Biology subjects

Sun, S.

Publications and source records attributed to Sun, S..

At least 343 records · Page 19Linked to original sources

bioRxiv2019

Reconstructing the complex evolutionary history of the fused Aco2 gene in fission yeast.

The Aco2 gene of Schizosaccharomyces pombe was formed by gene fusion between curious partners, namely genes encoding the enzyme aconitase and a mitochondrial ribosomal protein. In addition to a full-length transcript, a truncated mRNA encoding only the N-terminal aconitase domain is produced by polyadenylation at an internal site. Protein products of the gene are found in the nucleus, mitochondria and cytoplasm, consistent with the presence of multiple subcellular targeting signals. To reconstruct the evolution of this complex gene, we studied homologous genes from a range of related species. We find evidence for a dynamic history within Taphrinomycotina, including: early evolution of a nuclear localization signal; creation of a 3 intron that could be involved in regulating subcellular targeting; evolution of multiple peroxisomal targeting signals in different lineages; and recurrent gene loss. We present a likely stepwise model for the evolution of this remarkable gene and discuss alternative scenarios.

bioinformatics↗

bioRxiv2019

Separating overlapping bat calls with a bi-directional long short-term memory network

Acquiring clear and usable audio recordings is critical for acoustic analysis of animal vocalizations. Bioacoustics studies commonly face the problem of overlapping signals, but the issue is often ignored, as there is currently no satisfactory solution. This study presents a bi-directional long short-term memory (BLSTM) network to separate overlapping bat calls and reconstruct waveform audio sounds. The separation quality was evaluated using seven temporal-spectrum parameters. The applicability of this method for bat calls was assessed using six different species. In addition, clustering analysis was conducted with separated echolocation calls from each population. Results showed that all syllables in the overlapping calls were separated with high robustness across species. A comparison between the seven temporal-spectrum parameters showed no significant difference and negligible deviation between the extracted and original calls, indicating high separation quality. Clustering analysis of the separated echolocation calls also produced an accuracy of 93.8%, suggesting the reconstructed waveform sounds could be reliably used. These results suggest the proposed technique is a convenient and automated approach for separating overlapping calls using a BLSTM network. This powerful deep neural network approach has the potential to solve complex problems in bioacoustics. Author summaryIn recent years, the development of recording techniques and devices in animal acoustic experiment and population monitoring has led to a sharp increase in the volume of sound data. However, the collected sound would be overlapped because of the existence of multiple individuals, which laid restrictions on taking full advantage of experiment data. Besides, more convenient and automatic methods are needed to cope with the large datasets in animal acoustics. The echolocation calls and communication calls of bats are variable and often overlapped with each other both in the recordings from field and laboratory, which provides an excellent template for research on animal sound separation. Here, we firstly solved the problem of overlapping calls in bats successfully based on deep neural network. We built a network to separate the overlapping calls of six bat species. All the syllables in overlapping calls were separated and we found no significant difference between the separated syllables with non-overlapping syllables. We also demonstrated an instance of applying our method on species classification. Our study provides a useful and efficient model for sound data processing in acoustic research and the proposed method has the potential to be generalized to other animal species.

ecology↗

bioRxiv2019

The C-terminal tail guides assembly and degradation of membrane proteins

A large number of newly synthesized membrane proteins in the endoplasmic reticulum (ER) are assembled into multi-protein complexes, but little is known about the mechanisms required for either assembly or degradation of unassembled membrane proteins. We find that C-terminal transmembrane domains (C-TMDs) with shorter tails are inefficiently inserted into the ER membrane since the translation is terminated before they emerge from ribosomes. These TMDs of insufficient hydrophobicity are post-translationally retained by the Sec61 translocon, thus providing a time window for efficient assembly with TMDs from partner membrane proteins. The unassembled C-TMDs are slowly flipped into the ER lumen. While the luminal chaperone BiP captures flipped C-TMDs with long tails and routes them to the ER-associated quality control, C-TMDs with shorter tails are diffused into the nuclear membrane. Thus, our studies suggest that C-terminal tails harbor important biochemical features for both biosynthesis and quality control of membrane protein complexes.

cell biology↗

bioRxiv2019

CTRL: a label-free method for dynamic measurement of single-cell volume

Measuring the physical size of the cell is valuable in understanding cell growth control. Current single-cell volume measurement methods for mammalian cells are labor-intensive, inflexible, and can cause cell damage. We introduce CTRL: Cell Topography Reconstruction Learner, a label-free technique incorporating Deep Learning and Fluorescence Exclusion for reconstructing cell topography and estimating mammalian cell volume from DIC microscopy images alone. The method achieves quantitative accuracy, requires minimal sample preparation, and applies to extensive biological and experimental conditions. Using this method, we observe a noticeable reduction in cell size fluctuations during cell cycle, which is consistent with the presence of a cell size checkpoint. (https://GitHub.com/sxslabjhu/CTRL)

cell biology↗

bioRxiv2019

Centromere scission drives chromosome shuffling and reproductive isolation

A fundamental characteristic of eukaryotic organisms is the generation of genetic variation via sexual reproduction. Conversely, significant large-scale genome structure variations could hamper sexual reproduction, causing reproductive isolation and promote speciation. The underlying processes behind large-scale genome rearrangements are not well understood and include chromosome translocations involving centromeres. Recent genomic studies in the Cryptococcus species complex revealed that chromosome translocations generated via centromere recombination have reshaped the genomes of different species. In this study, multiple DNA double-strand breaks (DSBs) were generated via the CRISPR/Cas9 system at centromere-specific retrotransposons in the human fungal pathogen Cryptococcus neoformans. The resulting DSBs were repaired in a complex manner, leading to the formation of multiple inter-chromosomal rearrangements and new telomeres, similar to chromothripsis-like events. The newly generated strains harboring chromosome translocations exhibited normal vegetative growth but failed to undergo successful sexual reproduction with the parental wild-type strain. One of these strains failed to produce any spores, while another produced [~]3% viable progeny. The germinated progeny exhibited aneuploidy for multiple chromosomes and showed improved fertility with both parents. All chromosome translocation events were accompanied without any detectable change in gene sequences and thus, suggest that chromosomal translocations alone may play an underappreciated role in the onset of reproductive isolation and speciation.

genetics↗

bioRxiv2019

Statistical Analysis of Spatial Expression Pattern for Spatially Resolved Transcriptomic Studies

Recent development of various spatially resolved transcriptomic techniques has enabled gene expression profiling on complex tissues with spatial localization information. Identifying genes that display spatial expression pattern in these studies is an important first step towards characterizing the spatial transcriptomic landscape. Detecting spatially expressed genes requires the development of statistical methods that can properly model spatial count data, provide effective type I error control, have sufficient statistical power, and are computationally efficient. Here, we developed such a method, SPARK. SPARK directly models count data generated from various spatial resolved transcriptomic techniques through generalized linear spatial models. With a new efficient penalized quasi-likelihood based algorithm, SPARK is scalable to data sets with tens of thousands of genes measured on tens of thousands of samples. Importantly, SPARK relies on newly developed statistical formulas for hypothesis testing, producing well-calibrated p-values and yielding high statistical power. We illustrate the benefits of SPARK through extensive simulations and in-depth analysis of four published spatially resolved transcriptomic data sets. In the real data applications, SPARK is up to ten times more powerful than existing approaches. The high power of SPARK allows us to identify new genes and pathways that reveal new biology in the data that otherwise cannot be revealed by existing approaches.

genomics↗

bioRxiv2019

Uniparental mitochondrial inheritance in Cryptococcus is controlled by the pheromone and pheromone receptor mating-type locus

Mitochondria are inherited uniparentally during sexual reproduction in the majority of eukaryotic species studied, including humans, mice, nematodes, as well as many fungal species. Mitochondrial uniparental inheritance (mito-UPI) could be beneficial in that it avoids possible genetic conflicts between organelles with different genetic backgrounds, as recently shown in mice; and it could prevent the spread of selfish genetic elements in the mitochondrial genome. Despite the prevalence of observed mito-UPI, the underlying mechanisms and the genes involved in controlling this non-mendelian inheritance are poorly understood in many species. In Cryptococcus neoformans, a human pathogenic basidiomyceteous fungus, mating types (MAT and MATa) are defined by alternate alleles at the single MAT locus that evolved from fusion of the two MAT loci (P/R encoding pheromones and pheromone receptors, HD encoding homeodomain transcription factors) that are the ancestral state in the basidiomycota. Mitochondria are inherited uniparentally from the MATa parent in C. neoformans and this requires the SXI1 and SXI2a HD factors encoded by MAT. However, there is evidence additional genes contribute to control of mito-UPI in Cryptococcus. Here we show that in Cryptococcus amylolentus, a sibling species of C. neoformans with unlinked P/R and HD MAT loci, mitochondrial uniparental inheritance is controlled by the P/R locus, and is independent of the HD locus. Consistently, by replacing the MAT alleles of the pheromones (MF) and pheromone receptor (STE3) with the MATa alleles, we show that these P/R locus defining genes indeed affect mito-UPI in C. neoformans during sexual reproduction. Additionally, we show that during early stages of C. neoformans sexual reproduction, conjugation tubes are always produced by the MAT cells, resulting in unidirectional migration of the MAT nucleus into the MATa cell during zygote formation. This process is controlled by the P/R locus and could serve to physically restrict movement of MAT mitochondria in the zygotes, and thereby contribute to mito-UPI. We propose a model in which both physical and genetic mechanisms function in concert to prevent the coexistence of mitochondria from the two parents in the zygote and subsequently in the meiotic progeny, thus ensuring mito-UPI in pathogenic Cryptococcus, as well as in closely related non-pathogenic species. The implications of these findings are discussed in the context of the evolution of mito-UPI in fungi and other more diverse eukaryotes.

genetics↗

bioRxiv2019

Conserved nuclear receptors controlling a novel trait target fast-evolving genes expressed in a single cell

Environment shapes development through a phenomenon called developmental plasticity. Deciphering its genetic basis has implications for understanding evolution and adaptation to novel environments, yet molecular studies are scarce. Here, we expanded the gene regulatory network controlling predatory vs. non-predatory morphology in the nematode Pristionchus pacificus. First, we isolated a mutant in the nuclear hormone receptor nhr-1 with a previously unseen phenotypic effect. It disrupts mouth-form determination and results in animals combining features of both wild-type morphs. Further, we identified common targets of NHR-1 and the previously identified nuclear hormone receptor NHR-40 through transcriptomics. Unlike their highly conserved regulators, the target genes have no orthologs in Caenorhabditis elegans and likely result from lineage-specific expansions. An array of transcriptional reporters revealed co-expression of all tested targets in the same pharyngeal gland cell. The morphological remodeling of this cell accompanied the evolution of teeth and predation, linking rapid gene turnover with morphological innovations.

developmental biology↗

bioRxiv2019

The usage of six human IGHJ genes follows a particular nonrandom selection: The recombination signal sequence affects the usage frequency of six human IGHJ genes

The formation of the B cell receptor (BCR) heavy chain variable region is derived from the germline V(D)J gene rearrangement according to the \"12/23\" rule and the \"beyond 12/23\" rule. The usage frequency of each V(D)J gene in the peripheral BCR repertoires is related to the initial recombination, self-tolerance selection, and the clonal proliferative response. However, their specific differences and possible mechanisms are still unknown. We analyzed in-frame and out-of-frame BCR-H repertoires from human samples with physiological and various pathological conditions by high-throughput sequencing. Our results showed that IGHJ gene frequency follows a similar pattern where IGHJ4 is used at high frequency (>40%), IGHJ6/IGHJ3/IGHJ5 is used at medium frequencies (10%[~]20%), and IGH2/IGHJ1 is used at low frequency (<4%) under whether physiological or various pathological conditions. Furthermore, analysis of the recombination signal sequences suggested that the conserved nonamer and heptamer and certain 23 bp spacer length may affect the initial IGHD-IGHJ recombination, which results in different frequencies of IGHJ genes among the initial BCR-H repertoire. Based on this \"background repertoire\", we recommend that re-evaluation and further investigation are needed when analyzing the significance and mechanism of IGHJ gene frequency in self-tolerance selection and the clonal proliferative response.

genomics↗

bioRxiv2019

The genome of Mekong tiger perch (Datnioides undecimradiatus) provides insights into the phylogenic position of Lobotiformes and biological conservation

Mekong tiger perch (Datnioides undecimradiatus) is one ornamental fish and a vulnerable species, which belongs to order Lobotiformes. Here, we report a [~]595 Mb D. undecimradiatus genome, which is the first whole genome sequence in the order Lobotiformes. Based on this genome, the phylogenetic tree analysis suggested that Lobotiformes and Sciaenidae are closer than Tetraodontiformes, resolving a long-time dispute. We depicted the pigment synthesis pathway in Mekong tiger perch and result confirmed that this pathway had evolved from the shared whole genome duplication. We also estimated the demographic history of Mekong tiger perch, showing the effective population size suffered a continuous reduction possibly related to the contraction of immune-related genes. Our study provided a reference genome resource for the Lobotiformes, as well as insights into the phylogeny of Eupercaria and biological conservation.

genomics↗

bioRxiv2019

A pentylenetetrazole-induced kindling zebrafish larval model for evoked recurrent seizures

BackgroundTransient pentylenetetrazol (PTZ) treatment on zebrafish larvae has been widely accepted a promising animal model for human epilepsy. However, this model is not ideal due to its acuteness and lack of recurrent seizures, which are the key feature of epilepsy in human disease. It is important to develop a more sensitive zebrafish model for epilepsy with well-controlled, predictable, recurrent seizures.\n\nNew MethodThe new method includes an experimental setup and a treatment protocol. The setup tracks the locomotion activity of up to 48 larvae simultaneously, while a visual stimulus can be presented to each of the 48 animals individually. The protocol treated the larvae through a water bath in 5 mM PTZ while being stimulated with rotating grating stimuli for 1 hour/day from 5 to 7 days postfertilization.\n\nResultsThe setup captured the locomotion activity of zebrafish larvae during visual stimulation. The new protocol generated recurrent responses after flashing lights 4 hours post PTZ treatment. The effects could be suppressed by the anti-epileptic drug valproic acid. The characteristics of the visual stimulus play a major role in this kindling model.\n\nComparisons with Existing MethodsWe compared the proposed method with the transient PTZ model and confirmed that the flashing-light-evoked recurrent seizure is a new feature in addition to the transient changes.\n\nConclusionsThe new method generated non-drug-triggered predictable recurrent seizures in response to intermittent photic stimulation in zebrafish larvae and may serve as a sensitive method for anti-epileptic drug screening or a new research protocol in epilepsy research.

neuroscience↗

bioRxiv2019

The PAR2 signal peptide prevents premature receptor cleavage and activation

Unlike closely related GPCRs, protease-activated receptors (PAR1, PAR2, PAR3, and PAR4) have a predicted signal peptide at their N-terminus, which is encoded by a separate exon, suggesting that the signal peptides of PARs may serve an important and unique function, specific for PARs. In this report, we show that the PAR2 signal peptide, when fused to the N-terminus of IgG-Fc, effectively induced IgG-Fc secretion into culture medium, thus behaving like a classical signal peptide. The presence of PAR2 signal peptide has a strong effect on PAR2 cell surface expression, as deletion of the signal peptide (PAR2{Delta}SP) led to dramatic reduction of the cell surface expression and decreased responses to trypsin or the synthetic peptide ligand (SLIGKV). However, further deletion of the tethered ligand region (SLIGKV) at the N-terminus rescued the cell surface receptor expression and the response to the synthetic peptide ligand, suggesting that the signal peptide of PAR2 may be involved in preventing PAR2 from intracellular protease activation before reaching the cell surface. Supporting this hypothesis, an Arg36Ala mutation on PAR2{Delta}SP, which disabled the trypsin activation site, increased the receptor cell surface expression and the response to ligand stimulation. Similar effects were observed when PAR2{Delta}SP expressing cells were treated with protease inhibitors. Our findings indicated that these is a role of the PAR2 signal peptide in preventing the premature activation of PAR2 from intracellular protease cleavage before reaching the cells surface. The same mechanism may also apply to PAR1, PAR3, and PAR4.

biochemistry↗

bioRxiv2019

Regulatory kinase genetic interaction profiles differ between environmental conditions and cellular states

Cell growth and quiescence in eukaryotic cells is controlled by an evolutionarily conserved network of signaling pathways. Signal transduction networks operate to modulate a wide range of cellular processes and physiological properties when cells exit proliferative growth and initiate a quiescent state. How signaling networks function to respond to diverse signals that result in cell cycle exit and establishment of a quiescent state is poorly understood. Here, we studied the function of signaling pathways in quiescent cells using global genetic interaction mapping in the model eukaryotic cell, Saccharomyces cerevisiae (budding yeast). We performed pooled analysis of genotypes using molecular barcode sequencing to test the role of [~]3,900 gene deletion mutants and [~]11,700 pairwise interactions between all non-essential genes and the protein kinases TOR1, RIM15, PHO85 in three different nutrient-restricted conditions in both proliferative and quiescent cells. We detect nearly five-fold more genetic interactions in quiescent cells compared to proliferative cells. We find that both individual gene effects and genetic interaction profiles vary depending on the specific pro-quiescence signal. The master regulator of quiescence, RIM15 shows distinct genetic interaction profiles in response to different starvation signals. However, vacuole-related functions show consistent genetic interactions with RIM15 in response to different starvation signals suggesting that RIM15 integrates diverse signals to maintain protein homeostasis in quiescent cells. Our study expands genome-wide genetic interaction profiling to additional conditions, and phenotypes, highlighting the conditional dependence of epistasis.

genetics↗

bioRxiv2019

Cryptococcus neoformans recovered from olive trees (Olea europaea) in Turkey reveal allopatry with African and South American lineages

Cryptococcus species are life-threatening human fungal pathogens that cause cryptococcal meningoencephalitis in both immunocompromised and healthy hosts. The natural environmental niches of Cryptococcus include pigeon (Columba livia) guano, soil, and a variety of tree species such as Eucalyptus camaldulensis, Ceratonia siliqua, Platanus orientalis, and Pinus spp. Genetic and genomic studies of extensive sample collections have provided insights into the population distribution and composition of different Cryptococcus species in geographic regions around the world. However, few such studies examined Cryptococcus in Turkey. We sampled 388 Olea europaea (olive) and 132 E. camaldulensis trees from 7 locations in coastal and inland areas of the Aegean region of Anatolian Turkey in September 2016 to investigate the distribution and genetic diversity present in the natural Cryptococcus population. We isolated 84 Cryptococcus neoformans strains (83 MAT and 1 MATa) and 3 Cryptococcus deneoformans strains (all MATa) from 87 (22.4% of surveyed) O. europaea trees; a total of 32 C. neoformans strains were isolated from 32 (24.2%) of the E. camaldulensis trees, all of which were MAT. A statistically significant difference was observed in the frequency of C. neoformans isolation between coastal and inland areas (P < 0.05). Thus, O. europaea trees could represent a novel niche for C. neoformans. Interestingly, the MATa C. neoformans isolate was fertile in laboratory crosses with VNI and VNB MAT tester strains and produced robust hyphae, basidia, and basidiospores, thus suggesting potential sexual reproduction in the natural population. Sequencing analyses of the URA5 gene identified at least 5 different genotypes among the isolates. Population genetics and genomic analyses revealed that most of the isolates in Turkey belong to the VNBII lineage of C. neoformans, which is predominantly found in southern Africa; these isolates are part of a distinct minor clade within VNBII that includes several isolates from Zambia and Brazil. Our study provides insights into the geographic distribution of different C. neoformans lineages in the Mediterranean region and highlights the need for wider geographic sampling to gain a better understanding of the natural habitats, migration, epidemiology, and evolution of this important human fungal pathogen.

genetics↗

bioRxiv2019

Immune responses in mice induced by multi-epitope DNA vaccine and protein vaccine of Crimean-Congo Hemorrhagic Fever Virus

Crimean-Congo Hemorrhagic Fever (CCHF), caused by the CCHF virus (CCHFV), is a severe tick borne zoonosis widely distributed in over 30 countries and regions. Currently, there is no licensed vaccine available for CCHF in China. To evaluate the cellular and humoral immune responses induced by multi-epitope DNA and protein vaccine of CCHF in BALB/c mice, a multi-epitope gene (MEPX) segment with tandem including six highly conservative and immunedominant B cell epitopes was designed based on the analysis of hydrophilicity and antigenic determinant sites in amino acid sequences of nucleoprotein and glycoprotein from CCHFV strain YL04057. The single and double-copy multi-epitope gene (MEPX and MEPX2) were respectively cloned into the eukaryotic expression vector pVAX I to construct the recombinant (r) plasmid pVAX-MEPX and pVAX-MEPX2 as DNA vaccines. The results of immunofluorescence in vitro showed that the pVAX-MEPX and pVAX-MEPX2 could be expressed in 293T cells. The recombinant prokaryotic plasmid pET-32a-MEPX and pET-32a-MEPX2 constructed previously were transformed them into E. coli BL21 (DE3), and recombinant multi-epitope proteins (rMEPX and rMEPX2) were obtained and purificated by Nickel affinity chromatography. Western blot results showed that rMEPX and rMEPX2 had good antigenicity. BALB/c mice were immunized with DNA vaccine alone, protein vaccine alone, and DNA prime followed by recombinant protein boost immunization strategy, respectively. After three immunizations, MTT assay, cytokine content assay, and ELISA assay for antibody titers were used to evaluate the immune response. The proliferation of mouse specific T lymphocytes in the enhanced by pVAX-MEPX2 combined with rMEPX2 boosting group was significant, and the expression levels of serum IFN-{gamma} and IL-4 in mice were as high as 118.67 pg/mL and 135.33 pg/mL with significant difference compared to the control group (p<0.01), and serum antibody titer could reach up to 4.1x105. Double-copy multi-epitope vaccines groups (pVAX-MEPX2+ rMEPX2) generated better cellular and humoral immune responses by DNA prime-protein vaccine boost combinatorial immunization. This result could lay the foundation for the development of CCHFV multi-epitope vaccine candidates.

immunology↗

bioRxiv2019

Endoplasmic reticulum associated degradation preserves hematopoietic stem cell quiescence and self-renewal by restricting mTOR activity

Many tissue-specific stem cells require quiescence to sustain stem cell pool and maintain lifelong tissue integrity. It remains unclear whether protein quality control is required for stem cells in quiescence when RNA content, protein synthesis and metabolic activities are significantly reduced. Here, we report that endoplasmic reticulum associated degradation (ERAD) is required to preserve the function of quiescent hematopoietic stem cells (HSC). The Sel1L/Hrd1 ERAD genes are enriched in the quiescent and inactive HSCs, and conditional knockout of Sel1L in hematopoietic tissues drives HSCs to hyper-proliferation which leads to reduced self-renewal and HSC depletion. ERAD deficiency induces a non-apoptotic ER stress and activates unfolded protein response (UPR). Furthermore, Sel1L knockout leads to mTOR activation, and mTOR inhibition rescues the HSC defects in Sel1L knockout mice. Protein quality control is, therefore, tightly regulated and actively engaged in quiescent HSCs. Sel1L/Hrd1 ERAD maintains HSC quiescence and self-renewal via restricting mTOR activity.

cell biology↗

bioRxiv2019

Testing and controlling for horizontal pleiotropy with the probabilistic Mendelian randomization in transcriptome-wide association studies

Integrating association results from both genome-wide association studies (GWASs) and expression quantitative trait locus (eQTL) mapping studies has the potential to shed light on the molecular mechanisms underlying disease etiology. Several statistical methods have been recently developed to integrate GWASs with eQTL studies in the form of transcriptome-wide association studies (TWASs). These existing methods can all be viewed as a form of two sample Mendelian randomization (MR) analysis, which has been widely applied in various GWASs for inferring the causal relationship among complex traits. Unfortunately, most existing TWAS and MR methods make an unrealistic modeling assumption and assume that instrumental variables do not exhibit horizontal pleiotropic effects. However, horizontal pleiotropic effects have been recently discovered to be wide spread across complex traits, and, as we will show here, are also wide spread across gene expression traits. Therefore, not allowing for horizontal pleiotropic effects can be overly restrictive, and, as we will be show here, can lead to a substantial inflation of test statistics and subsequently false discoveries in TWAS applications. Here, we present a probabilistic MR method, which we refer to as PMR-Egger, for testing and controlling for horizontal pleiotropic effects in TWAS applications. PMR-Egger relies on an MR likelihood framework that unifies many existing TWAS and MR methods, accommodates multiple correlated instruments, tests the causal effect of gene on trait in the presence of horizontal pleiotropy, and, with a newly developed parameter expansion version of the expectation maximization algorithm, is scalable to hundreds of thousands of individuals. With extensive simulations, we show that PMR-Egger provides calibrated type I error control for causal effect testing in the presence of horizontal pleiotropic effects, is reasonably robust for various types of horizontal pleiotropic effect mis-specifications, is more powerful than existing MR approaches, and, as a by-product, can directly test for horizontal pleiotropy. We illustrate the benefits of PMR-Egger in applications to 39 diseases and complex traits obtained from three GWASs including the UK Biobank. In these applications, we show how PMR-Egger can lead to new biological discoveries through integrative analysis.

genetics↗

bioRxiv2019

Functional conservation of lncRNA JPX despite sequence and structural divergence

Long noncoding RNAs (lncRNAs) have been identified in all eukaryotes and are most abundant in the human genome. However, the functional importance and mechanisms of action for human lncRNAs are largely unknown. Using comparative sequence, structural, and functional analyses, we characterize the evolution and molecular function of human lncRNA JPX. We find that human JPX and its mouse homolog, lncRNA Jpx, have deep divergence in their nucleotide sequences and RNA secondary structures. Despite such differences, both lncRNAs demonstrate robust binding to CTCF, a protein that is central to Jpxs role in X chromosome inactivation. In addition, our functional rescue experiment using Jpx-deletion mutant cells, shows that human JPX can functionally complement the loss of Jpx in mouse embryonic stem cells. Our findings support a model for functional conservation of lncRNAs independent from sequence and structural changes. The study provides mechanistic insight into the evolution of lncRNA function.

molecular biology↗