Biology subjects

Fan, Y.

Publications and source records attributed to Fan, Y..

15 recordsLinked to original sources

bioRxiv2018

A novel core genome approach to enable prospective and dynamic monitoring of infectious outbreaks

Whole-genome sequencing is increasingly adopted in clinical settings to identify pathogen transmissions. Currently, such studies are performed largely retrospectively, but to be actionable they need to be carried out prospectively, in which samples are continuously added and compared to previous samples. To enable prospective pathogen comparison, genomic relatedness metrics based on single nucleotide differences must be consistent across time, efficient to compute and reliable for a large variety of samples. The choice of genomic regions to compare, i.e., the core genome, is critical to obtain a good metric.\n\nWe propose a novel core genome method that selects conserved sequences in the reference genome by comparing its k-mer content to that of publicly available genome assemblies. The conserved-sequence genome is sample set-independent, which enables prospective pathogen monitoring. Based on clinical data sets of 3436 S. aureus, 1362 K. pneumoniae and 348 E. faecium samples, we show that the conserved-sequence genome disambiguates same-patient samples better than a core genome consisting of conserved genes. The conserved-sequence genome confirms outbreak samples with high accuracy: in a set of 2335 S. aureus samples, it correctly identifies 44 out of 45 outbreak samples, whereas the conserved gene method confirms 38 out of 45 outbreak samples.

bioinformatics↗

bioRxiv2018

Marker-based watershed transform method for fully automatic mandibular segmentation from low-dose CBCT images

Introduction Introduction Methods and materials Results Discussion Conclusions Funding References Three-dimensional mandibular models are useful for planning maxillofacial surgery and orthodontic treatment.1,2 In studies of growth, mandibular models are important for assessing morphological changes over time.3,4 Such models are typically obtained from conventional computed tomography (CT), using high radiation dose to capture fine detail of the bony structure. Cone beam computed tomography (CBCT) shows promise for oral and craniofacial imaging applications due to lower radiation dose, lower cost and shorter acquisition time compared to CT. However, CBCT images have lower contrast and higher levels of ...

bioinformatics↗

bioRxiv2018

MYCN Amplification and ATRX Mutations are Incompatible in Neuroblastoma

Aggressive cancers often have activating mutations in growth-controlling oncogenes and inactivating mutations in tumor-suppressor genes. In neuroblastoma, amplification of the MYCN oncogene and inactivation of the ATRX tumor-suppressor gene correlate with high-risk disease and poor prognosis. Here we show that ATRX mutations and MYCN amplification are mutually exclusive across all ages and stages in neuroblastoma. Using human cell lines and mouse models, we found that elevated MYCN expression and ATRX mutations are incompatible. Elevated MYCN levels promote metabolic reprogramming, mitochondrial dysfunction, reactive-oxygen species generation, and DNA-replicative stress. The combination of replicative stress caused by defects in the ATRX-histone chaperone complex and that induced by MYCN-mediated metabolic reprogramming leads to synthetic lethality. Therefore, ATRX and MYCN represent an unusual example, where inactivation of a tumor-suppressor gene and activation of an oncogene are incompatible. This synthetic lethality may eventually be exploited to improve outcomes for patients with high-risk neuroblastoma.

cancer biology↗

bioRxiv2018

Portraits of genetic intra-tumour heterogeneity and subclonal selection across cancer types

Intra-tumor heterogeneity (ITH) is a mechanism of therapeutic resistance and therefore an important clinical challenge. However, the extent, origin and drivers of ITH across cancer types are poorly understood. To address this question, we extensively characterize ITH across whole-genome sequences of 2,658 cancer samples, spanning 38 cancer types. Nearly all informative samples (95.1%) contain evidence of distinct subclonal expansions, with frequent branching relationships between subclones. We observe positive selection of subclonal driver mutations across most cancer types, and identify cancer type specific subclonal patterns of driver gene mutations, fusions, structural variants and copy-number alterations, as well as dynamic changes in mutational processes between subclonal expansions. Our results underline the importance of ITH and its drivers in tumor evolution, and provide an unprecedented pan-cancer resource of comprehensively annotated subclonal events from whole-genome sequencing data.

cancer biology↗

bioRxiv2018

Baculovirus utilizes cholesterol transporter Niemann-Pick C1 for host cell entry

The dual roles of baculovirus for the control of natural insect populations as an insecticide, and for foreign gene expression and delivery, have called for a comprehensive understanding of the molecular mechanisms governing viral infection. Here, we demonstrate that the Bombyx mori Niemann-Pick C1 (BmNPC1) is essential for baculovirus infection in insect cells. Both pretreatment of Bombyx mori embryonic cells (BmE) with NPC1 antagonists (imipramine or U18666A) and down-regulation of NPC1 expression resulted in a significant reduction in baculovirus BmNPV (Bombyx mori nuclear polyhedrosis virus) infectivity. Furthermore, we show that the major glycoprotein gp64 of BmNPV, responsible for both receptor binding and fusion, is able to interact predominantly with the BmNPC1 C domain, with an enhanced binding capacity at low pH conditions, indicating that NPC1 most likely plays a role during viral fusion in endosomal compartments. Our results, combined with previous studies identifying an essential role of hNPC1 in filovirus infection, suggest that the glycoprotein of several enveloped viruses possess a shared strategy of exploiting host NPC1 proteins during virus intracellular entry events.\n\nIMPORTANCEBmNPV is one of the most important members of the Baculoviridae; many viruses in this family have been frequently employed as viral vectors for foreign gene delivery or expression and as biopesticides, but their host receptors still remain unclear. Here, we describe that the intracellular cholesterol transporter BmNPC1 is indispensable for BmNPV infection in insect cells, and it interacts with the major viral glycoprotein gp64. Our study on the role of BmNPC1 in baculovirus infection has further expanded the list of the enveloped viruses that require host NPC1 proteins for entry, and will ultimately help us to uncover the molecular mechanism of the involvement of NPC1 proteins in the entry process of many enveloped viruses.

microbiology↗

bioRxiv2018

The Drosophila TNF Eiger activates caspase-dependent necrosis when apoptosis is blocked

Eiger (Egr), the homolog of the mammalian tumor-necrosis factor (TNF), is the ligand of the c-Jun N-terminal kinase (JNK) stress response signaling pathway in Drosophila. Although expression of Egr frequently leads to apoptosis, it has also been implicated in activation of non-apoptotic cell death. However, it is not yet clear how Egr can induce both apoptosis and non-apoptotic cell death, and if so, how such processes are coordinated. Here, we show that expression of Egr in the developing Drosophila eye induces apoptosis and non-apoptotic developmental defects, both of which are JNK-dependent. Intriguingly, when apoptotic effector caspases DrICE and Dcp-1 are defective or inhibited, expression of Egr induces necrosis characterized by loss of cell membrane integrity, translucent cytoplasm and aggregation of cellular organelles. Surprisingly, the induction of necrosis depends on the catalytic activity of the initiator caspase Dronc and the input from JNK signaling independently of their roles in apoptosis. Therefore, similar to the mammalian caspase-8, caspases in Drosophila also have dual roles in promoting TNF-mediated apoptosis and inhibiting necrosis.

developmental biology↗

bioRxiv2018

Germline genetics encode the resistance, risk, and lymphatic metastasis of triple-negative breast cancer in the southern Chinese population

Early identification of the risk for triple-negative breast cancer (TNBC) at the asymptomatic phase could lead to better prognosis. Here we developed a machine learning method to quantify systematic impact of all rare germline mutations on each pathway. We collected 106 TNBC patients and 287 elder healthy women controls. The spectra of activity profiles in multiple pathways were mapped and most pathway activities exhibited globally suppressed by the portfolio of individual germline mutations in TNBC patients. Accordingly, all individuals were delineated into two types: A and B. Type A patients could be differentiated from controls (AUC = 0.89) and sensitive to BRCA1/2 damages; Type B patients can be also differentiated from controls (AUC = 0.69) but probably being protected from BRCA1/2 damages. Further we found that Individuals with the lowest activity of selected pathways had extreme high relative risk (up to 21.67 in type A) and increased lymph node metastasis in these patients. Our study showed that genomic DNA contains information of unimaginable pathogenic factors. And this information is in a distributed form that could be applied to risk assessment for more cancer types. SignificanceWe identified individuals who are more susceptible to triple negative breast cancer. Our method performs much better than previous assessments based on BRCA1/2 damages, even polygenic risk scores. We disclosed previously unimaginable pathogens in a distributed form on genome and extended risk prediction to scenarios for other cancers.

cancer biology↗

bioRxiv2018

Ongoing, rational calibration of reward-driven perceptual biases

Decision-making is often interpreted in terms of normative computations that maximize a particular reward function for stable, average behaviors. Aberrations from the reward-maximizing solutions, either across subjects or across different sessions for the same subject, are often interpreted as reflecting poor learning or physical limitations. Here we show that such aberrations may instead reflect the involvement of additional satisficing and heuristic principles. For an asymmetric-reward perceptual decision-making task, three monkeys produced adaptive biases in response to changes in reward asymmetries and perceptual sensitivity. Their choices and response times were consistent with a normative accumulate-to-bound process. However, their context-dependent adjustments to this process deviated slightly but systematically from the reward-maximizing solutions. These adjustments were instead consistent with a rational process to find satisficing solutions based on the gradient of each monkeys reward-rate function. These results suggest new dimensions for assessing the rational and idiosyncratic aspects of flexible decision-making.

neuroscience↗

bioRxiv2017

Horizontal Gene Transfer Can Help Maintain the Equilibrium of Microbial Communities

Horizontal gene transfer and species coexistence are two focal points in the study of microbial communities. The evolutionary advantage of horizontal gene transfer has not been well-understood and is constantly being debated. Here we propose a simple population dynamics model based on the frequency-dependent interactions between different genotypes to evaluate the influence of horizontal gene transfer on microbial communities. We find that both structural stability and robustness of the microbial community are strongly affected by the gene transfer rate and direction. An optimal gene flux can stablize the ecosystem, helping it recover from disturbance and maintain the species coexistence.

evolutionary biology↗

bioRxiv2017

Cpk2, a catalytic subunit of cyclic AMP-PKA, regulates growth and pathogenesis in rice blast

The cAMP-Protein Kinase A signalling, anchored on CpkA, is necessary for appressorium development and host penetration, but indispensable for infectious growth in Magnaporthe oryzae. In this study, we identified and characterized the gene encoding the second catalytic subunit, CPK2, whose expression was found to be lower compared to CPKA at various stages of pathogenic growth in M. oryzae. Deletion of CPK2 caused no alterations in vegetative growth, conidiation, appressorium formation, or pathogenicity. Surprisingly, the cpkA{Delta}cpk2{Delta} double deletion strain displayed significant reduction in growth rate and conidiation compared to the single deletion mutants. Interestingly, loss of CPKA and CPK2 resulted in morphogenetic defects in germ tubes (with curled/wavy and serpentine growth pattern) on hydrophobic surfaces, and a complete failure to produce appressoria therein, thus suggesting an important role for CPK2-mediated cAMP-PKA in surface sensing and response pathway. CPKA promoter-driven CPK2 expression partially suppressed the defects in host penetration and pathogenicity in the cpkA{Delta}. Such ectopic CPK2 expressing strain successfully penetrated the rice leaves, but was unable to produce proper secondary invasive hyphae, thus underscoring the importance of CpkA in growth and differentiation in planta. The Cpk2-GFP localized to the nucleus and cytoplasmic vesicles in conidia and the germ tubes. The Cpk2-GFP colocalized with CpkA-mCherry on vesicles in the cytosol, but such overlap was not evident in the nucleus. Our studies indicate that CpkA and Cpk2 share overlapping functions, but also play distinct roles during pathogenesis-associated signalling and morphogenesis in the rice blast fungus.

cell biology↗

bioRxiv2017

First Draft Genome Sequence of the Pathogenic Fungus Lomentospora prolificans (formerly Scedosporium prolificans)

Here we describe the sequencing and assembly of the pathogenic fungus Lomentospora prolificans using a combination of short, highly accurate Illumina reads and additional coverage in very long Oxford Nanopore reads. The resulting assembly is highly contiguous, containing a total of 37,630,066 bp with over 98% of the sequence in just 26 scaffolds. Annotation identified 8,656 protein-coding genes. Pulsed-field gel analysis suggests that this organism contains at least 7 and possibly 11 chromosomes, the two longest of which have sizes corresponding closely to the sizes of the longest scaffolds, at 6.6 and 5.7 Mb.

microbiology↗

bioRxiv2017

Evaluation of Topramezone on Zebrafish Retinoid Signaling

Topramezone is a highly selective herbicide developed for broadleaf and grass weeds control in corn. In this study, the effects of topramezone on zebrafish, especially in retinoid signaling were investigated. Zebrafish embryos were treated with topramezone from 4 hours post-fertilization (hpf) to 144 hpf. Exposed to topramezone significantly reduced the retinal and retinoic levels compared to controls. The transcriptional expression levels of retinol dehydrogenase (rdh1), retinoic acid receptor subunit (raraa), retinal dehydrogenase (raldh2), retinol binding protein (rbp1a), and cellular retinoic acid binding protein (crabp1a and crabp2a) were significantly decreased. Our results suggested that topramezone significantly impaired zebrafish retinoid signaling during a short time exposure. However, treatment with topramezone significantly increased the mRNA expression levels of zfblue, zfrho, zfgr1, zfuv, and zfred. Our data demonstrated that topramezone treatment could interrupt retinoid signaling and further affect zebrafish eye development.

molecular biology↗

bioRxiv2017

The evolutionary history of 2,658 cancers

Cancer develops through a process of somatic evolution. Here, we use whole-genome sequencing of 2,778 tumour samples from 2,658 donors to reconstruct the life history, evolution of mutational processes, and driver mutation sequences of 39 cancer types. The early phases of oncogenesis are driven by point mutations in a small set of driver genes, often including biallelic inactivation of tumour suppressors. Early oncogenesis is also characterised by specific copy number gains, such as trisomy 7 in glioblastoma or isochromosome 17q in medulloblastoma. By contrast, increased genomic instability, a nearly four-fold diversification of driver genes, and an acceleration of point mutation processes are features of later stages. Copy-number alterations often occur in mitotic crises leading to simultaneous gains of multiple chromosomal segments. Timing analysis suggests that driver mutations often precede diagnosis by many years, and in some cases decades, providing a window of opportunity for early cancer detection.

cancer biology↗

bioRxiv2017

Contribution Of Genetic Variation And Developmental Stage To Methylome Dynamics In Myeloid Differentiation

DNA methylation is important to establish a cells developmental identity. It also modulates cellular responses to endogenous developmental stimuli or environmental changes. We designed an in vitro myeloid differentiation model to analyze the genetic and developmental contribution to methylome dynamics using whole-genome bisulfide sequencing and transcriptome sequencing. Using a recursive partitioning approach, we identified 34,502 differentially methylated regions (DMRs) associated with genetic background and/or developmental stimuli. Specifically, 23,792 DMRs (69%) were significantly associated with inter-individual variations, of which 82% were associated with genetic polymorphisms in cis. Notably, inter-individual variations further modified 57 of 212 (26%) developmental DMRs with transcriptomic responses. Our study presents a novel analytical approach to determine the bona fide genetic contribution embedded in outlier patterns of CpG-SNPs in individual methylomes. This approach can be used to study genetic and epigenetic mechanisms underlying differential responses to developmental stimuli, environmental changes, and inter-individual differences in drug responses.

genomics↗

bioRxiv2017

Transposons modulate transcriptomic and phenotypic variation via the formation of circular RNAs in maize

Circular RNAs (circRNAs) are covalently closed, single-stranded RNA molecules. Recent studies in human showed that circRNAs can arise via transcription of reverse complementary pairs of transposons. Given the prevalence of transposons in the maize genome and dramatic genomic variation driven by transposons, we hypothesize that transposons in maize may be involved in the formation of circRNAs and further modulate phenotypic variation. To test our hypothesis, we performed circRNA-Seq on B73 seedling leaves and integrate these data with 977 publicly available mRNA-Seq datasets. We uncovered 1,551 high-confidence maize circRNAs, which show distinct genomic features as compared to linear transcripts. Comprehensive analyses demonstrated that LINE1-like elements (LLE) and their Reverse Complementary Pairs (LLERCPs) are significantly enriched in the flanking regions of circRNAs. Interestingly, the accumulation of circRNA transcripts increases, while the accumulation of linear transcripts decreases as the number of LLERCPs increases. Furthermore, genes with LLERCP-mediated circRNAs are enriched among loci that are associated with phenotypic variation. These results suggest that LLERCPs can modulate phenotypic variation by the formation of circRNAs. As a proof of concept, we showed that the presence/absence variation of LLERCPs could result in expression variation of one cicrRNA, circ352, and further related to plant height through the interaction between circRNA and functional linear transcript. Our first glimpse of circRNAs uncovers a new role for transposons in the modulation of transcriptomic and phenotypic variation via the formation of circRNAs.

genomics↗