Biology subjects

Lee, S.

Publications and source records attributed to Lee, S..

At least 703 records · Page 39Linked to original sources

bioRxiv2018

Real-time monitoring of bacterial growth and fast antimicrobial susceptibility tests exploiting multiple light scattering

AbstractAntimicrobial susceptibility test (AST) is widely used to provide the minimum inhibitory concentration of bacteria, and crucial to provide appropriate uses of antibiotics and to address the issue of drug-resistance bacteria. However, ASTs require the time-consuming incubation about 16-20 h for the visual determination of the growth of bacterial colonies, which has been a major obstacle to on-site applications of ASTs. In this study, we propose a rapid and non-invasive method based on laser speckles to evaluate the bacterial growth movements in real time, thus reducing the time for the agar dilution method. With a simple configuration compatible with conventional agar plates, the analysis of laser speckle from samples enables the early detection of the presence of growth as well as its detailed history of the colony-forming movement on agar plates. Using the samples prepared through the same procedure as the agar dilution method, we obtained the AST results at least 4-8 hours earlier than the conventional method without compromising the accuracy. This technique does not require for the use of exogenous agents, but works for most bacteria regardless of their species. Furthermore, the distinctive responses of several species to microbial agents were revealed through the present technique supporting a comprehensive analysis of the effect of the antibiotics. The findings suggest that this new method could be a useful tool for rapid, simple, and low-cost ASTs in addition to providing the historical information of the bacterial growth on agar plates.

microbiology↗

bioRxiv2018

3D brain angiogenesis model to reconstitute maturation of functional human blood-brain barrier in vitro

0.Human central nervous system (CNS) vasculature in brain expresses a distinctive barrier phenotype, the blood-brain barrier (BBB), which protects the brain against harmful pathogens. Since the BBB contributes to low success rate in CNS pharmacotherapy by restricting drug transportation, the development of an in vitro human BBB model has been in demand. Previous models were unable to fully represent the complex threedimensional (3D) anatomical structure or specific barrier phenotypes of the matured BBB. In this study, we present a physiological 3D microfluidic model of the human BBB that mimics its developmental process including CNS angiogenesis and subsequent maturation in concert with perivascular cells. We used microfluidic hydrogel patterning to precisely and sequentially load perivascular cells into the model, investigate the role of each cell type on BBB phenotypes. We confirmed the necessity of the tri-culture system (brain endothelium with pericytes and astrocytes) to attain the characteristic BBB vascular morphology such as minimized diameter and maximized junction expression. In addition, endothelial-perivascular cell interaction was also critical in reconstituting p-glycoprotein (p-gp), efflux transporter in our model that works as metabolic barrier of BBB and blocks drug to enter CNS. The 3D hydrogel matrix was tuned with hyaluronic acid (HA) to optimize the interaction between endothelial cells and astrocytes. Our in vitro BBB system mimics CNS angiogenesis and characteristic features of BBB. We expect the model will contribute to deeper understanding of neurodegenerative diseases and cost-efficient development of effective CNS medications.

bioengineering↗

bioRxiv2018

Comprehensive genetic analysis by whole exome sequencing in 352 Korean pediatric patients with unknown neurodevelopmental disorders

ImportanceAccurate diagnosis of pediatric patients with complicated neurological problems demands a well-coordinated combination of robust genetic analytic capability and delicate clinical evaluation. It should be tested whether this challenge can be augmented by whole exome sequencing (WES).\n\nObjectiveTo evaluate the utility of WES-based diagnosis and discovery of novel variants of undiagnosed patients with complex neurodevelopmental problems in a country with a centralized medical system.\n\nDesign, setting, and participantsA cohort of 352 Korean patients, believed to cover a major portion of the entire country from July 2014 to April 2017, with a broad spectrum of neurodevelopmental disorders without any pathogenic variants revealed by conventional methods were evaluated by trio-based WES at Seoul National University Childrens Hospital.\n\nExposuresWES of patients and parents and subsequent evaluation of genetic variants.\n\nMain outcomes and measuresGenetic variants from each patient were evaluated for known disease association and novel variants were assessed for possible involvement with neurodevelopment process.\n\nResultsWe identified disease-causing variants, including newly discovered variants, in 57.4% of the probands, who had underwent a mean of 5.6 years of undiagnosed periods and visited mean of 2.3 tertiary hospitals. The cohort included 112 patients with variants that were previously reported as pathogenic (31.8%), 16 patients with copy number variants (4.5%) and 27 patients with variants that were associated with different clinical symptoms (7.7%). We also discovered potentially pathogenic variants from 47 patients that required further functional assessments (13.4%) and demonstrated potential implications in neurodevelopmental disorders. Following the genetic analysis, we provided more precise treatments to selected patients. A few clinical vignettes are presented that illuminate the potential diagnostic pitfalls that one could have encountered without this approach.\n\nConclusions and relevanceOur results highlight the utility of WES-based diagnosis for improved patient care in a country with a centralized medical system and discovery of novel pathophysiology mechanisms.\n\nKey pointsO_ST_ABSQuestionC_ST_ABSWhat is the advantage of whole exome sequencing based diagnosis of pediatric neurology patients with unknown rare symptoms in a large tertiary clinic in a country with a centralized medical system?\n\nFindingsWhole exome sequencing of 352 Korean patients, with a mean of 5.7 years of undiagnosed period, yielded 44.0% of conservative diagnostic yield. A number of cases were directly benefitted by trio-based WES via termination of diagnostic odyssey, genetic counseling for next offspring, or suggestion of more effective and customized treatment options.\n\nMeaningWe report on the establishment of a national-level whole exome-based diagnosis system, with emphasis on deliberate integration of clinical interpretation and genetic analysis. Whole exome sequencing should be a choice of diagnostic tools for pediatric neurologic patients with ambiguous symptoms.

genetics↗

bioRxiv2018

Wolf-Hirschhorn Syndrome-associated genes are enriched in motile neural crest and affect craniofacial development in Xenopus laevis

Wolf-Hirschhorn Syndrome (WHS) is a human developmental disorder arising from a hemizygous perturbation, typically a microdeletion, on the short arm of chromosome four. In addition to pronounced intellectual disability, seizures, and delayed growth, WHS presents with a characteristic facial dysmorphism and varying prevalence of microcephaly, micrognathia, cartilage malformation in the ear and nose, and facial asymmetries. These affected craniofacial tissues all derive from a shared embryonic precursor, the cranial neural crest, inviting the hypothesis that one or more WHS-affected genes may be critical regulators of neural crest development or migration. To explore this, we characterized expression of multiple genes within or immediately proximal to defined WHS critical regions, across the span of craniofacial development in the vertebrate model system Xenopus laevis. This subset of genes, WHSC1, WHSC2, LETM1, and TACC3, are diverse in their currently-elucidated cellular functions; yet we find that their expression demonstrates shared tissue-specific enrichment within the anterior neural tube, pharyngeal arches, and later craniofacial structures. We examine the ramifications of this by characterizing craniofacial development and neural crest migration following individual gene depletion. We observe that several WHS-associated genes significantly impact facial patterning, cartilage formation, pharyngeal arch migration, and neural crest motility, and can separately contribute to forebrain scaling. Thus, we have determined that numerous genes within and surrounding the defined WHS critical regions potently impact craniofacial patterning, suggesting their role in WHS presentation may stem from essential functions during neural crest-derived tissue formation.\n\nAuthor SummaryWolf-Hirschhorn Syndrome (WHS), a developmental disorder caused by small deletions on chromosome four, manifests with pronounced and characteristic facial malformation. While genetic profiling and case studies provide insights into how broader regions of the genome affect the syndromes severity, we lack a key component of understanding its pathology; a basic knowledge of how individual WHS-affected genes function during development. Importantly, many tissues affected by WHS derive from shared embryonic origin, the cranial neural crest. This led us to hypothesize that genes deleted in WHS may hold especially critical roles in this tissue. To this end, we investigated the roles of four WHS-associated genes during neural crest cell migration and facial patterning. We show that during normal development, expression of these genes is enriched in migratory neural crest and craniofacial structures. Subsequently, we examine their functional roles during facial patterning, cartilage formation, and forebrain development, and find that their depletion recapitulates features of WHS craniofacial malformation. Additionally, two of these genes directly affect neural crest cell migration rate. We report that depletion of WHS-associated genes is a potent effector of neural crest-derived tissues, and suggest that this explains why WHS clinical presentation shares so many characteristics with classic neurochristopathies.

developmental biology↗

bioRxiv2018

Engineered developmental niche enables predictive phenotypic screening in human dystrophic cardiomyopathy

Directed differentiation of human pluripotent stem cells (hPSCs) into cardiomyocytes typically produces cells with structural, functional, and biochemical properties that most closely resemble those present in the fetal heart. Here we establish an in vitro engineered developmental cardiac niche to produce matured hPSC-derived cardiomyocytes (hPSC-CMs) with enhanced sarcomere development, electrophysiology, contractile function, mitochondrial capacity, and a more mature transcriptome. When this developmental cardiac niche was applied to dystrophin mutant hPSC-CMs, a robust disease phenotype emerged, which was not observed in non-matured diseased hPSC-CMs. Matured dystrophin mutant hPSC-CMs exhibited a greater propensity for arrhythmia as measured via beat rate variability, most likely due to higher resting cytosolic calcium content. Using a custom nanopatterned microelectrode array platform to screen functional output in hPSC-CMs exposed to our engineered developmental cardiac niche, we identified calcium channel blocker, nitrendipine, mitigated hPSC-CM arrhythmogenic behavior and correctly identified sildenafil as a false positive. Taken together, we demonstrate our developmental cardiac niche platform enables robust hPSC-CM maturation allowing for more accurate disease modeling and predictive drug screening.

bioengineering↗

bioRxiv2018

The whale shark genome reveals how genomic and physiological properties scale with body size

The endangered whale shark (Rhincodon typus) is the largest fish on Earth and is a long-lived member of the ancient Elasmobranchii clade. To characterize the relationship between genome features and biological traits, we sequenced and assembled the genome of the whale shark and compared its genomic and physiological features to those of 81 animals and yeast. We examined scaling relationships between body size, temperature, metabolic rates, and genomic features and found both general correlations across the animal kingdom and features specific to the whale shark genome. Among animals, increased lifespan is positively correlated to body size and metabolic rate. Several genomic features also significantly correlated with body size, including intron and gene length. Our large-scale comparative genomic analysis uncovered general features of metazoan genome architecture: GC content and codon adaptation index are negatively correlated, and neural connectivity genes are longer than average genes in most genomes. Focusing on the whale shark genome, we identified multiple features that significantly correlate with lifespan. Among these were very long gene length, due to large introns highly enriched in repetitive elements such as CR1-like LINEs, and considerably longer neural genes of several types, including connectivity, activity, and neurodegeneration genes. The whale sharks genome had an expansion of gene families related to fatty acid metabolism and neurogenesis, with the slowest evolutionary rate observed in vertebrates to date. Our comparative genomics approach uncovered multiple genetic features associated with body size, metabolic rate, and lifespan, and showed that the whale shark is a promising model for studies of neural architecture and lifespan.

genomics↗

bioRxiv2018

Tibanna: software for scalable execution of portable pipelines on the cloud

SummaryWe introduce Tibanna, an open-source software tool for automated execution of bioinformatics pipelines on Amazon Web Services (AWS). Tibanna accepts reproducible and portable pipeline standards including Common Workflow Language (CWL), Workflow Description Language (WDL) and Docker. It adopts a strategy of isolation and optimization of individual executions, combined with a serverless scheduling approach. Pipelines are executed and monitored using local commands or the Python Application Programming Interface (API) and cloud configuration is automatically handled. Tibanna is well suited for projects with a range of computational requirements, including those with large and widely fluctuating loads. Notably, it has been used to process terabytes of data for the 4D Nucleome (4DN) Network.\n\nAvailabilitySource code is available on GitHub at https://github.com/4dn-dcic/tibanna.

bioinformatics↗

bioRxiv2018

Drinking motives and alcohol use among college students with the alcohol flush reaction: A nationwide study

BackgroundThis study investigated the relationship between drinking motives and alcohol use among a nationally representative sample of college students with the alcohol flush reaction (AFR). We surveyed and analyzed the data of 2,245 male and 2,326 female college students in a nationally representative sample of 82 colleges in South Korea.\n\nMethodsOf our study population, 725 males (32.3%) and 812 females (34.9%) reported to currently suffering from AFR. Multiple regression analysis was used to identify the association between drinking motives and drinking behavior, measured via the AUDIT.\n\nResultsRelative to drinking because of peer pressure, students drinking for pleasure (males: {beta} = 2.622, p <.0001; females {beta} = 2.769, p <.0001) or stress/depression (males: {beta} = 2.479, p <.0001; females {beta} = 2.489, p <.0001) had higher AUDIT scores. Among students drinking because of stress/depression, seniors (males: {beta} = 3.603, p<.0001; females: {beta} = 3.791, p = 0.000), smokers (males: {beta} = 1.564, p = 0.000; females {beta} = 1.816, p = 0.007) and/or liberal arts students (males: {beta} = 6.1136, p<.0001; females {beta} = 4.2105, p <.0001) consumed more alcohol than their peers. Relative to conformity motives, enhancement and coping motives were found to have a greater influence on alcohol intake among college students with alcohol flush reaction.\n\nConclusionConsidering that the flush reaction can occur in AFR individuals after just one sip of wine, our results show that educators and policymakers must take action to deal with this problem.

epidemiology↗

bioRxiv2018

PUMILIO hyperactivity drives premature aging of Norad-deficient mice

Although numerous long noncoding RNAs (lncRNAs) have been identified, our understanding of their roles in mammalian physiology remains limited. Here we investigated the physiologic function of the conserved lncRNA Norad in vivo. Deletion of Norad in mice results in genomic instability and mitochondrial dysfunction, leading to a dramatic multi-system degenerative phenotype resembling premature aging. Loss of tissue homeostasis in Norad-deficient animals is attributable to augmented activity of PUMILIO proteins, which act as post-transcriptional repressors of target mRNAs to which they bind. Norad is the preferred RNA target of PUMILIO2 (PUM2) in mouse tissues and, upon loss of Norad, PUM2 hyperactively represses key genes required for mitosis and mitochondrial function. Remarkably, enforced Pum2 expression fully phenocopies Norad deletion, resulting in rapid-onset aging-associated phenotypes. These findings provide new insights and open new lines of investigation into the roles of noncoding RNAs and RNA binding proteins in normal physiology and aging.

molecular biology↗

bioRxiv2018

Cancer as a tissue anomaly: classifying tumor transcriptomes based only on healthy data

Since the turn of the century, researchers have sought to diagnose cancer based on gene expression signatures measured from the blood or biopsy as biomarkers. This task, known as classification, is typically solved using a suite of algorithms that learn a mathematical rule capable of discriminating one group (e.g., cases) from another (e.g., controls). However, discriminatory methods can only identify cancerous samples that resemble those that the algorithm already saw during training. As such, we argue that discriminatory methods are fundamentally ill-suited for the classification of cancer: because the possibility space of cancer is definitively large, the existence of a one-of-a-kind gene expression signature becomes very likely. Instead, we propose using an established surveillance method that detects anomalous samples based on their deviation from a learned normal steady-state structure. By transferring this method to transcriptomic data, we can create an anomaly detector for tissue transcriptomes, a \"tissue detector\", that is capable of identifying cancer without ever seeing a single cancer example. Using models trained on normal GTEx samples, we show that our \"tissue detector\" can accurately classify TCGA samples as normal or cancerous and that its performance is further improved by including more normal samples in the training set. We conclude this report by emphasizing the conceptual advantages of anomaly detection and by highlighting future directions for this field of study.

bioinformatics↗

bioRxiv2018

Sex-specific and pleiotropic effects underlying kidney function identified from GWAS meta-analysis

Chronic Kidney Disease (CKD) is a growing health burden currently affecting 10-15% of adults worldwide. Estimated glomerular filtration rate (eGFR) as a marker of kidney function is commonly used to diagnose CKD. Previous genome-wide association study (GWAS) meta-analyses of CKD and eGFR or related phenotypes have identified a number of variants associated with kidney function, but these only explain a fraction of the variability in kidney phenotypes attributed to genetic components. To extend these studies, we analyzed data from the Nord-Trondelag Health Study (HUNT), which is more densely imputed than previous studies, and performed a GWAS meta-analysis of eGFR with publicly available summary statistics, more than doubling the sample size of previous meta-analyses. We identified 147 loci (53 novel loci) associated with eGFR, including genes involved in transcriptional regulation, kidney development, cellular signaling, metabolism, and solute transport. Moreover, genes at these loci show enriched expression in urogenital tissues and highlight gene sets known to play a role in kidney function. In addition, sex-stratified analysis identified three regions (prioritized genes: PPM1J, MCL1, and SLC47A1) with more significant effects in women than men. Using genetic risk scores constructed from these eGFR meta-analysis results, we show that associated variants are generally predictive of CKD but improve detection only modestly compared with other known clinical risk factors. Collectively, these results yield additional insight into the genetic factors underlying kidney function and progression to CKD.

genomics↗

bioRxiv2018

A post-transcriptional program of chemoresistance by AU-rich elements/TTP in cancer quiescence

BackgroundQuiescence (G0) is a transient, cell cycle-arrested state. By entering G0, cancer cells survive unfavorable conditions such as chemotherapy and cause relapse. While G0 cells have been studied at the transcriptome level, how post-transcriptional regulation contributes to their chemoresistance remains unknown.\n\nResultsWe induced chemoresistant and quiescent (G0) leukemic cells by serum-starvation or chemotherapy treatment. To study post-transcriptional regulation in G0 leukemic cells, we systematically analyzed their transcriptome, translatome, and proteome. We find that our resistant G0 cells recapitulate gene expression profiles of in vivo chemoresistant leukemic and G0 models. In G0 cells, canonical translation initiation is inhibited; yet we find that inflammatory genes are highly translated, indicating alternative post-transcriptional regulation. Importantly, AU-rich elements (AREs) are significantly enriched in the up-regulated G0 translatome and transcriptome. Mechanistically, we find the stress-responsive p38 MAPK-MK2 signaling pathway stabilizes ARE mRNAs by phosphorylation and inactivation of mRNA decay factor, tristetraprolin (TTP) in G0. This permits expression of ARE-bearing TNF and DUSP1 that promote chemoresistance. Conversely, inhibition of TTP phophorylation by p38 MAPK inhibitors and non-phosphorylatable TTP mutant decreases ARE mRNAs and sensitizes leukemic cells to chemotherapy. Furthermore, co-inhibiting p38 MAPK and TNF--prior to or along with chemotherapy--substantially reduced chemoresistance in primary leukemic cells ex vivo and in vivo.\n\nConclusionsThese studies uncover post-transcriptional regulation underlying chemoresistance in leukemia. Our data reveal the p38 MAPK-MK2-TTP axis as a key regulator of expression of ARE bearing mRNAs that promote chemoresistance. By disrupting this pathway, we developed an effective combination therapy against chemosurvival.

cancer biology↗

bioRxiv2018

Genetic Determinants of Cortical Structure (Thickness, Surface Area and Volumes) among Disease Free Adults in the CHARGE Consortium

Cortical thickness, surface area and volumes (MRI cortical measures) vary with age and cognitive function, and in neurological and psychiatric diseases. We examined heritability, genetic correlations and genome-wide associations of cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprised 22,822 individuals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the United Kingdom Biobank. Significant associations were replicated in the Enhancing Neuroimaging Genetics through Meta-analysis (ENIGMA) consortium, and their biological implications explored using bioinformatic annotation and pathway analyses. We identified genetic heterogeneity between cortical measures and brain regions, and 161 genome-wide significant associations pointing to wnt/{beta}-catenin, TGF-{beta} and sonic hedgehog pathways. There was enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions. These data are a rich resource for studies of the biological mechanisms behind cortical development and aging.

genetics↗

bioRxiv2018

Loss of TLE3 Promotes Mitochondrial Program in Beige Adipocytes and Improves Glucose Metabolism

Prolonged cold exposure stimulates the recruitment of beige adipocytes within white adipose tissue. Beige adipocytes depend on mitochondrial oxidative phosphorylation to drive thermogenesis. The transcriptional mechanisms that promote remodeling in adipose tissue are not well understood. Here we demonstrate that the transcriptional coregulator TLE3 is induced with aging and inhibits mitochondrial gene expression in beige adipocytes. Conditional deletion of TLE3 in adipocytes prevents age- and diet-induced weight gain by promoting mitochondrial oxidative metabolism and increasing energy expenditure, thereby improving glucose control. Using chromatin immunoprecipitation and deep sequencing we found that TLE3 occupies distal enhancers in proximity to nuclear-encoded mitochondrial genes and that many of these enhancers are also enriched for EBF transcription factors. TLE3 interacts with EBF2 and blocks its ability to promote the thermogenic transcriptional program. Collectively, these studies demonstrate that TLE3 mediates age-dependent beige adipose thermogenic decline through inhibition of EBF2 transcriptional activity. Inhibition of TLE3 may provide a novel therapeutic approach for obesity and diabetes.

developmental biology↗

bioRxiv2018

Diagnosis and Prognosis Using Machine Learning Trained on BrainMorphometry and White Matter Connectomes

Accurate, reliable prediction of risk for Alzheimers disease (AD) is essential for early, disease-modifying therapeutics. Multimodal MRI, such as structural and diffusion MRI, is likely to contain complementary information of neurodegenerative processes in AD. Here we tested the utility of the multimodal MRI (T1-weighted structure and diffusion MRI), combined with high-throughput brain phenotyping--morphometry and structural connectomics--and machine learning, as a diagnostic tool for AD. We used, firstly, a clinical cohort at a dementia clinic (National Health Insurance Service-Ilsan Hospital [NHIS-IH]; N=211; 110 AD, 64 mild cognitive impairment [MCI], and 37 cognitively normal with subjective memory complaints [SMC]) to test the diagnostic models; and, secondly, Alzheimers Disease Neuroimaging Initiative (ADNI)-2 to test the generalizability. Our machine learning models trained on the morphometric and connectome estimates (number of features=34,646) showed optimal classification accuracy (AD/SMC: 97% accuracy, MCI/SMC: 83% accuracy; AD/MCI: 97% accuracy) in NHIS-IH cohort, outperforming a benchmark model (FLAIR-based white matter hyperintensity volumes). In ADNI-2 data, the combined connectome and morphometry model showed similar or superior accuracies (AD/HC: 96%; MCI/HC: 70%; AD/MCI: 75% accuracy) compared with the CSF biomarker model (t-tau, p-tau, and Amyloid {beta}, and ratios). In predicting MCI to AD progression in a smaller cohort of ADNI-2 (n=60), the morphometry model showed similar performance with 69% accuracy compared with CSF biomarker model with 70% accuracy. Our comparison of classifiers trained on structural MRI, diffusion MRI, FLAIR, and CSF biomarkers show the promising utility of the white matter structural connectomes in classifying AD and MCI in addition to the widely used structural MRI-based morphometry, when combined with machine learning.\n\nHighlightsO_LIWe showed the utility of multimodal MRI, combining morphometry and white matter connectomes, to classify the diagnosis of AD and MCI using machine learning.\nC_LIO_LIIn predicting the progression from MCI to AD, the morphometry model showed the best performance.\nC_LIO_LITwo independent clinical datasets were used in this study: one for model building, the other for generalizability testing.\nC_LI

neuroscience↗

bioRxiv2018

Real-time non-invasive intracranial state estimation using unscented Kalman filter

Intracranial pressure (ICP) monitoring is desirable as a first-line measure to assist decision-making in cases of increased ICP. Clinically, non-invasive ICP monitoring is also required to avoid infection and hemorrhage in patients. The relationships among the arterial blood pressure (Pa), ICP, cerebral blood flow, and its velocity (QCBFv) measured by transcranial Doppler ultrasound measurement have been reported. However, real-time non-invasive ICP estimation using these modalities is less well documented. Here, we present a novel algorithm for real-time and non-invasive ICP monitoring with QCBFv and Pa, called direct-current (DC)-ICP. This technique is compared with invasive ICP for 11 traumatic-brain-injury patients admitted to Cheju Halla Hospital and Gangnam Severance Hospital from July 2017 to June 2018. The inter-subject correlation coefficient between true and estimate was 0.70. The AUCs of the ROCs for prediction of increased ICP for the DC-ICP methods are 0.816. Thus, QCBFv monitoring can facilitate reliable real-time ICP tracking with our novel DC-ICP algorithm, which can provide valuable information under clinical conditions.

neuroscience↗

bioRxiv2018

Altitudinal range-size distribution of breeding birds and environmental factors for the determination of species richness: An empirical test of altitudinal Rapoports rule and rescue effect on a local scale

Range-size distributions are important for understanding species richness patterns and led to the development of the controversial Rapoports rule and Rapoport-rescue effect. This study aimed to understand the relationship between species richness and range-size distribution in relation to environmental factors. The present study tested the following: (1) altitudinal Rapoports rule, (2) climatic and ambient energy hypotheses, (3) non-directional rescue effect, and (4) effect of environmental factors on range-size group. Altitudinal species range-size distribution increased with increasing altitude and showed a negative relationship with climatic variables and habitat heterogeneity, and a positive relationship with primary productivity. These results support the altitudinal Rapoports rule and climatic hypothesis; however, they do not fully support the ambient energy hypothesis. Results from testing the non-directional rescue effect showed that the inflow intensity of species from both directions (high and low elevations) affected species richness. And we found that the 2nd and 3rd quartile species distribution were the main cause of a mid-peak of species richness and the non-directional rescue effect. Additionally, the 2nd quartile species richness was highly related to minimum temperature and possessed thermal specialist species features, and the 3rd quartile species richness was highly related to habitat heterogeneity and primary productivity. Although altitudinal range-size distribution results were similar to the altitudinal Rapoports rule, the mid-peak pattern of species richness could not be explained by the Rapoports-rescue effect; however, the non-directional rescue effect could explain a mid-peak pattern of species richness.

ecology↗

bioRxiv2018

Efficient variant set mixed model association tests for continuous and binary traits in large-scale whole genome sequencing studies

With advances in Whole Genome Sequencing (WGS) technology, more advanced statistical methods for testing genetic association with rare variants are being developed. Methods in which variants are grouped for analysis are also known as variant-set, gene-based, and aggregate unit tests. The burden test and Sequence Kernel Association Test (SKAT) are two widely used variant-set tests, which were originally developed for samples of unrelated individuals and later have been extended to family data with known pedigree structures. However, computationally-efficient and powerful variant-set tests are needed to make analyses tractable in large-scale WGS studies with complex study samples. In this paper, we propose the variant-Set Mixed Model Association Tests (SMMAT) for continuous and binary traits using the generalized linear mixed model framework. These tests can be applied to large-scale WGS studies involving samples with population structure and relatedness, such as in the National Heart, Lung, and Blood Institutes Trans-Omics for Precision Medicine (TOPMed) program. SMMAT tests share the same null model for different variant sets, and a virtue of this null model, which includes covariates only, is that it needs to be only fit once for all tests in each genome-wide analysis. Simulation studies show that all the proposed SMMAT tests correctly control type I error rates for both continuous and binary traits in the presence of population structure and relatedness. We also illustrate our tests in a real data example of analysis of plasma fibrinogen levels in the TOPMed program (n = 23,763), using the Analysis Commons, a cloud-based computing platform.

genetics↗