bioRxiv Science⌕ Search

Biology subjects

Xia, L.

Publications and source records attributed to Xia, L..

At least 37 records · Page 2Linked to original sources

Landscape of Large-Scale Somatic Genomic Insertions in Non-Small Cell Lung Carcinoma Revealed by Nanopore Sequencing

Previous NSCLC genomic studies were mostly based on the next-generation sequencing of short reads, which is an efficient approach for identifying single nucleotide variants and small indels but ineffective for identifying structural variants, especially large-scale insertions. Here, we studied 151 lung adenocarcinoma (LUAD) and 106 lung squamous cell carcinoma (LUSC) samples and paired blood samples using nanopore sequencing technology. We developed a rigorous computational pipeline and characterized the landscape of large-scale somatic insertions in NSCLC. Combining other omics data, we report three findings: 1. we identified an LUSC-enriched somatic simple repeat expansion shared by approximately 40% of LUSC patients that regulates PTPRZ1 gene expression through distal enhancers; 2. the somatic insertion of transposable elements (TEs) in NSCLC were mostly complex TEs consisting of multiple TE elements; and 3. the insertion of short interspersed nuclear elements, especially from the Alu family in young lineages, is a frequent somatic mutation type that shapes the transcriptome of NSCLC through the expression of these elements.

genomics↗

Artificial neural networks for model identification and parameter estimation in computational cognitive models

1Computational cognitive models have been used extensively to formalize cognitive processes. Model parameters offer a simple way to quantify individual differences in how humans process information. Similarly, model comparison allows researchers to identify which theories, embedded in different models, provide the best accounts of the data. Cognitive modeling uses statistical tools to quantitatively relate models to data that often rely on computing/estimating the likelihood of the data under the model. However, this likelihood is computationally intractable for a substantial number of models. These relevant models may embody reasonable theories of cognition, but are often under-explored due to the limited range of tools available to relate them to data. We contribute to filling this gap in a simple way using artificial neural networks (ANNs) to map data directly onto model identity and parameters, bypassing the likelihood estimation. We test our instantiation of an ANN as a cognitive model fitting tool on classes of cognitive models with strong inter-trial dependencies (such as reinforcement learning models), which offer unique challenges to most methods. We show that we can adequately perform both parameter estimation and model identification using our ANN approach, including for models that cannot be fit using traditional likelihood-based methods. We further discuss our work in the context of the ongoing research leveraging simulation-based approaches to parameter estimation and model identification, and how these approaches broaden the class of cognitive models researchers can quantitatively investigate. 2 Author SummaryComputational cognitive models occupy an important position in cognitive science research, as they offer a simple way of quantifying cognitive processes (such as how fast someone learns, or how noisy they are in choice selection), and testing which cognitive theories offer a better explanation of the behavior. To relate cognitive models to the behavioral data, researchers rely on statistical tools that require estimating the likelihood of observed data under the assumptions of the cognitive model. This is, however, not possible to do for all models as some models present significant challenges to likelihood computation. In this work, we use artificial neural networks (ANNs) to bypass likelihood computation and approximation altogether, and demonstrate the success of this approach applied to model parameter estimation and model comparison. The proposed method is a contribution to ongoing development of modeling tools which will enable cognitive researchers to test a broader range of theories of cognition.

animal behavior and cognition↗

PROX1 inhibits PDGF-B expression to prevent myxomatous degeneration of heart valves

BackgroundCardiac valve disease (CVD) is observed in 2.5% of the general population and 10% of the elderly people. Effective pharmacological treatments are currently not available, and patients with severe CVD require surgery. PROX1 and FOXC2 are transcription factors that are required for the development of lymphatic and venous valves. We found that PROX1 and FOXC2 are expressed in a subset of valvular endothelial cells (VECs) that are located on the downstream (fibrosa) side of cardiac valves. Whether PROX1 and FOXC2 regulate cardiac valve development and disease is not known. MethodsWe used histology, electron microscopy and echocardiography to investigate the structure and functioning of heart valves from Prox1{Delta}VEC mice in which Prox1 was conditionally deleted from VECs. Isolated valve endothelial cells and valve interstitial cells were used to identify the molecular mechanisms in vitro, which were tested in vivo by RNAScope, additional mouse models and pharmacological approaches. The significance of our findings was tested by evaluation of human samples of mitral valve prolapse (MVP) and aortic valve insufficiency. ResultsHistological analysis revealed that the aortic and mitral valves of Prox1{Delta}VEC mice become progressively thick and myxomatous. Echocardiography revealed that the aortic valves of Prox1{Delta}VEC mice are stenotic. FOXC2 was downregulated and platelet-derived growth factor-B (PDGF-B) was upregulated in the VECs of Prox1{Delta}VEC mice. Conditional knockdown of FOXC2 and conditional overexpression of PDGF-B in VECs recapitulated the phenotype of Prox1{Delta}VEC mice. PDGF-B was also increased in mice lacking FOXC2 and in human MVP and insufficient aortic valve samples. Pharmacological inhibition of PDGF-B signaling with imatinib partially ameliorated the valve defects of Prox1{Delta}VEC mice. ConclusionPROX1 antagonizes PDGF-B signaling partially via FOXC2 to maintain the extracellular matrix composition and prevent myxomatous degeneration of cardiac valves. Novelty and SignificanceWhat Is Known? O_LIThe transcription factors PROX1 and FOXC2 are critical regulators of lymphatic and venous valve development. C_LIO_LIPROX1 and FOXC2 are expressed in the downstream valvular endothelial cells of heart valves. C_LI What Is New? O_LIDeletion of Prox1 from the valvular endothelial cells of mice results in enlarged and myxomatous aortic and mitral valves. Aortic valves of the mutant (Prox1{Delta}VEC) mice were stenotic. C_LIO_LIFOXC2 is partially responsible for the phenotype of Prox1{Delta}VEC mice. C_LIO_LIPROX1 and FOXC2 inhibit the expression of the cytokine PDGF-B in heart valves. C_LIO_LIHyperactivation of PDGF-B signaling results in aortic and mitral valve thickening. C_LIO_LIInhibition of PDGF-B signaling ameliorates aortic valve stenosis in Prox1{Delta}VEC mice. C_LIO_LIPDGFB is overexpressed and PROX1 is downregulated in human mitral valve prolapse (MVP) samples. C_LI Our findings suggest that PROX1 is an inhibitor of myxomatous valve disease that afflicts ~10% of the elderly population. We have also identified PDGF-B as a potential target for treating myxomatous valve disease.

developmental biology↗

scDEED: a statistical method for detecting dubious 2D single-cell embeddings

Two-dimensional (2D) embedding methods are crucial for single-cell data visualization. Popular methods such as t-SNE and UMAP are commonly used for visualizing cell clusters; however, it is well known that t-SNE and UMAPs 2D embedding might not reliably inform the similarities among cell clusters. Motivated by this challenge, we developed a statistical method, scDEED, for detecting dubious cell embeddings output by any 2D-embedding method. By calculating a reliability score for every cell embedding, scDEED identifies the cell embeddings with low reliability scores as dubious and those with high reliability scores as trustworthy. Moreover, by minimizing the number of dubious cell embeddings, scDEED provides intuitive guidance for optimizing the hyperparameters of an embedding method. Applied to multiple scRNA-seq datasets, scDEED demonstrates its effectiveness for detecting dubious cell embeddings and optimizing the hyperparameters of t-SNE and UMAP.

bioinformatics↗

Stray cats and dogs carrying zoonotic Enterocytozoon bieneusi genotype D in China: a public health concern

Enterocytozoon bieneusi is reported to be a common microsporidian of humans and animals in various countries. However, scarce information on E. bieneusi has been recorded in cats (Felis catus) and dogs (Canis familiaris) in China. As such, we undertook molecular epidemiological investigation of E. bieneusi in cats and dogs in Shanghai, China. A total of 359 genomic DNAs were extracted from individual faecal samples from cats (n = 59) and dogs (n = 300), and then tested using a nested PCR-based sequencing approach employing internal transcribed spacer (ITS) of nuclear ribosomal DNA as the genetic marker. Enterocytozoon bieneusi was detected in 34 of all 359 (9.5%) faecal samples from cats (32.2%; 19/59) and dogs (5.0%; 15/300), including 24 stray cats and dogs (22.6%; 24/106), as well as ten household/raised cats and dogs (4.0%; 10/253). Correlation analyses revealed that E. bieneusi positive rates were significantly associated with stray cats and dogs (P < 0.05). The analysis of ITS sequence data revealed the presentation of five known genotypes CD7, CHN-HD2, D, PtEb IX and Type IV and two novel genotypes D-like1 and PtEb IX-like1. Zoonotic genotype D was the predominant type with percentage of 61.8 (21/34). Phylogenetic analysis of ITS sequence data sets showed that genotypes D, D-like1 and Type IV clustered within Group 1, showing zoonotic potential. The others were assigned into Group 10 with host specificity. These findings suggested that cats and dogs in Shanghai harbor zoonotic genotype D of E. bieneusi and may have a significant risk for zoonotic transmission. Further insight into the epidemiology of E. bieneusi in animals, water and the environment from other areas in China will be important to have an informed position on the public health significance of microsporidiosis caused by this microbe.

genetics↗

Strain-specific changes in nucleus accumbens transcriptome and motivation for food reward in mice exposed to maternal separation

Adversity in childhood exerts enduring effects on brain and increases the vulnerability to psychiatric diseases. It also leads to a higher risk for eating disorders and obesity. We hypothesised that neonatal stress in mice affects motivation to obtain palatable food in adulthood and changes gene expression in reward system. Male and female pups from C57Bl/6J and C3H/HeN mice strains were subjected to a daily maternal separation (MS) protocol from PND2 to PND14. In adulthood, their motivation for palatable food reward was assessed in operant cages. Compared to control mice, male and female C3H/Hen mice exposed to MS significantly did more lever presses to obtain palatable food especially when the effort required to obtain the reward is high. Transcriptional analysis reveals 375 genes differentially expressed in the nucleus accumbens of male MS C3H/HeN mice compared to the control group, some of these being associated with the regulation of the reward system (e.g. Gnas, Pnoc). Interestingly, C57Bl/6J mice exposed to MS did not show any alteration in their motivation to obtain a palatable reward nor significant changes in gene expression in the nucleus accumbens. In conclusion, neonatal stress produces lasting changes in motivation for palatable food in C3H/HeN offspring but has no impact in C57Bl/6J offspring. These behavioural alterations are accompanied by drastic changes in gene expression specifically within the nucleus accumbens, a key structure in the regulation of motivational processes.

neuroscience↗

MIIP downregulation promotes colorectal cancer progression via inducing adjacent adipocytes browning

The enrichment of peri-cancerous adipocytes is one of the distinctive features of colorectal cancer (CRC), which accelerates the disease progression and worsens the prognosis. The communication between tumor cells and adjacent adipocytes plays an important role in this process. However, the detailed mechanisms remain largely unknown. Here we demonstrated MIIP is downregulated in high-grade CRC, and revealed its role and mechanism in tumor cell-adipocyte communication. By detecting MIIP expression in CRC tissues and adjacent normal tissues, we found MIIP was significantly decreased in CRC, and was closely related to adjacent adipocytes browning. In detail, MIIP reduction altered the N-linked glycosylation modification of AZGP1 and thus alleviated the inhibition of secretion. AZGP1, a critical lipid mobilization factor, led to the intensification of adipocytes browning and the release of free fatty acids (FFAs), which in turn fueled for CRC progression. Our data demonstrate that MIIP plays a key regulatory role in the communication between CRC and neighboring adipocytes by mediating AZGP1 secretion, and MIIP reduction leads to adipose browning-induced cancer rapid progression and poor prognosis.

cancer biology↗

Smart squirrels use a mortise-tenon structure to fix nuts on understory twigs

Squirrels of temperate zones commonly store nuts or seeds under leaf litter, in hollow logs or even in holes in the ground; however, in humid rainforests, it is an evolutionary challenge for squirrels to hang elliptical or oblate nuts securely on trees to minimize germination or fungal infection. Here, we report a unique behaviour used by two species of small flying squirrels (Hylopetes phayrei electilis (G. M. Allen, 1925) and Hylopetes alboniger (Hodgson, 1870)) to cache nuts on Hainan Island. Squirrels intentionally carved grooves encircling ellipsoid nuts or distributed on the bottom of oblate nuts and used these grooves to fix nuts tightly between small twigs 0.1-0.6 cm in diameter and connected at angles of 25-40{degrees}. The resulting structures were similar to the mortise-tenon joint of ancient Chinese architecture. Cache sites were on small plants located 10-25 m away from the closest potentially nut-producing tree, a behaviour that likely deters discovery and consumption of the nuts by other animals. Their ability to shape individual nuts to store them more securely suggests it is a smart behavior, which is likely formed by the adaption to life in humid tropical rainforests to guarantee food supply and impacts the distribution of tree species.

ecology↗

Comprehensive structural analysis reveals broad-spectrum neutralizing antibodies against Omicron

The pandemic of COVID-19 caused by SARS-CoV-2 continues to spread around the world. Mutant strains of SARS-CoV-2 are constantly emerging. At present, Omicron variants have become mainstream. In this work, we carried out a systematic and comprehensive analysis of the reported spike protein antibodies, counting the antibodies epitopes and genotypes. We further comprehensively analyzed the impact of Omicron mutations on antibody epitopes and classified these antibodies according to their binding patterns. We found that the epitopes of one class of antibodies were significantly less affected by Omicron mutations than other classes. Binding and virus neutralization experiments show that such antibodies can effectively inhibit the immune escape of Omicron. Cryo-EM results show that this class of antibodies utilizes a conserved mechanism to neutralize SARS-CoV-2. Our results greatly help us deeply understand the impact of Omicron mutations. At the same time, it also provides guidance and insights for developing Omicron antibodies and vaccines.

microbiology↗

Inverted genomic regions between reference genome builds in humans impact imputation accuracy and decrease the power of association testing

Over the last two decades, the human reference genome has undergone multiple updates as we complete a linear representation of our genome. There are two versions of human references currently used in the biomedical literature, GRCh37/hg19 and GRCh38, and conversions between these versions are critical for quality control, imputation, and association analysis. In the present study we show that genomic coordinates for single nucleotide variants (SNVs) in regions inverted between different builds of the reference genome are erroneously converted by the TOPMed imputation server. Depending on the array type, we estimate the inappropriate conversions of variant coordinates would occur in about 2-5 Mb of the genome. Independent of the imputation server, however, in-house conversions of variant coordinates are routine yet impact of mapped variants to these inverted regions and its downstream analytical consequences are underrecognized. We observed that errors for palindromic variants in these inverted regions cannot be detected by standard quality control procedures and destabilize the local haplotype structure, leading to loss of imputation accuracy and power in association analyses. Though only a small proportion of the genome is affected, we show that these regions include important disease susceptibility variants that would be lost due to poor imputation. For example, we show that a known locus associated with prostate cancer on chr10 would have its association P-value drop from 2.86x10-7 to 0.0011 in a case-control analysis of 20,286 Africans and African Americans (10,643 cases and 9,643 controls). We devise a straight-forward heuristic based on the popular tool liftOver that can easily detect and correct these variants in the inverted regions between genome builds to locally improve imputation accuracy.

genomics↗

CXCL8/CXCR2 signaling mediates bone marrow fibrosis and represents a therapeutic target in myelofibrosis

Pro-inflammatory signaling is a hallmark feature of human cancer, including in myeloproliferative neoplasms (MPNs), most notably myelofibrosis (MF). Dysregulated inflammatory signaling contributes to fibrotic progression in MF; however, the individual cytokine mediators elicited by malignant MPN cells to promote collagen-producing fibrosis and disease evolution remain yet to be fully elucidated. Previously we identified a critical role for combined constitutive JAK/STAT and aberrant NF-{kappa}B pro-inflammatory signaling in myelofibrosis development. Using single-cell transcriptional and cytokine-secretion studies of primary MF patient cells and two separate murine models of myelofibrosis, we extend this previous work and delineate the role of CXCL8/CXCR2 signaling in MF pathogenesis and bone marrow fibrosis progression. MF patient hematopoietic stem/progenitor cells are enriched in a CXCL8/CXCR2 gene signature and display dose-dependent proliferation and fitness in response to exogenous CXCL8 ligand in vitro. Genetic deletion of Cxcr2 in the hMPLW515L adoptive transfer model abrogates fibrosis and extends overall survival, and pharmacologic inhibition of the CXCR1/2 pathway improves hematologic parameters, attenuates bone marrow fibrosis, and synergizes with JAK inhibitor therapy. Our mechanistic insights provide a rationale for therapeutic targeting of the CXCL8/CXCR2 pathway in MF patients at risk for continued fibrotic progression.

cancer biology↗

Remodeling of dermal adipose tissue alleviates cutaneous toxicity induced by anti-EGFR therapy

Anti-epidermal growth factor receptor (EGFR) therapy-associated cutaneous toxicity is a syndrome characterized by papulopustular rash, local inflammation, folliculitis and microbial infection, resulting in a decrease in quality of life and dose interruption. However, no effective clinical intervention is available for this adverse effect. Here, we report the atrophy of dermal white adipose tissue (dWAT), a highly plastic adipose tissue with various skin-specific functions, correlates with rash occurrence and exacerbation in a murine model of EGFR inhibitor-induced rash. The reduction in dWAT is due to the inhibition of adipogenic differentiation by defects in peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) signaling, and increased lipolysis by the induced expression of the lipolytic cytokine IL6. The activation of PPAR{gamma} by rosiglitazone maintains adipogenic differentiation and represses the transcription of IL6, eventually improving skin functions and ameliorating the severity of rash without altering the antitumor effects. Thus, activation of PPAR{gamma} represents a promising approach to ameliorate cutaneous toxicity in patients with cancer who receive anti-EGFR therapy. Graphical abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

pharmacology and toxicology↗

CaPti1/CaERF4 module positively regulates pepper resistance to bacterial wilt disease through coupling enhanced immunity and dehydration tolerance

Bacterial wilt, a severe disease that affects over 250 plant species, is caused by Ralstonia solanacearum through vascular system blockade. Although both plant immunity and dehydration tolerance might contribute to disease resistance, whether and how they are related are still unclear. Herein, we provide evidence that immunity against R. solanacearum and dehydration tolerance are coupled and regulated by CaPti1-CaERF4 module. By expression profiling, virus-induced gene silencing in pepper and overexpression in Nicotiana benthamiana, both CaPti1 and CaERF4 were upregulated by R. solanacearum inoculation, dehydration stress and exogenously applied ABA. They in turn phenocopied with each other in promoting pepper resistance to bacterial wilt not only by activating HR cell death and SA-dependent CaPR1, but also by activating dehydration tolerance related CaOSM1 and CaOSR1, and stomata closure to reduce water loss in ABA signaling dependent manner. Yeast-two hybrid assay showed that CaERF4 interacts with CaPti1, which was confirmed by co-immunoprecipitation and pull-down assays. Chromatin immunoprecipitation and electrophoretic mobility shift assay showed that, upon R. solanacearum inoculation, CaPR1, CaOSM1 and CaOSR1 were directly targeted and positively regulated by CaERF4 via binding GCC-box or DRE-box, which was potentiated by CaPti1. In addition, our data indicate that CaPti1-CaERF4 complex might act downstream ABA signaling, since the exogenously applied ABA did not alter stomata aperture regulated by CaPti1-CaERF4 module. Importantly, CaPti1-CaERF4 module was found also acts positively in pepper growth and response to dehydration stress. Collectively, the results suggest that immunity and dehydration tolerance are coupled and positively regulated by CaPti1-CaERF4 in pepper plants to enhance resistance against R. solanacearum. SummaryPepper immunity and dehydration tolerance are coupled and regulated by the CaPti1-CaERF4 module partially in a way related to ABA signaling and stomata closure.

physiology↗

Performance Comparison of Computational Prediction Methods for the Function and Pathogenicity of Non-coding Variants

Non-coding variants in the human genome greatly influence some traits and complex diseases by their own regulation and modification effects. Hence, an increasing number of computational methods are developed to predict the effects of variants in the human non-coding sequences. However, it is difficult for users with insufficient knowledge about the performances of computational methods to select appropriate computational methods from dozens of methods. In order to solve this problem, we assessed 12 performance measures of 24 methods on four independent non-coding variant benchmark datasets: (I) rare germline variant from ClinVar, (II) rare somatic variant from COSMIC, (III) common regulatory variant dataset, and (IV) disease associated common variant dataset. All 24 tested methods performed differently under various conditions, indicating that these methods have varying strengths and weaknesses under different scenarios. Importantly, the performance of existing methods was acceptable in the rare germline variant from ClinVar with area under curves (AUCs) of 0.4481 - 0.8033 and poor in the rare somatic variant from COSMIC (AUCs: 0.4984 - 0.7131), common regulatory variant dataset (AUCs: 0.4837 - 0.6472), and disease associated common variant dataset (AUCs: 0.4766 -0.5188). We also compared the prediction performance among 24 methods for non-coding de novo mutations in autism spectrum disorder and found that the CADD and CDTS methods showed better performance. Summarily, we assessed the performances of 24 computational methods under diverse scenarios, providing preliminary advice for proper tool selection and new method development in interpreting non-coding variants.

bioinformatics↗

Biosynthetic gene cluster profiling predicts the positive association between antagonism and phylogeny in Bacillus

Understanding the driving forces and intrinsic mechanisms of microbial competition is a fundamental question in microbial ecology. Despite the well-established negative correlation between exploitation competition and phylogenetic distance, the process of interference competition that is exemplified by antagonism remains controversial. Here, we studied the genus Bacillus, a commonly recognized producer of multifarious antibiotics, to explore the role of phylogenetic patterns of biosynthetic gene clusters (BGCs) in mediating the relationship between antagonism and phylogeny. Comparative genomic analysis revealed a positive association between BGC distance and phylogenetic distance. Antagonistic tests demonstrated that the inhibition phenotype positively correlated with both phylogenetic and predicted BGC distance, especially for antagonistic strains possessing abundant BGCs. Mutant-based verification showed that the antagonism was dependent on the BGCs that specifically harbored by the antagonistic strain. These findings highlight that BGC-phylogeny coherence regulates the positive correlation between congeneric antagonism and phylogenetic distance, which deepens our understanding of the driving force and intrinsic mechanism of microbial interactions.

ecology↗

Learning Rates Are Not All the Same: The Interpretation of Computational Model Parameters Depends on the Context

Reinforcement Learning (RL) models have revolutionized the cognitive and brain sciences, promising to explain behavior from simple conditioning to complex problem solving, to shed light on developmental and individual differences, and to anchor cognitive processes in specific brain mechanisms. However, the RL literature increasingly reveals contradictory results, which might cast doubt on these claims. We hypothesized that many contradictions arise from two commonly-held assumptions about computational model parameters that are actually often invalid: That parameters generalize between contexts (e.g., tasks, models) and that they capture interpretable (i.e., unique, distinctive) neurocognitive processes. To test this, we asked 291 participants aged 8-30 years to complete three learning tasks in one experimental session, and fitted RL models to each. We found that some parameters (exploration / decision noise) showed significant generalization: they followed similar developmental trajectories, and were reciprocally predictive between tasks. However, generalization was significantly below ceiling. Furthermore, other parameters (learning rates, forgetting) did not show evidence of generalization, and sometimes even opposite developmental trajectories. Interpretability was low for all parameters. We conclude that the systematic study of context factors (e.g., reward stochasticity; task volatility) will be necessary to enhance the generalizability and interpretability of computational cognitive models. HighlightsO_LIComputational cognitive modeling often makes two implicit assumptions: 1) Model parameters generalize between studies and models. 2) Parameters are interpretable, i.e., neurally, cognitively, and/or mechanistically specific. C_LIO_LIWe empirically investigate these assumptions in Reinforcement Learning (RL), using a large developmental dataset featuring three different learning tasks in a within-participant design. C_LIO_LIWe find that no parameters generalize between tasks in terms of absolute parameter values. However, RL decision noise/exploration parameters generalize in terms of between-participant variation, showing similar age trajectories across tasks. Interpretability was low for all parameters, especially those related to learning and memory. C_LIO_LIEven for parameters that showed generalization, the degree of generalization was significantly lower than in an artificial sample with perfect generalization for most parameters, revealing a relative lack of generalization. C_LIO_LIThese findings are in accordance with previous claims about the developmental trajectory of decision noise/exploration parameters, but suggest that claims about the development of learning rates or Forgetting might not be generalizable: these parameters are unlikely to capture the same neuro-cognitive processes across different tasks. C_LIO_LIWe suggest ways forward to improve the generalizability and interpretability of model parameters, in particular by focusing more on task context. C_LI

neuroscience↗

Genome-wide Association Study of Pancreatic Fat: The Multiethnic Cohort Adiposity Phenotype Study

Several studies have found associations between higher pancreatic fat content and adverse health outcomes, such as diabetes and the metabolic syndrome, but investigations into the genetic contributions to pancreatic fat are limited. This genome-wide association study, comprised of 804 participants with MRI-assessed pancreatic fat measurements, was conducted in the ethnically diverse Multiethnic Cohort-Adiposity Phenotype Study (MEC-APS). Two genetic variants reaching genome-wide significance, rs73449607 on chromosome 13q21.2 (Beta = -0.67, P = 4.50x10-8) and rs7996760 on chromosome 6q14 (Beta = -0.90, P = 4.91x10-8) were associated with percent pancreatic fat on the log scale. Rs73449607 was most common in the African American population (13%) and rs79967607 was most common in the European American population (6%). Rs73449607 was also suggestively associated with lower risk of type 2 diabetes (OR = 0.95, 95% CI = 0.89-1.00, P = 0.047) in the Population Architecture Genomics and Epidemiology (PAGE) Study and the DIAbetes Genetics Replication and Meta-analysis (DIAGRAM), which included substantial numbers of non-European ancestry participants (53,102 cases and 193,679 controls). Rs73449607 is located in an intergenic region between GSX1 and PLUT, and rs79967607 is in intron 1 of EPM2A. PLUT, a linkRNA, regulates transcription of an adjacent gene, PDX1, that controls beta-cell function in the mature pancreas, and EPM2A encodes the protein laforin, which plays a critical role in regulating glycogen production. If validated, these variants may suggest a genetic component for pancreatic fat and a common etiologic link between pancreatic fat and type 2 diabetes.

cell biology↗

Resequencing 250 soybean accessions: new insights into genes associated with agronomic traits and genetic networks

Limited knowledge on genomic diversity and the functional genes associated with soybean variety traits has resulted in slow breeding progress. We sequenced the genome of 250 soybean landraces and cultivars from China, America and Europe, and investigated their population structure, genetic diversity and architecture and selective sweep regions of accessions. We identified five novel agronomically important genes and studied the effects of functional mutations in respective genes. We found candidate genes GSTT1, GL3 and GSTL3 associated with isoflavone content, CKX3 associated with yield traits, and CYP85A2 associated with both architecture and yield traits. Our phenotype-gene network analysis revealed that hub nodes play a role in complex phenotypic associations. In this work, we describe novel agronomic trait associated genes and a complex genetic network, providing a valuable resource for future soybean molecular breeding.

genomics↗