Biology subjects

Zhou, X.

Publications and source records attributed to Zhou, X..

767 records · Page 43Linked to original sources

bioRxiv2017

Integrated transcriptome and epigenome analyses identify alternative splicing as a novel candidate linking histone modifications to embryonic stem cell fate decision

BackgroundUnderstanding the embryonic stem cell (ESC) fate decision between self-renewal and proper differentiation is important for developmental biology and regenerative medicine. Attention has focused on mechanisms involving histone modifications, alternative pre-mRNA splicing, and cell-cycle progression. However, their intricate interrelations and joint contributions to ESC fate decision remain unclear.\n\nResultsWe analyze the transcriptomes and epigenomes of human ESC and five types of differentiated cells. We identify thousands of alternatively spliced exons and reveal their development and lineage-dependent characterizations. Several histone modifications show dynamic changes in alternatively spliced exons and three are strongly associated with 52.8% of alternative splicing events upon hESC differentiation. The histone modification-associated alternatively spliced genes predominantly function in G2/M phases and ATM/ATR-mediated DNA damage response pathway for cell differentiation, whereas other alternatively spliced genes are enriched in the G1 phase and pathways for self-renewal. These results imply a potential epigenetic mechanism by which some histone modifications contribute to ESC fate decision through the regulation of alternative splicing in specific pathways and cell-cycle genes. Supported by experimental validations and extended dataset from Roadmap/ENCODE projects, we exemplify this mechanism by a cell cycle-related transcription factor, PBX1, which regulates the pluripotency regulatory network by binding to NANOG. We suggest that the isoform switch from PBX1a to PBX1b links H3K36me3 to hESC fate determination through the PSIP1/SRSF1 adaptor, which results in the exon skipping of PBX1.\n\nConclusionWe reveal the mechanism by which alternative splicing links histone modifications to stem cell fate decision.

bioinformatics↗

bioRxiv2017

Quartet-based computations of internode certainty provide accurate and robust measures of phylogenetic incongruence

Incongruence, or topological conflict, is prevalent in genome-scale data sets but relatively few measures have been developed to quantify it. Internode Certainty (IC) and related measures were recently introduced to explicitly quantify the level of incongruence of a given internode (or internal branch) among a set of phylogenetic trees and complement regular branch support statistics in assessing the confidence of the inferred phylogenetic relationships. Since most phylogenomic studies contain data partitions (e.g., genes) with missing taxa and IC scores stem from the frequencies of bipartitions (or splits) on a set of trees, the calculation of IC scores requires adjusting the frequencies of bipartitions from these partial gene trees. However, when the proportion of missing data is high, current approaches that adjust bipartition frequencies in partial gene trees tend to overestimate IC scores and alternative adjustment approaches differ substantially from each other in their scores. To overcome these issues, we developed three new measures for calculating internode certainty that are based on the frequencies of quartets, which naturally apply to both comprehensive and partial trees. Our comparison of these new quartet-based measures to previous bipartition-based measures on simulated data shows that: 1) on comprehensive trees, both types of measures yield highly similar IC scores; 2) on partial trees, quartet-based measures generate more accurate IC scores; and 3) quartet-based measures are more robust to the absence of phylogenetic signal and errors in the phylogenetic relationships to be assessed. Additionally, analysis of 15 empirical phylogenomic data sets using our quartet-based measures suggests that numerous relationships remain unresolved despite the availability of genome-scale data. Finally, we provide an efficient open-source implementation of these quartet-based measures in the program QuartetScores, which is freely available at https://github.com/algomaus/QuartetScores.

evolutionary biology↗

bioRxiv2017

Non-Parametric Genetic Prediction of Complex Traits with Latent Dirichlet Process Regression Models

Using genotype data to perform accurate genetic prediction of complex traits can facilitate genomic selection in animal and plant breeding programs, and can aid in the development of personalized medicine in humans. Because most complex traits have a polygenic architecture, accurate genetic prediction often requires modeling all genetic variants together via polygenic methods. Here, we develop such a polygenic method, which we refer to as the latent Dirichlet process regression model (DPR). DPR is non-parametric in nature, relies on the Dirichlet process to flexibly and adaptively model the effect size distribution, and thus enjoys robust prediction performance across a broad spectrum of genetic architectures. We compare DPR with several commonly used prediction methods with simulations. We further apply DPR to predict gene expressions, to conduct PrediXcan based gene set test, to perform genomic selection of four traits in two species, and to predict eight complex traits in a human cohort.

genetics↗

bioRxiv2017

Large Meta-Analysis Provides Evidence For An Association Of Serum Vitamin D With Pulmonary Function

The role that vitamin D plays in pulmonary function remains uncertain. Epidemiological studies reported mixed findings for the association of serum 25-hydroxyvitamin D [25(OH)D] and pulmonary function. We conducted the largest cross-sectional meta-analysis of the 25(OH)D- pulmonary function association to date, based on nine European ancestry (EA) cohorts (n=22,838) and five African ancestry (AA) cohorts (n=4,290) in the CHARGE Consortium. Data were analyzed using linear models by cohort and ancestry. Effect modification by smoking status (current/former/never) was tested. Results were combined using fixed-effects meta-analysis. Mean (SD) serum 25(OH)D was 68 (29) nmol/L for EAs and 49 (21) nmol/L for AAs. For each 1 nmol/L higher 25(OH)D, forced expiratory volume in the first second (FEV1) was higher by 1.1 mL in EAs (95% CI: 0.9,1.3; P=2.5x10-21) and 1.8 mL (95% CI: 1.1,2.5; P=1.6x10-7) in Aas (Prace difference=0.06), and forced vital capacity (FVC) was higher by 1.3 mL in EAs (95% CI: 1.0,1.6; P=1.1x10-20) and 1.5 mL (95% CI: 0.8,2.3; P=1.2x10-4) in AAs (Prace difference=0.56). Among EAs, the 25(OH)D-FVC association was stronger in smokers: per 1nmol/L higher 25(OH)D, FVC was higher by 1.7 mL (95% CI: 1.1,2.3) for current smokers and 1.7 mL (95% CI: 1.2,2.1) for former smokers, compared to 0.8 mL (95% CI: 0.4,1.2) for never smokers. In summary, the 25(OH)D associations with FEV1 and FVC were positive in both ancestries. In EAs, a stronger association was observed for smokers compared to never smokers, which supports the importance of vitamin D in vulnerable populations.\n\nCohort FundingThis work was supported by National Institutes of Health (NIH) grant number R21 HL125574 funded by the National Heart, Lung, and Blood Institute (NHLBI) and the NIH Office of Dietary Supplements (ODS) (co-Principal Investigators [co-PIs]: DBH and PAC). The corresponding author (PAC) had full access to the data for the meta-analysis, and had final responsibility for the decision to submit for publication. No funding source had any role in the analysis of the data, the writing of the manuscript, or the decision to submit it. This work was also supported in part by R01HL077612 (PI: RGB) and by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Environmental Health Sciences (ZO1 ES043012, PI: SJL). SJL is supported by the Intramural Research Program of NIH, National Institute of Environmental Health Sciences. Infrastructure for the CHARGE Consortium is supported in part by the NHLBI grant R01HL105756.\n\nThe Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study has been funded by NIH contracts N01-AG-1-2100 and 271201200022C, the National Institute on Aging (NIA) Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The study is approved by the Icelandic National Bioethics Committee, VSN: 00-063. The researchers are indebted to the participants for their willingness to participate in the study.\n\nThe Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by NHLBI contracts HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C. 25(OH)D measurements were conducted with the support of R01 HL103706 from the NHLBI and R01 HL103706-S1 from the NIH ODS. The authors thank the staff and participants of the ARIC study for their important contributions.\n\nThis Cardiovascular Health Study (CHS) research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and NHLBI grants U01HL080295, R01HL085251, R01HL087652, R01HL105756, R01HL103612, R01HL120393, and R01HL130114 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from NIA. A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Vitamin D measurements were made possible by NHLBI (R01HL084443-01A2).\n\nThis work in Framingham Heart Study was supported by NHLBIs Framingham Heart Study contract (N01-HC-25195 and HHSN268201500001I). Vitamin D measurements in the Framingham study were made possible by NIA (R01 AG14759 to SLB.).\n\nThe Health Aging and Body Composition cohort study was supported by NIA contracts N01AG62101, N01AG2103, and N01AG62106, NIA grant R01-AG028050, NINR grant R01-NR012459, and in part by the Intramural Research Program of the NIA, NIH. This research was further supported by RC1AG035835, and the serum vitamin D assays were supported by R01AG029364.\n\nThe Multi-Ethnic Study of Atherosclerosis (MESA) study is conducted and supported by NHLBI in collaboration with MESA investigators. Support for MESA is provided by contracts HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, and N01-HC-95169 from NHLBI, UL1-TR-000040, UL1-TR-001079, and UL1-TR-001881 from NCRR, and DK063491 from the NIDDK. The MESA Lung study was supported by grants R01 HL077612, RC1 HL100543 and R01 HL093081 from NHLBI. Support for the Mineral Metabolite dataset was provided by grant HL096875.\n\nThe Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, the Netherlands; the Organization for the Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly (RIDE); the Dutch Ministry of Education, Culture, and Science; the Dutch Ministry for Health, Welfare, and Sports; the European Commission (DG XII), and the Municipality of Rotterdam. LL was a postdoctoral fellow of the Research Foundation--Flanders (FWO) in Brussels, Belgium. Part of this work was supported by a FWO-grant G035014N. DSM Nutritional Products AG, Kaiseraugst, Switzerland, sponsored the Vitamin D serum analyses. The authors are grateful to the study participants, the staff from the Rotterdam Study, and the participating general practitioners and pharmacists.\n\nThe Coronary Artery Risk Development in Young Adults Study (CARDIA) is supported by contracts HHSN268201300025C, HHSN268201300026C, HHSN268201300027C, HHSN268201300028C, HHSN268201300029C, and HHSN268200900041C from the National Heart, Lung, and Blood Institute (NHLBI), the Intramural Research Program of the National Institute on Aging (NIA), and an intra-agency agreement between NIA and NHLBI (AG0005).\n\nAuthor DisclosureDr. Psaty serves on the DSMB of a clinical trial funded by the manufacturer (Zoll LifeCor) and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson.\n\nAll other authors have no conflicts of interest. There is no commercial support or financial interest from the tobacco industry for the research presented.\n\nThe study sponsors were not involved in study design, data collection, data analysis, data interpretation, report writing, or decisions to submit the paper for publication. PAC and DBH had final responsibility for the decision to submit for publication.\n\nOnline Supporting MaterialSupplemental table, figures, and methods are available.\n\nAbbreviation Footnote

epidemiology↗

bioRxiv2017

Root Interactions And Plant Growth In A Tomato/Potato Onion Intercropping System Under Different Phosphorus Levels

Intercropping systems have been implemented in many parts of the world due to their beneficial effects on yield and biomass. In intercropping systems, changes in plant growth are usually related to variations in root distribution and phosphorus (P) levels, however, root distributions and root tendencies are difficult to study, as root systems grow beneath the soil surface. Therefore, we have a relatively poor understanding of the relationship between plant root interactions and plant growth in intercropping systems. In this study, a custom apparatus consisting of a transparent manual root box was used to observe intact root systems in situ. We investigated how root distribution and root tendency changed in a tomato/potato onion intercropping system under two P treatments, and how tomato plant growth was influenced. The results showed that the shoot and total biomass for the tomato plants were increased by intercropping with potato onion plants under both tested P levels, the root distribution of intercropped tomato plants was deeper than that of monocultured plants, and the tomato roots tended to grow away from the potato onion roots. Our research reveals that a deeper and more evasive root distribution is more conductive to the plant growth of the intercropped tomato.\n\nSUMMARY STATEMENTOur study can help more people clearly know the relationship between the root interactions and plant growth in mixed cultures.

ecology↗

bioRxiv2017

Olfactory Receptors Are Required For Social Behavior And Neural Plasticity In Ants, As Evidenced By CRISPR-Mediated Gene Knockout

The chemosensory system is key to establishing and maintaining social structure in eusocial insects. Ants exhibit cooperative colonial behaviors reflective of an advanced form of sociality with an extensive dependency on communication. Cuticular hydrocarbons (CHCs) serve as pheromones and cues that regulate multiple aspects of social interactions and behaviors in ants. The perception of CHCs entails odorant receptor neurons (ORNs) that express specific odorant receptors (ORs) encoded by a dramatically expanded Or gene family in ants. Until recently, studies of the biological functions of ORs in eusocial insects were stymied by the lack of genetic tools. In most eusocial insect species, only one or a few queens in a colony can transmit the genetic information to their progeny. In contrast, any worker in the ant Harpegnathos saltator can be converted into a gamergate (pseudo-queen), and used as a foundress to engender an entire new colony and be crossed for genetic experiments. This feature facilitated CRISPR-Cas9 gene targeting to generate a germline mutation in the orco gene that encodes the obligate co-receptor whose mutation should significantly impact ant olfaction. Our results show that Orco exhibits a conserved role in the perception of general odorants but also a role in reproductive physiology and social behavior plasticity in ants. Surprisingly, and in contrast to other insect systems, the loss of OR functionality also dramatically reduces the development of the ant antennal lobe where ORNs project. Taken together, these findings open the possibility of studying the genetics of eusociality and provide inroads towards understanding the function of the expanded ORs family in eusocial insects in regulating caste determination, social communication and neuronal plasticity.

neuroscience↗

bioRxiv2017

Evaluating Fast Maximum Likelihood-Based Phylogenetic Programs Using Empirical Phylogenomic Data Sets

Phylogenetics has witnessed dramatic increases in the sizes of data matrices assembled to resolve branches of the tree of life, motivating the development of programs for fast, yet accurate, inference. For example, several different fast programs have been developed in the very popular maximum likelihood framework, including RAxML/ExaML, PhyML, IQ-TREE, and FastTree. Although these four programs are widely used, a systematic evaluation and comparison of their performance using empirical genome-scale data matrices has so far been lacking. To address this question, we evaluated these four programs on 19 empirical phylogenomic data sets from diverse animal, plant, and fungal lineages with respect to likelihood maximization, tree topology, and computational speed. For single-gene tree inference, we found that the more exhaustive and slower strategies (ten searches per alignment) outperformed faster strategies (one tree search per alignment) using RAxML, PhyML, or IQ-TREE. Interestingly, single-gene trees inferred by the three programs yielded comparable coalescent-based species tree estimations. For concatenation-based species tree inference, IQ-TREE consistently achieved the best-observed likelihoods for all data sets, and RAxML/ExaML was a close second. In contrast, PhyML often failed to complete concatenation-based analyses, whereas FastTree was the fastest but generated lower likelihood values and more dissimilar tree topologies in both types of analyses. Finally, data matrix properties, such as the number of taxa and the strength of phylogenetic signal, sometimes substantially influenced the relative performance of the programs. Our results provide real-world gene and species tree phylogenetic inference benchmarks to inform the design and execution of large-scale phylogenomic data analyses.

evolutionary biology↗

bioRxiv2017

Sex-specific inhibition and stimulation of worker-reproductive transition in a termite

In social insects, the postembryonic development of individuals exhibits strong phenotypic plasticity in response to environment, thus generating the caste system. Different from eusocial Hymenoptera, in which queens dominate reproduction and inhibit worker fertility, the primary reproductive caste in termites (kings and queens) can be replaced by neotenic reproductives derived from functionally sterile individuals. Feedback regulation of nestmate differentiation into reproductives has been suggested, but the sex-specificity remains inconclusive. In the eastern subterranean termite, Reticulitermes flavipes, we tested the hypothesis that neotenic reproductives regulate worker-reproductive transition in a sex-specific manner. With this R. flavipes system, we demonstrate a sex-specific regulatory mechanism with both inhibitory and stimulatory functions. Neotenics inhibit workers of the same sex from differentiating into additional reproductives, but stimulate workers of the opposite sex to undergo this transition. Furthermore, this process is not affected by the presence of soldiers. Our results highlight the extraordinary reproductive plasticity of termites in response to social cues, and provide insights into the regulation of reproductive division of labour in a hemimetabolous social insect.

animal behavior and cognition↗

bioRxiv2017

Rapid Automated Large Structural Variation Detection in a Diploid Genome by NanoChannel Based Next-Generation Mapping

The human genome is diploid with one haploid genome inherited from the maternal and one from the paternal lineage. Within each haploid genome, large structural variants such as deletions, duplications, inversions, and translocations are extensively present and many are known to affect biological functions and cause disease. The ultimate goal is to resolve these large complex structural variants (SVs) and place them in the correct haploid genome with correct location, orientation, and copy number. Current methods such as karyotyping, chromosomal microarray (CMA), PCR-based tests, and next-generation sequencing fail to reach this goal either due to limited resolution, low throughput, or short read length.\n\nBionano Genomics next-generation mapping (NGM) offers a high-throughput, genome-wide method able to detect SVs of one kilobase pairs (kbp) and up. By imaging extremely long genomic molecules of up to megabases in size, the structure and copy number of complex regions of the g ...

genomics↗

bioRxiv2017

A scalable Bayesian method for integrating functional information in genome-wide association studies

Although genome-wide association studies (GWASs) have identified many risk loci for complex traits and common diseases, most of the identified associations reside in noncoding regions and have unknown biological functions. Recent genomic sequencing studies have produced a rich resource of annotations that help characterize the function of genetic variants. Integrative analysis that incorporates these functional annotations into GWAS can help elucidate the biological mechanisms underlying the identified associations and help prioritize causal-variants. Here, we develop a novel, flexible Bayesian variable selection model with efficient computational techniques for such integrative analysis. Different from previous approaches, our method models the effect-size distribution and probability of causality for variants with different annotations and jointly models genome-wide variants to account for linkage disequilibrium (LD), thus prioritizing associations based on the quantification of the annotations and allowing for multiple causal-variants per locus. Our efficient computational algorithm dramatically improves both computational speed and posterior sampling convergence by taking advantage of the block-wise LD structures of human genomes. With simulations, we show that our method accurately quantifies the functional enrichment and performs more powerful for identifying true causal-variants than several competing methods. The power gain brought up by our method is especially apparent in cases when multiple causal-variants in LD reside in the same locus. We also apply our method for an in-depth GWAS of age-related macular degeneration with 33,976 individuals and 9,857,286 variants. We find the strongest enrichment for causality among non-synonymous variants (54x more likely to be causal, 1.4x larger effect-sizes) and variants in active promoter (7.8x more likely, 1.4x larger effect-sizes), as well as identify 5 potentially novel loci in addition to the 32 known AMD risk loci. In conclusion, our method is shown to efficiently integrate functional information in GWASs, helping identify causal variants and underlying biology.\n\nAuthor summaryWe propose a novel Bayesian hierarchical model to account for linkage disequilibrium (LD) and multiple functional annotations in GWAS, paired with an expectation-maximization Markov chain Monte Carlo (EM-MCMC) computational algorithm to jointly analyze genome-wide variants. Our method improves the MCMC convergence property to ensure accurate Bayesian inference of the quantifications of the functional enrichment pattern and fine-mapped association results. By applying our method to the real GWAS of age-related macular degeneration (AMD) with various functional annotations (i.e., gene-based, regulatory, and chromatin states), we find that the variants of non-synonymous, coding, and active promoter annotations have the highest causal probability and the largest effect-sizes. In addition, our method produces fine-mapped association results in the identified risk loci, two of which are shown as examples (C2/CFB/SKIV2L and C3) with justifications by haplotype analysis, model comparison, and conditional analysis. Therefore, we believe our integrative method will be useful for quantifying the enrichment pattern of functional annotations in GWAS, and then prioritizing associations with respect to the learned functional enrichment pattern.

genetics↗

bioRxiv2017

Evolution of Reduced Co-Activator Dependence Led to Target Expansion of a Starvation Response Pathway

In S. cerevisiae, the phosphate starvation (PHO) responsive transcription factors Pho4 and Pho2 are jointly required for induction of phosphate response genes and survival in phosphate starvation conditions. In the related human commensal and pathogen C. glabrata, Pho4 is required but Pho2 is dispensable for survival in phosphate-limited conditions and is only partially required for inducing the phosphate response genes. This reduced dependence on Pho2 evolved in C. glabrata and closely related species. Pho4 orthologs that are less dependent on Pho2 induce more genes when introduced into the S. cerevisiae background, and Pho4 in C. glabrata both binds to more sites and induces more genes with expanded functional roles compared to Pho4 in S. cerevisiae. Our work reveals an evolutionary mechanism for rapidly expanding the targets of a transcription factor by changing its dependence on a co-activator, potentially refining the physiological response it regulates.

evolutionary biology↗