS resistance in homologs of each of the two species that strongly depend on intramolecular interactions with other residues. Removing the insertion in the chinchilla NKA unexpectedly increases CTS resistance and decreases NKA activity. In the sandgrouse NKA, the amino acid insertion and substitution Q111R both contribute to an augmented CTS resistance without compromising ATPase activity levels. Molecular docking simulations provide additional insight into the biophysical mechanisms responsible for the context-specific mutational effects on CTS insensitivity of the enzyme. Our results highlight the diversity of genetic substrates that underlie CTS insensitivity in vertebrate NKA and reveal how amino acid insertions can alter the phenotypic effects of point mutations at key sites in the same protein domain.

Guideline-based and restricted fluid resuscitation strategy in sepsis patients with heart failure: A systematic review and meta-analysis.

OBJECTIVES: To examine whether a fluid resuscitation strategy based on guidelines (at least 30 mL/kg IV crystalloids) vs. a restrictive approach with <30 mL/kg within three hours affects in-hospital mortality in patients with sepsis and a history of heart failure (HF). DATA SOURCES: On 03/07/2023, we searched Embase, PubMed, and Scopus for peer-reviewed papers and abstracts using the PRISMA guidelines. STUDY SELECTION: The language was limited to English. Studies published since 2016 included if they had sepsis patients with a history of HF, or a subgroup of patients with HF, and in-hospital mortality data on these patients that did or did not meet the 30 mL/kg by 3 h (30 × 3) goal. Duplicate studies, studies that focused on a broader period than 3 h from the diagnosis of sepsis or without mortality breakdown for HF patients or with unrelated title/abstract, or without an IRB approval were excluded. DATA EXTRACTION: In-hospital mortality data was taken from the final studies for HF patients with sepsis who did or did not meet the 30 × 3 goal. DATA SYNTHESIS: The meta-analysis was performed using the Review Manager 5.4 program with ORs as the effect measure. The ProMeta program version 3.0 was used to evaluate the publication bias. Egger's linear regression and Berg and Mazumdar's rank correlation was used to evaluate the publication bias. The result was visually represented by a funnel plot. To estimate the proportion of variance attributable to heterogeneity, the I2 statistic was calculated. RESULTS: The search yielded 26,069 records, which were narrowed down to 4 studies. Compared to those who met the 30 × 3 goal, the <30 × 3 group had a significantly higher risk of in-hospital mortality (OR = 1.81, 95% CI = 1.13-2.89, P = 0.01). CONCLUSIONS: Restrictive fluid resuscitation increased the risk of in-hospital mortality in HF patients with sepsis. More rigorous research is required to determine the optimal fluid resuscitation strategy for this population.

First evidence of ranavirus in native and invasive amphibians in Colombia.

Ranaviruses can cause mass mortality events in amphibians, thereby becoming a threat to populations that are already facing dramatic declines. Ranaviruses affect all life stages and persist in multiple amphibian hosts. The detrimental effects of ranavirus infections to amphibian populations have already been observed in the UK and in North America. In Central and South America, the virus has been reported in several countries, but the presence of the genus Ranavirus (Rv) in Colombia is unknown. To help fill this knowledge gap, we surveyed for Rv in 60 species of frogs (including one invasive species) in Colombia. We also tested for co-infection with Batrachochytrium dendrobatidis (Bd) in a subset of individuals. For Rv, we sampled 274 vouchered liver tissue samples collected between 2014 and 2019 from 41 localities covering lowlands to mountaintop páramo habitat across the country. Using quantitative polymerase chain reaction (qPCR) and end-point PCR, we detected Rv in 14 individuals from 8 localities, representing 6 species, including 5 native frogs of the genera Osornophryne, Pristimantis and Leptodactylus, and the invasive American bullfrog Rana catesbeiana. Bd was detected in 7 of 140 individuals, with 1 co-infection of Rv and Bd in an R. catesbeiana specimen collected in 2018. This constitutes the first report of ranavirus in Colombia and should set off alarms about this new emerging threat to amphibian populations in the country. Our findings provide some preliminary clues about how and when Rv may have spread and contribute to understanding how the pathogen is distributed globally.

How to Make a Rodent Giant: Genomic Basis and Tradeoffs of Gigantism in the Capybara, the World's Largest Rodent.

Gigantism results when one lineage within a clade evolves extremely large body size relative to its small-bodied ancestors, a common phenomenon in animals. Theory predicts that the evolution of giants should be constrained by two tradeoffs. First, because body size is negatively correlated with population size, purifying selection is expected to be less efficient in species of large body size, leading to increased mutational load. Second, gigantism is achieved through generating a higher number of cells along with higher rates of cell proliferation, thus increasing the likelihood of cancer. To explore the genetic basis of gigantism in rodents and uncover genomic signatures of gigantism-related tradeoffs, we assembled a draft genome of the capybara (Hydrochoerus hydrochaeris), the world's largest living rodent. We found that the genome-wide ratio of nonsynonymous to synonymous mutations (ω) is elevated in the capybara relative to other rodents, likely caused by a generation-time effect and consistent with a nearly neutral model of molecular evolution. A genome-wide scan for adaptive protein evolution in the capybara highlighted several genes controlling postnatal bone growth regulation and musculoskeletal development, which are relevant to anatomical and developmental modifications for an increase in overall body size. Capybara-specific gene-family expansions included a putative novel anticancer adaptation that involves T-cell-mediated tumor suppression, offering a potential resolution to the increased cancer risk in this lineage. Our comparative genomic results uncovered the signature of an intragenomic conflict where the evolution of gigantism in the capybara involved selection on genes and pathways that are directly linked to cancer.

The impact of California wildfires on patient access to prescription opioids.

BACKGROUND: Patients on long-term opioid therapy are particularly vulnerable to disruptions in medication access, especially during traumatic and chaotic events such as wildfires and other natural disasters. OBJECTIVES: To determine whether past highly destructive California wildfires were associated with disrupted access to prescription opioids for patients receiving long-term, and therefore physically dependent on, opioid medications. METHODS: Using California prescription drug monitoring program data, this retrospective study selected patients with long-term prescription opioid use episodes residing in ZIP code tabulation areas impacted by either the Camp Fire or Tubbs Fire. Autoregressive integrated moving average time series models were fit to pre-fire data to forecast post-fire expected values and then compared with observed post-fire data, specifically for weekly proportions of long-term episodes with early fills, late fills, changes in patients' prescriber and pharmacy, and fills within a different ZIP code tabulation area than the patient's residence. RESULTS: After the Camp Fire, there were significant spikes in the proportions of early fills (peak at 56% of total, week 1 after fire), late fills (peak at 29%, week 6), and immediate significant increases in prescriber (peak at 37%, week 3) and pharmacy changes (peak at 71%, week 1) in high-impact ZIP code tabulation areas. Low-impact ZIP code tabulation areas experienced no similar disruptions. Disruptions due to the Tubbs Fire were far less severe. CONCLUSION: Access to prescription opioids was greatly disrupted for patients living in areas most impacted by the Camp Fire. Future research should explore effectiveness of current state and federal controlled substance prescribing policies to determine what improvements are needed to minimize disruptions in medication access due to wildfires and other natural disasters.

Maternal Stressful Life Events During the Periconceptional Period and Orofacial Clefts: A Systematic Review and Meta-Analysis.

OBJECTIVE: To assess whether women who experience stressful life events during the periconceptional period are at higher risk of giving birth to a baby with an orofacial cleft (OFC). DESIGN: Systematic review and meta-analysis of studies reporting the proportion of babies born with OFC to mothers exposed and unexposed to population-level or personal-level stressful life events during the periconceptional period. Six electronic databases were searched from inception to August 2020. Risk of bias was assessed using the Newcastle-Ottawa scale. Odds ratios (ORs) for the odds of OFC in babies of exposed mothers relative to unexposed controls were extracted and/or calculated. Random effects meta-analysis was undertaken, stratified by cleft subtype. RESULTS: Of 12 eligible studies, 8 examined experience of personal events and 4 examined population-level events. Studies demonstrated low-moderate risk of bias and there was indication of publication bias. There was some evidence that personal stressful life events were associated with greater odds of cleft lip and/or palate (six studies, OR 1.63, 95% confidence interval (CI) 1.16, 2.30, P = 0.001) and cleft palate only (six studies, OR 1.45, 95% CI 1.02, 2.06, P = 0.04). Population-level events were associated with higher odds of OFC in studies that did not specify subtype (three studies, OR 1.64, 95% CI 1.19, 2.25, P = 0.002), but subtype stratified analyses were underpowered. Heterogeneity was high. CONCLUSIONS: Limited evidence indicated a weak positive association between maternal stressful life events during the periconceptional period and risk of OFC in the offspring, but further studies with greater consistency in research design are needed.

Gross, computed tomographic, and endoscopic anatomy of the equine carpal extensor tendon sheaths.

OBJECTIVE: (1) To describe the computed tomography (CT) and gross anatomy of the equine extensor carpi radialis sheath (ECRS) and common digital extensor sheath (CDETS); (2) to describe a single-portal endoscopic examination of the ECRS and CDETS. STUDY DESIGN: Ex vivo experimental. SAMPLE POPULATION: Thirty clinically normal cadaver thoracic equine limbs severed at the humeral diaphysis. METHODS: Ten limbs underwent plain and intrathecal contrast CT examinations and gross dissection of the ECRS and CDETS. Single-portal endoscopic examination of ECRS and CDETS was attempted in 4 limbs and endoscopic examination was performed on 16 limbs. Endoscopic video recordings were reviewed by 3 observers for quality of visualization before dissection and examination for iatrogenic damage. Interobserver agreement for ECRS and CDETS visualization was determined with Fleiss' κ agreement. RESULTS: Extensor carpi radialis sheath and CDETS anatomy was consistent between gross dissection and CT examinations. The ECRS endoscopic portal was medial at the level of the intersection between the extensor carpi obliquus and extensor carpi radialis tendon. The CDETS endoscopic portal was lateral, 5 cm proximal to the lateral styloid process of the ulna. The ECRS and CDETS were well visualized and interobserver agreement was substantial (κ = .73; P < .0001) and moderate (κ = .53; P < .0001), respectively. CONCLUSION: Computed tomography examinations provided useful anatomical information, consistent with gross dissection of the ECRS and CDETS. The described single-portal endoscopic techniques allowed consistent tenoscopic examination of the majority of the ECRS and CDETS. CLINICAL SIGNIFICANCE: Awareness of the intrathecal anatomy of the ECRS and CDETS should facilitate the treatment of these tendon sheaths. The proposed portals provide good to excellent single-site endoscopic visualization of the majority of the ECRS and CDETS.

Abridged spectral matrix inversion: parametric fitting of X-ray fluorescence spectra following integrative data reduction.

Recent improvements in both X-ray detectors and readout speeds have led to a substantial increase in the volume of X-ray fluorescence data being produced at synchrotron facilities. This in turn results in increased challenges associated with processing and fitting such data, both temporally and computationally. Herein an abridging approach is described that both reduces and partially integrates X-ray fluorescence (XRF) data sets to obtain a fivefold total improvement in processing time with negligible decrease in quality of fitting. The approach is demonstrated using linear least-squares matrix inversion on XRF data with strongly overlapping fluorescent peaks. This approach is applicable to any type of linear algebra based fitting algorithm to fit spectra containing overlapping signals wherein the spectra also contain unimportant (non-characteristic) regions which add little (or no) weight to fitted values, e.g. energy regions in XRF spectra that contain little or no peak information.

Variation in the SERPINA6/SERPINA1 locus alters morning plasma cortisol, hepatic corticosteroid binding globulin expression, gene expression in peripheral tissues, and risk of cardiovascular disease.

The stress hormone cortisol modulates fuel metabolism, cardiovascular homoeostasis, mood, inflammation and cognition. The CORtisol NETwork (CORNET) consortium previously identified a single locus associated with morning plasma cortisol. Identifying additional genetic variants that explain more of the variance in cortisol could provide new insights into cortisol biology and provide statistical power to test the causative role of cortisol in common diseases. The CORNET consortium extended its genome-wide association meta-analysis for morning plasma cortisol from 12,597 to 25,314 subjects and from ~2.2 M to ~7 M SNPs, in 17 population-based cohorts of European ancestries. We confirmed the genetic association with SERPINA6/SERPINA1. This locus contains genes encoding corticosteroid binding globulin (CBG) and α1-antitrypsin. Expression quantitative trait loci (eQTL) analyses undertaken in the STARNET cohort of 600 individuals showed that specific genetic variants within the SERPINA6/SERPINA1 locus influence expression of SERPINA6 rather than SERPINA1 in the liver. Moreover, trans-eQTL analysis demonstrated effects on adipose tissue gene expression, suggesting that variations in CBG levels have an effect on delivery of cortisol to peripheral tissues. Two-sample Mendelian randomisation analyses provided evidence that each genetically-determined standard deviation (SD) increase in morning plasma cortisol was associated with increased odds of chronic ischaemic heart disease (0.32, 95% CI 0.06-0.59) and myocardial infarction (0.21, 95% CI 0.00-0.43) in UK Biobank and similarly in CARDIoGRAMplusC4D. These findings reveal a causative pathway for CBG in determining cortisol action in peripheral tissues and thereby contributing to the aetiology of cardiovascular disease.

A Risk Prediction Model for Long-term Prescription Opioid Use.

BACKGROUND: Tools are needed to aid clinicians in estimating their patients' risk of transitioning to long-term opioid use and to inform prescribing decisions. OBJECTIVE: The objective of this study was to develop and validate a model that predicts previously opioid-naive patients' risk of transitioning to long-term use. RESEARCH DESIGN: This was a statewide population-based prognostic study. SUBJECTS: Opioid-naive (no prescriptions in previous 2 y) patients aged 12 years old and above who received a pill-form opioid analgesic in 2016-2018 and whose prescriptions were registered in the California Prescription Drug Monitoring Program (PDMP). MEASURES: A multiple logistic regression approach was used to construct a prediction model with long-term (ie, >90 d) opioid use as the outcome. Models were developed using 2016-2017 data and validated using 2018 data. Discrimination (c-statistic), calibration (calibration slope, intercept, and visual inspection of calibration plots), and clinical utility (decision curve analysis) were evaluated to assess performance. RESULTS: Development and validation cohorts included 7,175,885 and 2,788,837 opioid-naive patients with outcome rates of 5.0% and 4.7%, respectively. The model showed high discrimination (c-statistic: 0.904 for development, 0.913 for validation), was well-calibrated after intercept adjustment (intercept, -0.006; 95% confidence interval, -0.016 to 0.004; slope, 1.049; 95% confidence interval, 1.045-1.053), and had a net benefit over a wide range of probability thresholds. CONCLUSIONS: A model for the transition from opioid-naive status to long-term use had high discrimination and was well-calibrated. Given its high predictive performance, this model shows promise for future integration into PDMPs to aid clinicians in formulating opioid prescribing decisions at the point of care.

Using Prescription Drug Monitoring Program Data to Assess Likelihood of Incident Long-Term Opioid Use: a Statewide Cohort Study.

BACKGROUND: Limiting the incidence of opioid-naïve patients who transition to long-term opioid use (i.e., continual use for > 90 days) is a key strategy for reducing opioid-related harms. OBJECTIVE: To identify variables constructed from data routinely collected by prescription drug monitoring programs that are associated with opioid-naïve patients' likelihood of transitioning to long-term use after an initial opioid prescription. DESIGN: Statewide cohort study using prescription drug monitoring program data PARTICIPANTS: All opioid-naïve patients in California (no opioid prescriptions within the prior 2 years) age ≥ 12 years prescribed an initial oral opioid analgesic from 2010 to 2017. METHODS AND MAIN MEASURES: Multiple logistic regression models using variables constructed from prescription drug monitoring program data through the day of each patient's initial opioid prescription, and, alternatively, data available up to 30 and 60 days after the initial prescription were constructed to identify probability of transition to long-term use. Model fit was determined by the area under the receiver operating characteristic curve (C-statistic). KEY RESULTS: Among 30,569,125 episodes of patients receiving new opioid prescriptions, 1,809,750 (5.9%) resulted in long-term use. Variables with the highest adjusted odds ratios included concurrent benzodiazepine use, ≥ 2 unique prescribers, and receipt of non-pill, non-liquid formulations. C-statistics for the day 0, day 30, and day 60 models were 0.81, 0.88, and 0.94, respectively. Models assessing opioid dose using the number of pills prescribed had greater discriminative capacity than those using milligram morphine equivalents. CONCLUSIONS: Data routinely collected by prescription drug monitoring programs can be used to identify patients who are likely to develop long-term use. Guidelines for new opioid prescriptions based on pill counts may be simpler and more clinically useful than guidelines based on days' supply or milligram morphine equivalents.

Idiosyncratic responses to drivers of genetic differentiation in the complex landscapes of Isthmian Central America.

Isthmian Central America (ICA) is one of the most biodiverse regions in the world, hosting an exceptionally high number of species per unit area. ICA was formed <25 million years ago and, consequently, its biotic assemblage is relatively young and derived from both colonization and in situ diversification. Despite intensive taxonomic work on the local fauna, the potential forces driving genetic divergences and ultimately speciation in ICA remain poorly studied. Here, we used a landscape genetics approach to test whether isolation by distance, topography, habitat suitability, or environment drive the genetic diversity of the regional frog assemblage. To this end, we combined data on landscape features and mitochondrial DNA sequence variation for nine codistributed amphibian species with disparate life histories. In five species, we found that at least one of the factors tested explained patterns of genetic divergence. However, rather than finding a general pattern, our results revealed idiosyncratic responses to historical and ecological processes, indicating that intrinsic life-history characteristics may determine the effect of different drivers of isolation on genetic divergence in ICA. Our work also suggests that the convergence of several factors promoting isolation among populations over a heterogeneous landscape might maximize genetic differentiation, despite short geographical distances. In conclusion, abiotic factors and geographical features have differentially affected the genetic diversity across the regional frog assemblage. Much more complex models (i.e., considering multiple drivers), beyond simple vicariance of Caribbean and Pacific lineages, are needed to better understand the evolutionary history of ICA's diverse biotas.

Correction to: Is population structure in the genetic biobank era irrelevant, a challenge, or an opportunity?

In the original article publication, there is an incorrect impression that Fig. 1 formed a formal Directed Acyclic Graph (DAG) by describing it as a causal model. However, it was not correct if interpreted in this way.

Is population structure in the genetic biobank era irrelevant, a challenge, or an opportunity?

Replicable genetic association signals have consistently been found through genome-wide association studies in recent years. The recent dramatic expansion of study sizes improves power of estimation of effect sizes, genomic prediction, causal inference, and polygenic selection, but it simultaneously increases susceptibility of these methods to bias due to subtle population structure. Standard methods using genetic principal components to correct for structure might not always be appropriate and we use a simulation study to illustrate when correction might be ineffective for avoiding biases. New methods such as trans-ethnic modeling and chromosome painting allow for a richer understanding of the relationship between traits and population structure. We illustrate the arguments using real examples (stroke and educational attainment) and provide a more nuanced understanding of population structure, which is set to be revisited as a critical aspect of future analyses in genetic epidemiology. We also make simple recommendations for how problems can be avoided in the future. Our results have particular importance for the implementation of GWAS meta-analysis, for prediction of traits, and for causal inference.

Whole-Genome Sequencing Coupled to Imputation Discovers Genetic Signals for Anthropometric Traits.

Deep sequence-based imputation can enhance the discovery power of genome-wide association studies by assessing previously unexplored variation across the common- and low-frequency spectra. We applied a hybrid whole-genome sequencing (WGS) and deep imputation approach to examine the broader allelic architecture of 12 anthropometric traits associated with height, body mass, and fat distribution in up to 267,616 individuals. We report 106 genome-wide significant signals that have not been previously identified, including 9 low-frequency variants pointing to functional candidates. Of the 106 signals, 6 are in genomic regions that have not been implicated with related traits before, 28 are independent signals at previously reported regions, and 72 represent previously reported signals for a different anthropometric trait. 71% of signals reside within genes and fine mapping resolves 23 signals to one or two likely causal variants. We confirm genetic overlap between human monogenic and polygenic anthropometric traits and find signal enrichment in cis expression QTLs in relevant tissues. Our results highlight the potential of WGS strategies to enhance biologically relevant discoveries across the frequency spectrum.