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  • Structural and immunogenomic insights for B cell receptor activation
    J. Genet. Genomics (IF 4.650) Pub Date : 2020-01-09
    Yangyang Feng; Yu Wang; Shaocun Zhang; Kabeer Haneef; Wanli Liu

    B cells express B-cell receptors (BCRs) which recognize antigen to trigger signaling cascades for B cell activation and subsequent antibody production. BCR activation has a crucial influence on B cell fate. How BCR is activated upon encountering antigen remains to be solved, although tremendous progresses have been achieved in the past a few years. Here, we summarized the models that have been proposed to explain BCR activation, including the cross-linking model, the conformation-induced oligomerization model, the dissociation activation model and conformational change model. Especially, we elucidated the partially resolved structures of antibodies and/or BCRs by far and discussed how these current structural and further immunogenomic messages and more importantly the future studies may shed light on the explanation of BCR activation and the relevant diseases in the case of dysregulation.

    更新日期:2020-01-09
  • MpbR, an essential transcriptional factor for Mycobacterium tuberculosis survival in the host, modulates PIM biosynthesis and reduces innate immune responses
    J. Genet. Genomics (IF 4.650) Pub Date : 2019-12-28
    Yugang Li; Weihui Li; Zhiwei Xie; Hui Xu; Zheng-Guo He

    Mycobacterium tuberculosis possesses unique cellular envelope components that contribute to bacterial escape from host immune surveillance. Phosphatidylinositol mannosides (PIMs) and their higher derivatives are important molecules implicated in host-pathogen interactions in the course of tuberculosis. However, the biosynthetic regulation of these specific lipids and its effect on the bacterial fate in the infected host remain unclear. Here, we show that a hypothetical M. tuberculosis transcriptional factor designated as MpbR negatively regulates two transporter genes and affects mycobacterial PIM biosynthesis and biofilm formation. MpbR inhibits the accumulation of acylated PIM lipids and triggers the mycobacterium to reduce the production of reactive oxygen species and NO during infection, which enhances the survival of M. tuberculosis in macrophages. MpbR deletion reduces M. tuberculosis lung burdens and inflammation of infected mice. These findings provide new insights into the regulation of mycobacterial lipid metabolism and its correlation with pathogenesis of M. tuberculosis.

    更新日期:2019-12-29
  • Genome-wide evolution analysis reveals low CpG contents of fast-evolving genes and identifies antiviral microRNAs
    J. Genet. Genomics (IF 4.650) Pub Date : 2019-12-23
    Wen-Hong Zu; Hang Zhang; Xun Lan; Xu Tan

    Noncoding RNAs play important roles in many biological processes and provide material for evolutionary adaptations beyond protein-coding genes, such as in the arms race between host and pathogen. However, currently, a comprehensive high-resolution analysis of primate genomes that includes the latest annotated noncoding RNAs is not available. Here we developed a computational pipeline to estimate the selections that act on noncoding regions based on comparisons with a large number of reference sequences in introns adjacent to the interested regions. Our method yields result comparable to those of the established codon-based method and phyloP method for coding genes; thus, it provides a holistic framework for estimating the selection on the entire genome. We further show that fast-evolving protein-coding genes and their corresponding 5′ untranslated regions have a significantly lower frequency of the CpG dinucleotide than those evolving at an average pace, and these fast-evolving genes are enriched in the process of immunity and host defense. We also identified fast-evolving miRNAs with antiviral functions in cells. Our results provide a resource for high-resolution evolution analysis of the primate genomes.

    更新日期:2019-12-23
  • Integration of lipidomics and metabolomics for in-depth understanding of cellular mechanism and disease progression
    J. Genet. Genomics (IF 4.650) Pub Date : 2019-12-18
    Raoxu Wang; Bowen Li; Sin Man Lam; Guanghou Shui

    Mass spectrometry (MS)-based omics technologies are now widely used to profile small molecules in multiple matrices to confer comprehensive snapshots of cellular metabolic phenotypes. The metabolomes of cells, tissues and organisms comprise a variety of molecules including lipids, amino acids, sugars, organic acids, etc. Metabolomics mainly focus on the last three classes, while lipidomics has emerged as an independent omics owing to the complexities of the organismal lipidomes. The potential roles of lipids and small metabolites in disease pathogenesis have been widely investigated in various human diseases, but system-level understanding is largely lacking, which could be partly attributed to the insufficiency in terms of metabolite coverage and quantitation accuracy in current analytical technologies. While scientists are continuously striving to develop high-coverage omics approaches, integration of metabolomics and lipidomics is becoming an emerging approach to for mechanistic investigation. Integration of metabolome and lipidome offers a complete atlas of the metabolic landscape, enabling comprehensive network analysis to identify critical metabolic drivers in disease pathology, facilitating the study of interconnection between lipids and other metabolites in disease progression. In this review, we summarize omics-based findings on the roles of lipids and metabolites in the pathogenesis of selected major diseases threatening public health. We also discuss the advantages of integrating lipidomics and metabolomics for in-depth understanding of molecular mechanism in disease pathogenesis.

    更新日期:2019-12-19
  • Glycolysis regulates gene expression by promoting the crosstalk between H3K4me3 and H3K14ac in Saccharomyces cerevisiae
    J. Genet. Genomics (IF 4.650) Pub Date : 2019-12-11
    Yinsheng Wu, Shihao Zhang, Xuanyunjing Gong, Qi Yu, Yuan Zhang, Mingdan Luo, Xianhua Zhang, Jerry L. Workman, Xilan Yu, Shanshan Li

    Cells need to coordinate gene expression with their metabolic states to maintain cell homeostasis and growth. However, how cells transduce nutrient availability to appropriate gene expression response via histone modifications remains largely unknown. Here, we report that glucose specifically induces histone H3K4 trimethylation (H3K4me3), an evolutionarily conserved histone covalent modification associated with active gene transcription and glycolytic enzymes and metabolites are require for this induction. Although glycolysis supplies S-adenosylmethionine (SAM) for histone methyltransferase Set1 to catalyze H3K4me3, glucose induces H3K4me3 primarily by inhibiting histone demethylase Jhd2-catalyzed H3K4 demethylation. Glycolysis provides acetyl-CoA to stimulate histone acetyltransferase Gcn5 to acetylate H3K14, which then inhibits the binding of Jhd2 to chromatin to increase H3K4me3. By repressing Jhd2-mediated H3K4 demethylation, glycolytic enzymes regulate gene expression as well as cell survival during chronological aging. Thus, our results elucidate how cells reprogram their gene expression programs in response to glucose availability via histone modifications.

    更新日期:2019-12-11
  • Drosophila CTP synthase can form distinct substrate- and product-bound filaments
    J. Genet. Genomics (IF 4.650) Pub Date : 2019-11-29
    Xian Zhou, Chen-Jun Guo, Huanhuan Hu, Jiale Zhong, Qianqian Sun, Dandan Liu, Shuang Zhou, Chia Chun Chang, Ji-Long Liu

    Intracellular compartmentation is a key strategy for the functioning of a cell. In 2010, several studies revealed that the metabolic enzyme CTP synthase (CTPs) can form filamentous structures termed cytoophidia in prokaryotic and eukaryotic cells. However, recent structural studies showed that CTPs only forms inactive product-bound filaments in bacteria while forming active substrate-bound filaments in eukaryotic cells. In this study, using negative staining and cryo-electron microscopy, we demonstrate that Drosophila CTPs, whether in substrate-bound or product-bound form, can form filaments. Our results challenge the previous model and indicate that substrate-bound and product-bound filaments can co-exist in the same species. We speculate that the ability to switch between active and inactive cytoophidia in the same cells provides an additional layer of metabolic regulation.

    更新日期:2019-11-30
  • Site-directed RNA editing (SDRE): Off-target effects and their countermeasures
    J. Genet. Genomics (IF 4.650) Pub Date : 2019-11-27
    Shaoshuai Mao, Yajing Liu, Shisheng Huang, Xingxu Huang, Tian Chi

    Site-directed RNA editing (SDRE) is invaluable to basic research and medicine, and has emerged as a new frontier in genome editing. The past few years have witnessed a surge of interest in SDRE, with SDRE tools emerging at a breathtaking pace. However, off-target effects of SDRE remain a tough problem, which constitutes a major hurdle to their clinical applications. Here we discuss the diverse strategies for combating off-target editing, drawing lessons from the published studies as well as our ongoing research. Overall, SDRE is still at its infancy, with significant challenges and exciting opportunities ahead.

    更新日期:2019-11-28
  • PDGF signaling from pharyngeal pouches promotes arch artery morphogenesis
    J. Genet. Genomics (IF 4.650) Pub Date : 2019-11-25
    Aihua Mao, Mingming Zhang, Jie Liu, Yu Cao, Qiang Wang

    The great vessels of the heart originate from the pharyngeal arch arteries (PAAs). Anomalies of the PAAs often occur together with pharyngeal pouch malformations, but the reasons for this phenomenon are not fully understood. In the current study, we show that PDGF signaling derived from the pharyngeal pouches plays an important function in PAA vasculogenesis. During PAA development in zebrafish embryos, pdgfαa and pdgfαb are expressed in the developing pharyngeal pouches. Results from loss-of-function experiments revealed a critical role of these genes in PAA formation. We found that nitroreductase (NTR)-mediated pouch ablation distinctly decreased PDGF receptor tyrosine phosphorylation, yielding a severe loss of PAAs. Importantly, pouch-specific overexpression of pdgfαa and pdgfαb in pdgfαa-/-;pdgfαb-/- mutants significantly relieved the PAA defects, which indicated a primary role of pharyngeal pouch-expressed PDGF ligands in signal activation and PAA morphogenesis. Our findings further showed that PDGF signaling was indispensable for the proliferation of PAA angioblasts. Together, these results established a role for PDGFαa- and PDGFαb-mediated tissue-tissue interaction during PAA development.

    更新日期:2019-11-26
  • Engineering guide RNA to reduce the off-target effects of CRISPR
    J. Genet. Genomics (IF 4.650) Pub Date : 2019-11-23
    Jing Wu, Hao Yin

    As versatile and robust genome editing tools, clustered regularly interspaced short palindromic repeats (CRISPR) technologies have been broadly used in basic research, biotechnology and therapeutic development. Off-target mutagenesis by CRISPR systems has been demonstrated, and various methods have been developed to markedly increase their specificity. In this review, we highlight the efforts of producing and modifying guide RNA to minimize off-target activities, including sequence and structure design, tuning expression and chemical modification. The modalities of guide RNA engineering can be applied across CRISPR systems. In conjunction with CRISPR protein effectors, the engineered guide RNA enables efficient and precise genome editing.

    更新日期:2019-11-26
  • Advances in Detecting and Reducing Off-target Effects Generated by CRISPR-mediated Genome Editing
    J. Genet. Genomics (IF 4.650) Pub Date : 2019-11-22
    Jin-Jing Li, Shunyan Hong, Wan-Jin Chen, Erwei Zuo, Hui Yang

    CRISPR-mediated genome editing is a revolutionary technology for genome manipulation that utilizes the CRISPR-Cas systems and base editors. Currently, poor efficiency and off-target problems have impeded the application of CRISPR systems. The on-target efficiency has been improved in several advanced versions of CRISPR systems, whereas the off-target detection still remains a key challenge. Here, we outline the different versions of CRISPR systems and off-target detection strategies, discuss the merits and limitations of off-target detection methods, and provide potential implications for further gene editing research.

    更新日期:2019-11-22
  • RASSF6-TRIM16 axis promotes cell proliferation, migration and invasion in esophageal squamous cell carcinoma
    J. Genet. Genomics (IF 4.650) Pub Date : 2019-11-14
    Leilei Zheng, Zitong Zhao, Lulu Rong, Liyan Xue, Yongmei Song

    Ras-association (RA) domain family number 6 (RASSF6) is a member of the Ras-association domain protein family. It is epigenetically inactive and negatively regulates the malignant progression of some tumors. However, its precise role in esophageal squamous cell carcinoma (ESCC) has not been reported. In this study, we performed immunohistochemistry (IHC) assay. The results show that RASSF6 is upregulated in ESCC and that the elevated expression level of RASSF6 is associated with lymph node metastasis and poor survival of ESCC patients. Consistent with the clinical observations, the upregulation of RASSF6 greatly promotes ESCC cell proliferation, migration and invasion as well as the cell cycle transition to G1/S phase in vitro. According to models in vivo, the downregulation of RASSF6 considerably inhibits ESCC tumor growth and lung metastasis. Mechanistically, RASSF6 negatively regulates the tumor suppressor tripartite-motif-containing protein 16 (TRIM16) by promoting its ubiquitination-dependent degradation and eventually activates pathways associated with the cell cycle and epithelial-mesenchymal transition (EMT). Together, these results indicate that the RASSF6-TRIM16 axis is a key effector in ESCC progression and that RASSF6 serves as a potential target for the treatment of ESCC.

    更新日期:2019-11-14
  • Embryonic lineage tracing with Procr-CreER marks balanced hematopoietic stem cell fate during entire mouse lifespan
    J. Genet. Genomics (IF 4.650) Pub Date : 2019-11-04
    Xiaona Zheng, Guangyu Zhang, Yandong Gong, Xiaowei Ning, Zhijie Bai, Jian He, Fan Zhou, Yanli Ni, Yu Lan, Bing Liu

    The functional heterogeneity of hematopoietic stem cells (HSCs) has been comprehensively investigated by single-cell transplantation assay. However, the heterogeneity regarding their physiological contribution remains an open question, especially for those with life-long hematopoietic fate of rigorous self-renewing and balanced differentiation capacities. In this study, we revealed that Procr expression was detected principally in phenotypical vascular endothelium co-expressing Dll4 and CD44 in the mid-gestation mouse embryos, and could enrich all the HSCs of the embryonic day 11.5 (E11.5) aorta-gonad-mesonephros (AGM) region. We then used a temporally restricted genetic tracing strategy to irreversibly label the Procr-expressing cells at E9.5. Interestingly, most labeled mature HSCs in multiple sites (such as AGM) around E11.5 were functionally categorized as lymphomyeloid-balanced HSCs assessed by direct transplantation. Furthermore, the labeled cells contributed to an average of 7.8% of immunophenotypically defined HSCs in E14.5 fetal liver (FL) and 6.9% of leukocytes in peripheral blood (PB) during one-year follow-up. Surprisingly, in aged mice of 24 months, the embryonically tagged cells displayed constant contribution to leukocytes with no bias to myeloid or lymphoid lineages. Altogether, we demonstrated, for the first time, the existence of a subtype of physiologically long-lived balanced HSCs as hypothesized, whose precise embryonic origin and molecular identity await further characterization.

    更新日期:2019-11-04
  • Histone modifications and their regulatory roles in plant development and environmental memory
    J. Genet. Genomics (IF 4.650) Pub Date : 2019-11-02
    Ting Zhao, Zhenping Zhan, Danhua Jiang

    Plants grow in dynamic environments where they receive diverse environmental signals. Swift and precise control of gene expression is essential for plants to align their development and metabolism with fluctuating surroundings. Modifications on histones serve as “histone code” to specify chromatin and gene activities. Different modifications execute distinct functions on the chromatin, promoting either active transcription or gene silencing. Histone writers, erasers, and readers mediate the regulation of histone modifications by catalyzing, removing and recognizing modifications respectively. Growing evidence indicates the important function of histone modifications in plant development and environmental responses. Histone modifications also serve as environmental memory for plants to adapt to environmental changes. Here we review recent progress on the regulation of histone modifications in plants, the impact of histone modifications on environment controlled developmental transitions including germination and flowering, and the role of histone modifications in environmental memory.

    更新日期:2019-11-04
  • Acquisition of functional neurons by direct conversion: Switching the developmental clock directly
    J. Genet. Genomics (IF 4.650) Pub Date : 2019-10-28
    Shuangquan Chen, Juan Zhang, Dongming Zhang, Jianwei Jiao

    Identifying approaches for treating neurodegeneration is a thorny task but is important for a growing number of patients. Researchers have focused on discovering the underlying molecular mechanisms of reprogramming and optimizing the technologies for acquiring neurons. Direct conversion is one of the most important processes for treating neurological disorders. Induced neurons (iNs) derived from direct conversion, which bypass the pluripotency stage, are more effective, more quickly obtained and safer than those produced via induced pluripotent stem cells (iPSCs). Based on iPSC strategies, scientists have derived methods to obtain functional neurons by direct conversion, such as neuron-related transcriptional factors (TFs), small molecules, microRNAs, and epigenetic modifiers. In this review, we discuss the present strategies for the direct conversion of somatic cells into functional neurons and the potentials of direct conversion for producing functional neurons and treating neurodegeneration.

    更新日期:2019-10-28
  • Identification of transcriptional isoforms associated with survival in cancer patient
    J. Genet. Genomics (IF 4.650) Pub Date : 2019-09-25
    Zefang Tang, Tianxiang Chen, Xianwen Ren, Zemin Zhang

    The Cancer Genome Atlas (TCGA) project produced RNA-Seq data for tens of thousands of cancer and non-cancer samples with clinical survival information, providing an unprecedented opportunity for analyzing prognostic genes and their isoforms. In this study we performed the first large-scale identification of transcriptional isoforms that are specifically associated with patient prognosis, even without gene-level association. These specific isoforms are defined as Transcripts Associated with Patient Prognosis (TAPP). Although a group of TAPPs are the principal isoforms of their genes with intact functional protein domains, another group of TAPPs lack important protein domains found in their canonical gene isoforms. This dichotomy in the distribution of protein domains may indicate different patterns of TAPP association with cancer. TAPPs in protein-coding genes, especially those with altered protein domains, are rich in known cancer driver genes. We further identified multiple types of cancer recurrent TAPPs across, including DCAF17-201, providing a new approach for the detection of cancer-associated events. In order to make the wide research community to study prognostic isoforms, we developed a portal named GESUR (http://gesur.cancer-pku.cn/), which illustrates the detailed prognostic characteristics of TAPPs and other isoforms. Overall, our integrated analysis of gene expression and clinical parameters provides a new perspective for understanding the applications of different gene isoforms in tumor progression.

    更新日期:2019-09-25
  • Temperature-sensitive cytoophidium assembly in Schizosaccharomyces pombe
    J. Genet. Genomics (IF 4.650) Pub Date : 2019-09-24
    Jing Zhang, Ji-Long Liu

    The metabolic enzyme CTP synthase (CTPS) is able to compartmentalize into filaments, termed cytoophidia, in a variety of organisms including bacteria, budding yeast, fission yeast, fruit flies and mammals. A previous study in budding yeast shows that the filament-forming process of CTPS is not sensitive to temperature shift. Here we study CTPS filamentation in the fission yeast Schizosaccharomyces pombe. To our surprise, we find that both the length and the occurrence of cytoophidia in S. pombe decrease upon cold shock or heat shock. The temperature-dependent changes of cytoophidia are fast and reversible. Taking advantage of yeast genetics, we demonstrate that heat-shock proteins are required for cytoophidium assembly in S. pombe. Temperature sensitivity of cytoophidia makes S. pombe an attractive model system for future investigations of this novel membraneless organelle.

    更新日期:2019-09-25
  • Examining the practical limits of batch effect-correction algorithms: When should you care about batch effects?
    J. Genet. Genomics (IF 4.650) Pub Date : 2019-09-20
    Longjian Zhou, Andrew Chi-Hau Sue, Wilson Wen Bin Goh

    Batch effects are technical sources of variation and can confound analysis. While many performance ranking exercises have been conducted to establish the best batch effect-correction algorithm (BECA), we hold the viewpoint that the notion of best is context-dependent. Moreover, alternative questions beyond the simplistic notion of “best” are also interesting: are BECAs robust against various degrees of confounding and if so, what is the limit? Using two different methods for simulating class (phenotype) and batch effects and taking various representative datasets across both genomics (RNA-Seq) and proteomics platforms, we demonstrate that up till situations where sample classes and batch factors are moderately confounded, and most BECAs are remarkably robust and only weakly affected by upstream normalization procedures. This observation is consistently supported across the multitude of test datasets. BECAs do have limits: When sample classes and batch factors are strongly confounded, BECA performance declines, with variable performance in precision, recall and also batch correction. We also report that while conventional normalization methods have minimal impact on batch effect correction, they do not affect downstream statistical feature selection, and in strongly confounded scenarios, may even outperform BECAs. In other words, removing batch effects is no guarantee of optimal functional analysis. Overall, this study suggests that simplistic performance ranking exercises are quite trivial, and all BECAs have their compromises in some context or another.

    更新日期:2019-09-21
  • Blocking CD38-driven fratricide among T cells enables effective antitumor activity by CD38-specific chimeric antigen receptor T cells
    J. Genet. Genomics (IF 4.650) Pub Date : 2019-08-13
    Zhitao Gao, Chuan Tong, Yao Wang, Deyun Chen, Zhiqiang Wu, Weidong Han

    Chimeric antigen receptor T-cell (CAR T) therapy is a kind of effective cancer immunotherapy. However, designing CARs remains a challenge because many targetable antigens are shared by T cells and tumor cells. This shared expression of antigens can cause CAR T cell fratricide. CD38-targeting approaches (e.g., daratumumab) have been used in clinical therapy and have shown promising results. CD38 is a kind of surface glycoprotein present in a variety of cells, such as T lymphocytes and tumor cells. It was previously reported that CD38-based CAR T cells may undergo apoptosis or T cell-mediated killing (fratricide) during cell manufacturing. In this study, a CAR containing a sequence targeting human CD38 was designed to be functional. To avoid fratricide driven by CD38 and ensure the production of CAR T cells, two distinct strategies based on antibodies (clone MM12T or clone MM27) or proteins (H02H or H08H) were used to block CD38 or the CAR single-chain variable fragment (scFv) domain, respectively, on the T cell surface. The results indicated that the antibodies or proteins, especially the antibody MM27, could affect CAR T cells by inhibiting fratricide while promoting expansion and enrichment. Anti-CD38 CAR T cells exhibited robust and specific cytotoxicity to CD38+ cell lines and tumor cells. Furthermore, the levels of the proinflammatory factors TNF-α, IFN-γ and IL-2 were significantly upregulated in the supernatants of A549CD38+ cells. Finally, significant control of disease progression was demonstrated in xenograft mouse models. In conclusion, these findings will help to further enhance the expansion, persistence and function of anti-CD38 CAR T cells in subsequent clinical trials.

    更新日期:2019-08-14
  • The expression tractability of biological traits shaped by natural selection
    J. Genet. Genomics (IF 4.650) Pub Date : 2019-08-13
    Li Liu, Jianguo Wang, Jianrong Yang, Feng Wang, Xionglei He

    Understanding how gene expression is translated to phenotype is central to modern molecular biology, and the success is contingent on the intrinsic tractability of the specific traits under examination. However, an a priori estimate of trait tractability from the perspective of gene expression is unavailable. Motivated by the concept of entropy in a thermodynamic system, we here propose such an estimate (ST) by gauging the number (N) of expression states that underlie the same trait abnormality, with large ST corresponding to large N. By analyzing over 200 yeast morphological traits, we show that ST predicts the tractability of an expression-trait relationship. We further show that ST is ultimately determined by natural selection, which builds co-regulated gene modules to minimize possible expression states.

    更新日期:2019-08-14
  • OSBPL2-disrupted pigs recapitulate dual features of human hearing loss and hypercholesterolaemia
    J. Genet. Genomics (IF 4.650) Pub Date : 2019-08-13
    Jun Yao, Huasha Zeng, Min Zhang, Qinjun Wei, Ying Wang, Haiyuan Yang, Yajie Lu, Rongfeng Li, Qiang Xiong, Lining Zhang, Zhibin Chen, Guangqian Xing, Xin Cao, Yifan Dai

    Oxysterol binding protein like 2 (OSBPL2), an important regulator in cellular lipid metabolism and transport, was identified as a novel deafness-causative gene in our previous work. To resemble the phenotypic features of OSBPL2 mutation in animal models and elucidate the potential genotype-phenotype associations, the OSBPL2-disrupted Bama miniature (BM) pig model was constructed using CRISPR/Cas9-mediated gene editing, somatic cell nuclear transfer (SCNT) and embryo transplantation approaches and then subjected to phenotypic characterization of auditory function and serum lipid profiles. The OSBPL2-disrupted pigs displayed progressive hearing loss (HL) with degeneration/apoptosis of cochlea hair cells (HCs) and morphological abnormalities in HC stereocilia, as well as hypercholesterolaemia. High-fat diet (HFD) feeding aggravated the development of HL and led to more severe hypercholesterolaemia. The dual phenotypes of progressive HL and hypercholesterolaemia resembled in OSBPL2-disrupted pigs confirmed the implication of OSBPL2 mutation in nonsydromic hearing loss (NSHL) and contributed to the potential linkage between auditory dysfunction and dyslipidaemia/hypercholesterolaemia.

    更新日期:2019-08-14
  • Progressive heterosis in genetically defined tetraploid maize
    J. Genet. Genomics (IF 4.650) Pub Date : 2019-08-09
    Jacob D. Washburn, Mitchell J. McElfresh, James A. Birchler

    Progressive heterosis, i.e., the additional hybrid vigor in double-cross tetraploid hybrids not found in their single-cross tetraploid parents, has been documented in a number of species including alfalfa, potato, and maize. In this study, four artificially induced maize tetraploids, directly derived from standard inbred lines, were crossed in pairs to create two single-cross hybrids. These hybrids were then crossed to create double-cross hybrids containing genetic material from all four original lines. Replicated field-based phenotyping of the materials over four years indicated a strong progressive heterosis phenotype in tetraploids but not in their diploid counterparts. In particular, the above ground dry weight phenotype of double-cross tetraploid hybrids was on average 34 % and 56% heavier than that of the single-cross tetraploid hybrids and the double-cross diploid counterparts, respectively. Additionally, whole-genome resequencing of the original inbred lines and further analysis of these data did not show the expected spectrum of alleles to explain tetraploid progressive heterosis under the complementation of complete recessive model. These results underscore the reality of the progressive heterosis phenotype, its potential utility for increasing crop biomass production, and the need for exploring alternative hypothesis to explain it at a molecular level.

    更新日期:2019-08-10
  • Mapping quantitative trait loci using binned genotypes
    J. Genet. Genomics (IF 4.650) Pub Date : 2019-07-23
    Wen Yao, Guangwei Li, Yanru Cui, Yiming Yu, Qifa Zhang, Shizhong Xu

    Precise mapping of quantitative trait loci (QTLs) is critical for assessing the genetic effects and identification of candidate genes for quantitative traits. Interval and composite interval mappings have been the methods of choice for several decades, which have provided tools for identifying genomic regions harboring causal genes for quantitative traits. Historically, the concept was developed on the basis of sparse marker maps where genotypes of loci within intervals could not be observed. Currently, genomes of many organisms have been saturated with markers due to the new sequencing technologies. Genotyping by sequencing usually generates hundreds of thousands of single nucleotide polymorphisms (SNPs), which often include the causal polymorphisms. The concept of interval no longer exists, prompting the necessity of a norm change in QTL mapping technology to make use of the high-volume genomic data. Here we developed a statistical method and a software package to map QTL by binning markers into haplotype blocks, called bins. The new method detects associations of bins with quantitative traits. It borrows the mixed model methodology with a polygenic control from genome-wide association studies (GWAS) and can handle all kinds of experimental populations under the linear mixed model (LMM) framework. We tested the method using both simulated data and data from populations of rice. The results showed that this method has higher power than the current methods. An R package named binQTL is available from GitHub.

    更新日期:2019-07-24
  • Production of non-mosaic genome edited porcine embryos by injection of CRISPR/Cas9 into germinal vesicle oocytes
    J. Genet. Genomics (IF 4.650) Pub Date : 2019-07-20
    Xiaohu Su, Wei Chen, Qingqing Cai, Puping Liang, Yaosheng Chen, Peiqing Cong, Junjiu Huang

    Genetically modified pigs represent a great promise for generating models of human diseases and producing new breeds. Generation of genetically edited pigs using somatic cell nuclear transfer (SCNT) or zygote cytoplasmic microinjection is a tedious process due to the low developmental rate or mosaicism of the founder (F0). Herein, we developed a method termed germinal vesicle oocyte gene editing (GVGE) to produce non-mosaic porcine embryos by editing maternal alleles during the GV to MⅡ transition. Injection of Cas9 mRNA and X-linked Dmd gene-specific gRNA into GV oocytes did not affect their developmental potential. The MⅡ oocytes edited during in vitro maturation (IVM) could develop into blastocysts after parthenogenetic activation (PA) or in vitro fertilization (IVF). Genotyping results indicated that the maternal gene X-linked Dmd could be efficiently edited during oocyte maturation. Up to 81.3% of the edited IVF embryos were non-mosaic Dmd gene mutant embryos. In conclusion, GVGE might be a valuable method for the generation of non-mosaic maternal allele edited F0 embryos in a short simple step.

    更新日期:2019-07-21
  • Gene redundancy and gene compensation: an updated view
    J. Genet. Genomics (IF 4.650) Pub Date : 2019-07-19
    Jinrong Peng

    Gene knockdown approaches using antisense oligo nucleotides or analogs such as siRNAs and morpholinos have been widely adopted to study gene functions although the off-target issue has been always a concern in these studies. On the other hand, classic genetic analysis relies on the availability of loss-of-function or gain-of-function mutants. The fast development of gene editing technologies such as TALEN and CRISPR/Cas9 has greatly facilitated the generation of null mutants for the functional studies of target genes in a variety of organism including zebrafish. Surprisingly, an unexpected discrepancy was observed between morphant phenotype and mutant phenotype for many genes in zebrafish, i.e., while the morphant often displays an obvious phenotype, the corresponding null mutant appears relatively normal or only exhibits a mild phenotype due to gene compensation. Two recent reports have partially answered this intriguing question by showing that a pre-mature termination and homologous sequence are required to elicit the gene compensation and the histone modifying complex COMPASS is involved in activating the expression of the compensatory genes. Here, I summarize these exciting new progress and try to redefine the concept of genetic compensation and gene compensation.

    更新日期:2019-07-19
  • Dissecting PCNA function with a systematically designed mutant library in yeast
    J. Genet. Genomics (IF 4.650) Pub Date : 2019-06-24
    Qingwen Jiang, Weimin Zhang, Chenghao Liu, Yicong Lin, Qingyu Wu, Junbiao Dai

    Proliferating cell nuclear antigen (PCNA), encoded by POL30 in Saccharomyces cerevisiae, is a key component of DNA metabolism. Here, a library consisting of 304 PCNA mutants was designed and constructed to probe the contribution of each residue to the biological function of PCNA. Five regions with elevated sensitivity to DNA damaging reagents were identified using high-throughput phenotype screening. Using a series of genetic and biochemical analyses, we demonstrated that one particular mutant, K168A, has defects in the DNA damage tolerance (DDT) pathway by disrupting the interaction between PCNA and Rad5. Subsequent domain analysis showed that the PCNA-Rad5 interaction is a prerequisite for the function of Rad5 in DDT. Our study not only provides a resource in the form of a library of versatile mutants to study the functions of PCNA, but also reveals a key residue on PCNA (K168) which highlights the importance of the PCNA-Rad5 interaction in the TS pathway.

    更新日期:2019-06-24
  • Nlrc3-like is required for microglia maintenance in zebrafish
    J. Genet. Genomics (IF 4.650) Pub Date : 2019-06-22
    Tienan Wang, Bo Yan, Liang Lou, Xi Lin, Tao Yu, Shuting Wu, Qing Lu, Wei Liu, Zhibin Huang, Mingjie Zhang, Wenqing Zhang, Zilong Wen

    Microglia are tissue-resident macrophages resided in the central nervous system (CNS) and play critical roles in removing cellular debris and infectious agents as well as regulating neurogenesis and neuronal activities. Yet, the molecular basis underlying the establishment of microglia pool and the maintenance of their homeostasis in the CNS remain largely undefined. Here we report the identification and characterization of a mutant zebrafish, which harbors a point mutation in the nucleotide-binding oligomerization domain (NOD) receptor gene nlrc3-like, resulting in the loss of microglia in a temperature sensitive manner. Temperature shift assay reveals that the late onset of nlrc3-like deficiency leads to excessive microglia cell death. Further analysis shows that the excessive microglia death in nlrc3-like deficient mutants is attributed, at least in part, to aberrant activation of canonical inflammasome pathway. Our study indicates that proper regulation of inflammasome cascade is critical for the maintenance of microglia homeostasis.

    更新日期:2019-06-24
  • RSBP15 interacts with and stabilizes dRSPH3 during sperm axoneme assembly in Drosophila
    J. Genet. Genomics (IF 4.650) Pub Date : 2019-06-01
    Ya Wang, Rui Xu, Yiwei Cheng, Haowei Cao, Zibin Wang, Tianyu Zhu, Jiayin Jiang, Hao Zhang, Chang Wang, Lin Qi, Mingxi Liu, Xuejiang Guo, Juan Huang, Jiahao Sha

    Flagellum in sperm is composed of over 200 different proteins and is essential for sperm motility. In particular, defects in the assembly of the radial spoke in the flagellum result in male infertility due to loss of sperm motility. However, mechanisms regulating radial spoke assembly remain unclear in metazoans. Here, we identified a novel Drosophila protein radial spoke binding protein 15 (RSBP15) which plays an important role in regulating radial spoke assembly. Loss of RSBP15 results in complete lack of mature sperms in seminal vesicles (SVs), asynchronous individualization complex (IC) and defective “9+2” structure in flagella. RSBP15is colocalized with dRSPH3 in sperm flagella, and interacts with dRSPH3 through its DD_R_PKA superfamily domain which is important for the stabilization of dRSPH3. Moreover, loss of dRSPH3, as well as dRSPH1, dRSPH4a and dRSPH9, showed similar phenotypes to rsbp15KO mutant. Together, our results suggest that RSBP15 acts in stabilizing the radial spoke protein complex to anchor and strengthen the radial spoke structures in sperm flagella.

    更新日期:2019-06-03
  • mTOR/miR-145-regulated exosomal GOLM1 promotes hepatocellular carcinoma through augmented GSK-3β/MMPs
    J. Genet. Genomics (IF 4.650) Pub Date : 2019-05-18
    Xiaochen Gai, Bufu Tang, Fangming Liu, Yuting Wu, Fang Wang, Yanling Jing, Fuqiang Huang, Di Jin, Ling Wang, Hongbing Zhang

    Golgi membrane protein 1 (GOLM1/GP73) is a serum marker of hepatocellular carcinoma (HCC). We have previously shown that mTOR promoted tumorigenesis of HCC through stimulating GOLM1 expression. In this study, we demonstrated that the mammalian target of rapamycin (mTOR) was a negative regulator of microRNA-145 (miR-145) expression. miR-145 inhibited GOLM1 expression by targeting a coding sequence of GOLM1 gene. GOLM1 and miR-145 were inversely correlated in human HCC tissues. GOLM1-enriched exosomes activated the glycogen synthase kinase-3β/matrix metalloproteinases (GSK-3β/MMPs) signaling axis of recipient cells and accelerated cell proliferation and migration. In contrast, miR-145 suppressed tumorigenesis and metastasis. We suggest that mTOR/miR-145/GOLM1 signaling pathway should be targeted for HCC treatment.

    更新日期:2019-05-20
  • Rare inherited missense variants of POGZ associate with autism risk and disrupt neuronal development
    J. Genet. Genomics (IF 4.650) Pub Date : 2019-05-18
    Wenjing Zhao, Jieqiong Tan, Tengfei Zhu, Jianjun Ou, Ying Li, Lu Shen, Huidan Wu, Lin Han, Yanling Liu, Xiangbin Jia, Ting Bai, Honghui Li, Xiaoyan Ke, Jingping Zhao, Xiaobing Zou, Zhengmao Hu, Hui Guo, Kun Xia

    Excess de novo likely gene-disruptive and missense variants within dozens of genes have been identified in autism spectrum disorder (ASD) and other neurodevelopmental disorders. However, many rare inherited missense variants of these high-risk genes have not been thoroughly evaluated. Here, we analyzed the rare missense variant burden of POGZ in a large cohort of ASD patients from the Autism Clinical and Genetic Resources in China (ACGC) and further dissected the functional effect of disease-associated missense variants on neuronal development. Our results showed a significant burden of rare missense variants in ASD patients compared to the control population (P = 4.6×10-5, OR = 3.96), and missense variants in ASD patients showed more severe predicted functional outcomes than those in controls. Furthermore, by leveraging published large-scale sequencing data of neurodevelopmental disorders (NDDs) and sporadic case reports, we identified 8 de novo missense variants of POGZ in NDD patients. Functional analysis revealed that two inherited, but not de novo, missense variants influenced the cellular localization of POGZ and failed to rescue the defects in neurite and dendritic spine development caused by Pogz knockdown. Significantly, L1CAM, an autism candidate gene, is differentially expressed in POGZ knockout cell lines. Reduced expression of L1cam was able to partially rescue the neurite length defects. Our study showed the important roles of rare inherited missense variants of POGZ in ASD risk and neuronal development and identified the potential downstream targets of POGZ, which are important for further molecular mechanism studies.

    更新日期:2019-05-20
  • Organelle aging: lessons from model organisms
    J. Genet. Genomics (IF 4.650) Pub Date : 2019-04-25
    Mark Bouska, Kerui Huang, Ping Kang, Hua Bai

    Most cellular processes descend into failure during aging. While a large collection of longevity pathways has been identified in the past decades, the mechanism for age-related decline of cellular homeostasis and organelle function remains largely unsolved. It is known that many organelles undergo structural and functional changes during normal aging, which significantly contributes to the decline of tissue function at old ages. Since recent studies have revealed an emerging role of organelles as regulatory hubs in maintaining cellular homeostasis, understanding of organelle aging will provide important insights into the cellular basis of organismal aging. Here we review current progress on the characterization of age-dependent structural and functional alterations in the more well-studied organelles, as well as the known mechanisms governing organelle aging in model organisms, with a special focus on the fruit fly Drosophila melanogaster.

    更新日期:2019-04-25
  • Understanding the importance of autophagy in human diseases using Drosophila
    J. Genet. Genomics (IF 4.650) Pub Date : 2019-04-23
    Arindam Bhattacharjee, Áron Szabó, Tamás Csizmadia, Hajnalka Laczkó-Dobos, Gábor Juhász

    Autophagy is a lysosome-dependent intracellular degradation pathway that has been implicated in the pathogenesis of various human diseases, either positively or negatively impacting disease outcomes depending on the specific context. The majority of medical conditions including cancer, neurodegenerative diseases, infections and immune system disorders and inflammatory bowel disease could probably benefit from therapeutic modulation of the autophagy machinery. Drosophila represents an excellent model animal to study disease mechanisms thanks to its sophisticated genetic toolkit, and the conservation of human disease genes and autophagic processes. Here, we provide an overview of the various autophagy pathways observed both in flies and human cells (macroautophagy, microautophagy and chaperone-mediated autophagy), and discuss Drosophila models of the above-mentioned diseases where fly research has already helped to understand how defects in autophagy genes and pathways contribute to the relevant pathomechanisms.

    更新日期:2019-04-24
  • Human mitochondrial DNA diseases and Drosophila models
    J. Genet. Genomics (IF 4.650) Pub Date : 2019-04-23
    Zhe Chen, Fan Zhang, Hong Xu

    Mutations that disrupt the mitochondrial genome cause a number of human diseases whose phenotypic presentation varies widely among tissues and individuals. This variability owes in part to the unconventional genetics of mitochondrial DNA (mtDNA), which includes polyploidy, maternal inheritance and dependence on nuclear-encoded factors. The recent development of genetic tools for manipulating mitochondrial genome in Drosophila melanogaster renders this powerful model organism an attractive alternative to mammalian systems for understanding mtDNA-related diseases. In this review, we summarize mtDNA genetics and human mtDNA-related diseases. We highlight existing Drosophila models of mtDNA mutations and discuss their potential use in advancing our knowledge of mitochondrial biology and in modeling human mitochondrial disorders. We also discuss the potential and present challenges of gene therapy for the future treatment of mtDNA diseases.

    更新日期:2019-04-23
  • Die in pieces: How Drosophila sheds light on neurite degeneration and clearance
    J. Genet. Genomics (IF 4.650) Pub Date : 2019-04-23
    Maria L. Sapar, Chun Han

    Dendrites and axons are delicate neuronal membrane extensions that undergo degeneration after physical injuries. In neurodegenerative diseases, these processes often degenerate prior to neuronal death. Understanding the mechanisms of neurite degeneration has been an intense focus of neurobiology research in the last two decades. As a result, many discoveries have been made in the molecular pathways that lead to neurite degeneration and the cell-cell interactions responsible for the subsequent clearance of neuronal debris. Drosophila melanogaster has served as a prime in vivo model system for identifying and characterizing the key molecular players in neurite degeneration, thanks to its genetic tractability and easy access to its nervous system. The knowledge learned in the fly provided targets and fuel for studies in other model systems that have further enhanced our understanding of neurodegeneration. In this review, we will introduce the experimental systems developed in Drosophila to investigate injury-induced neurite degeneration, and then discuss the biological pathways that drive degeneration. We will also cover what is known about the mechanisms of how phagocytes recognize and clear degenerating neurites, and how recent findings in this area enhance our understanding of neurodegenerative disease pathology.

    更新日期:2019-04-23
  • HDAC6 regulates lipid droplet turnover in response to nutrient deprivation via p62-mediated selective autophagy
    J. Genet. Genomics (IF 4.650) Pub Date : 2019-04-21
    Yan Yan, Hao Wang, Chuanxian Wei, Yuanhang Xiang, Xuehong Liang, Chung-Weng Phang, Renjie Jiao

    Autophagy has been evolved as one of the adaptive cellular processes in response to stresses such as nutrient deprivation. Various cellular cargos such as damaged organelles and protein aggregates can be selectively degraded through autophagy. Recently, the lipid storage organelle, lipid droplet (LD), has been reported to be the cargo of starvation-induced autophagy. However, it remains largely unknown how the autophagy machinery recognizes the LDs and whether it can selectively degrade LDs. In this study, we show that Drosophila histone deacetylase 6 (dHDAC6), a key regulator of selective autophagy, is required for the LD turnover in the hepatocyte-like oenocytes in response to starvation. HDAC6 regulates LD turnover via p62/SQSTM1-mediated aggresome formation, suggesting that the selective autophagy machinery is required for LD recognition and degradation. Furthermore, our results show that the loss of dHDAC6 causes steatosis in response to starvation. Our findings suggest that there is a potential link between selective autophagy and susceptible predisposition to lipid metabolism associated diseases in stress conditions.

    更新日期:2019-04-22
  • Perspectives on gene expression regulation techniques in Drosophila
    J. Genet. Genomics (IF 4.650) Pub Date : 2019-04-17
    Rong-Gang Xu, Xia Wang, Da Shen, Jin Sun, Huan-Huan Qiao, Fang Wang, Lu-Ping Liu, Jian-Quan Ni

    Gene expression regulation, including loss-of-function and gain-of-function assays, is a powerful method to study developmental and disease mechanisms. Drosophila melanogaster is an ideal model system particularly well-equipped with many genetic tools. In this review, we describe and discuss the gene expression regulation techniques recently developed and their applications, including the CRISPR/Cas9-triggered heritable mutation system, CRISPR/dCas9-based transcriptional activation (CRISPRa) system, and CRISPR/dCas9-based transcriptional repression (CRISPRi) system, as well as the next-generation transgenic RNAi system. The main purpose of this review is to provide the fly research community with an updated summary of newly developed gene expression regulation techniques and help the community to select appropriate methods and optimize the research strategy.

    更新日期:2019-04-20
  • Arabidopsis AGC protein kinases IREH1 and IRE3 control root skewing
    J. Genet. Genomics (IF 4.650) Pub Date : 2019-03-22
    Xiaozhen Yue, Zhiai Guo, Teng Shi, Lizhen Song, Youfa Cheng

    AGC protein kinases play important roles in plant growth and development. Several AGC kinases in Arabidopsis have been functionally characterized. However, the “AGC Other” subfamily, including IRE, IREH1, IRE3 and IRE4, has not been well understood. Here, we reported that ireh1 mutants displayed a root skewing phenotype, which can be enhanced by ire3 mutation. IREH1 and IRE3 were expressed in roots, consistent with their function in controlling root skewing. The florescence intensities of the microtubule marker KNpro::EGFP-MBD were decreased in ireh1, ire3 and ireh1 ire3 mutants compared to wild type. The microtubule arrangements in ireh1 and ireh1 ire3 mutants were also altered. IREH1 physically interacted with IRE3 in vitro and in planta. Thus, our findings demonstrate that IREH1 and IRE3 protein kinases play important roles in controlling root skewing, and maintaining microtubule network in Arabidopsis.

    更新日期:2019-03-22
  • Zfhx3 is essential for progesterone/progesterone receptor signaling to drive ductal side-branching and alveologenesis in mouse mammary glands
    J. Genet. Genomics (IF 4.650) Pub Date : 2019-03-22
    Gui Ma, Ang Gao, Yinan Yang, Yuan He, Xi Zhang, Baotong Zhang, Zhiqian Zhang, Mei Li, Xing Fu, Dan Zhao, Rui Wu, Leilei Qi, Qingxia Hu, Juan Li, Liya Fu, Zhengmao Zhu, Jin-Tang Dong

    Progesterone (Pg)/progesterone receptor (PR) signaling drives mammary gland side-branching and alveologenesis, but the mechanisms through which Pg/PR signaling functions remain to be clarified. Using in vitro and in vivo models and histological and molecular analyses, we determined the role of Zfhx3 transcription factor in mammary gland development driven by Pg/PR signaling. Postnatal deletion of Zfhx3 in mouse mammary epithelial cells attenuated side-branching morphogenesis and alveologenesis. These effects were undetectable in the absence of Pg/PR signaling. During the estrus cycle, Zfhx3 expression corresponded to that of Pg, being at the highest level at the diestrus stage; Zfhx3 deletion inhibited mammary gland branching more potently at diestrus than estrus stage. Loss of Zfhx3 not only attenuated the expansion of stem/progenitor cells driven by Pg/PR signaling, but also impaired the function of Pg/PR signaling in the transcriptional activation of multiple genes. In addition, Pg/PR signaling significantly expanded PR- and Zfhx3-positive epithelial cells, and induced the physical association of ZFHX3 with PR. These findings establish Zfhx3 as an integral transcription factor of Pg/PR signaling in driving side-branching and alveologenesis during mammary gland development.

    更新日期:2019-03-22
  • CPI-17-mediated contraction of vascular smooth muscle is essential for the development of hypertension in obese mice
    J. Genet. Genomics (IF 4.650) Pub Date : 2019-03-15
    Jie Sun, Tao Tao, Wei Zhao, Lisha Wei, Fan She, Pei Wang, Yeqiong Li, Yanyan Zheng, Xin Chen, Wei Wang, Yanning Qiao, Xue-Na Zhang, Min-Sheng Zhu

    Several factors have been implicated in obesity-related hypertension, but the genesis of the hypertension is largely unknown. We found a significantly upregulated expression of CPI-17 and protein kinase C (PKC) isoforms in the vascular smooth muscles of the high fat diet (HFD)-fed obese mice. The obese wild-type mice showed a significant elevation of blood pressure and enhanced calcium-sensitized contraction of vascular smooth muscles. However, the obese CPI-17-deficient mice showed a normotensive blood pressure, and the calcium-sensitized contraction was consistently reduced. In addition, the mutant muscle displayed an abolished responsive force to a PKC activator and a 30%–50% reduced force in response to various G protein-coupled receptor (GPCR) agonists in both the initial peak force and the sustained force phases. Our observations showed that CPI-17-mediated calcium sensitization is mediated through a GPCR/PKC/CPI-17/MLCP/RLC signaling pathway. We therefore propose that the upregulation of CPI-17-mediated calcium-sensitized vasocontraction by obesity contributes to the development of obesity-related hypertension.

    更新日期:2019-03-15
  • Control of de novo root regeneration efficiency by developmental status of Arabidopsis leaf explants
    J. Genet. Genomics (IF 4.650) Pub Date : 2019-03-05
    Jing Pan, Fei Zhao, Guifang Zhang, Yu Pan, Lijun Sun, Ning Bao, Peng Qin, Lyuqin Chen, Jie Yu, Yijing Zhang, Lin Xu

    De novo root regeneration (DNRR) has wide applications in agriculture such as those related to cutting technology. Detached Arabidopsis thaliana leaf explants can regenerate adventitious roots without added hormones. The regenerative ability is highly dependent on the developmental status of the leaf. An immature leaf has a higher regenerative ability, while a mature leaf is difficult to regenerate. Using RNA-Seq analysis, we showed that the expression levels of many genes, including those in the auxin network, changed during leaf maturation. Particularly, the expression levels of many YUCCA (YUC) genes in the auxin biosynthesis pathway are responsive to leaf maturation. Overexpression of YUC1 in the yuc-1D dominant mutant rescued the rooting defect caused by leaf maturation. In addition, YUC4 expression levels were also affected by circadian rhythms. The regenerative ability was reduced in both immature and mature mutant leaf explants from the new wuschel-related homeobox 11-3 (wox11-3) and wox12-3 mutant alleles created by the CRISPR/Cas9 method. Overall, the transcriptome and genetic data, together with the auxin concentration analysis, indicate that the ability to upregulate auxin levels upon detachment may be reduced during leaf maturation. Thus, multiple developmental and environmental signals may converge to control auxin accumulation, which affects the efficiency of the WOX11/12-mediated DNRR from leaf explants.

    更新日期:2019-03-05
  • Distinct functions of Trio GEF domains in axon outgrowth of cerebellar granule neurons
    J. Genet. Genomics (IF 4.650) Pub Date : 2019-02-23
    Tao Tao, Jie Sun, Yajing Peng, Pei Wang, Xin Chen, Wei Zhao, Yeqiong Li, Lisha Wei, Wei Wang, Yan-Yan Zheng, Ye Wang, Xuena Zhang, Min-Sheng Zhu

    As a critical guanine nucleotide exchange factor (GEF) regulating neurite outgrowth, Trio coordinates multiple processes of cytoskeletal dynamics through activating Rac1, Cdc42 and RhoA small GTPases by two GEF domains, but the in vivo roles of these GEF domains and corresponding downstream effectors have not been determined yet. We established multiple lines of knockout mice and assessed the respective roles of Trio GEF domains and Rac1 in axon outgrowth. Knockout of total Trio in cerebellar granule neurons (CGNs) led to an impaired F-actin rearrangement of growth cone and hence a retarded neurite outgrowth. Such a retardation was reproduced by inhibition of GEF1 domain or knockdown of Cdc42 and restored apparently by introduction of active Cdc42. As Rac1 deficiency did not affect the neurite outgrowth of CGNs, we suggested that Trio GEF1-mediated Cdc42 activation was required for neurite outgrowth. We established a GEF2-knockout line with deletion of all Trio isoforms except a cerebella-specific Trio8, a short isoform of Trio without GEF2 domain, and used this line as a GEF2-deficient animal model. The GEF2-deficient CGNs had a normal neurite outgrowth but abolished Netrin-1-promoted growth, without affecting Netrin-1 induced Rac1 activation. We thus suggested that Trio GEF1-mediated Cdc42 activation rather than Rac1 activation drives the F-actin dynamics necessary for neurite outgrowth, while GEF2 functions in Netrin-1-promoted neurite elongation. Our results delineated the distinct roles of Trio GEF domains in neurite outgrowth, which is instructive to understand the pathogenesis of clinical Trio-related neurodevelopmental disorders.

    更新日期:2019-02-25
  • The genome-wide landscape of small insertion and deletion mutations in Monopterus albus
    J. Genet. Genomics (IF 4.650) Pub Date : 2019-02-23
    Feng Chen, Fengling lai, Majing Luo, Yu-San Han, Hanhua Cheng, Rongjia Zhou

    Insertion and deletion (indel) mutations, which can trigger single nucleotide substitutions on the flanking regions of genes, may generate abundant materials for disease defense, reproduction, species survival and evolution. However, genetic and evolutionary mechanisms of indels remain elusive. We establish a comparative genome-transcriptome-alignment approach for a large-scale identification of indels in Monopterus population. Over 2000 indels in 1738 indel genes, including 1‒21 bp deletions and 1‒15 bp insertions, were detected. Each indel gene had ∼1.1 deletions/insertions, and 2‒4 alleles in population. Frequencies of deletions were prominently higher than those of insertions on both genome and population levels. Most of the indels led to in frame mutations with multiples of three and majorly occurred in non-domain regions, indicating functional constraint or tolerance of the indels. All indel genes showed higher expression levels than non-indel genes during sex reversal. Slide window analysis of global expression levels in gonads showed a significant positive correlation with indel density in the genome. Moreover, indel genes were evolutionarily conserved and evolved slowly compared to non-indel genes. Notably, population genetic structure of indels revealed divergent evolution of Monopterus population, as bottleneck effect of biogeographic isolation by Taiwan Strait.

    更新日期:2019-02-25
  • mTOR-S6K1 pathway mediates cytoophidium assembly
    J. Genet. Genomics (IF 4.650) Pub Date : 2019-01-31
    Zhe Sun, Ji-Long Liu

    CTP synthase (CTPS), the rate-limiting enzyme in de novo CTP biosynthesis, has been demonstrated to assemble into evolutionarily conserved filamentous structures, termed cytoophidia, in Drosophila, bacteria, yeast and mammalian cells. However, the regulation and function of the cytoophidium remain elusive. Here, we provide evidence that the mechanistic target of rapamycin (mTOR) pathway controls cytoophidium assembly in mammalian and Drosophila cells. In mammalian cells, we find that inhibition of mTOR pathway attenuates cytoophidium formation. Moreover, CTPS cytoophidium assembly appears to be dependent on the mTOR complex 1 (mTORC1) mainly. In addition, knockdown of the mTORC1 downstream target S6K1 can inhibit cytoophidium formation, while overexpression of the constitutively active S6K1 reverses mTOR knockdown-induced cytoophidium disassembly. Finally, reducing mTOR protein expression results in a decrease of the length of cytoophidium in Drosophila follicle cells. Therefore, our study connects CTPS cytoophidium formation with the mTOR signaling pathway.

    更新日期:2019-01-31
  • Defining gene networks controlling the maintenance and function of the differentiation niche by an in vivo systematic RNAi screen
    J. Genet. Genomics (IF 4.650) Pub Date : 2019-01-30
    Yuan Gao, Ying Mao, Rong-Gang Xu, Ruibao Zhu, Ming Zhang, Jin Sun, Da Shen, Ping Peng, Ting Xie, Jian-Quan Ni

    In the Drosophila ovary, escort cells (ECs) extrinsically control germline stem cell (GSC) maintenance and progeny differentiation. However, the underlying mechanisms remain poorly understood. In this study, we identified 173 EC genes for their roles in controlling GSC maintenance and progeny differentiation by using an in vivo systematic RNAi approach. Of the identified genes, 10 and 163 are required in ECs to promote GSC maintenance and progeny differentiation, respectively. The genes required for progeny differentiation fall into different functional categories, including transcription, mRNA splicing, protein degradation, signal transduction and cytoskeleton regulation. In addition, the GSC progeny differentiation defects caused by defective ECs are often associated with BMP signaling elevation, indicating that preventing BMP signaling is a general functional feature of the differentiation niche. Lastly, exon junction complex (EJC) components, which are essential for mRNA splicing, are required in ECs to promote GSC progeny differentiation by maintaining ECs and preventing BMP signaling. Therefore, this study has identified the major regulators of the differentiation niche, which provides important insights into how stem cell progeny differentiation is extrinsically controlled.

    更新日期:2019-01-30
  • Whole-brain patterns of the presynaptic inputs and axonal projections of BDNF neurons in the paraventricular nucleus
    J. Genet. Genomics (IF 4.650) Pub Date : 2019-01-26
    Fang Luo, Yuling Mu, Cuicui Gao, Yan Xiao, Qian Zhou, Yiqing Yang, Xinyan Ni, Wei L. Shen, Jiajun Yang

    Brain-derived neurotrophic factor (BDNF) plays a crucial role in human obesity. Yet, the neural circuitry supporting the BDNF-mediated control of energy homeostasis remains largely undefined. To map key regions that might provide inputs to or receive inputs from the paraventricular nucleus (PVN) BDNF neurons, a key type of cells in regulating feeding and thermogenesis, we used rabies virus-based transsynaptic labeling and adeno-associated virus based anterograde tracing techniques to reveal their whole-brain distributions. We found that dozens of brain regions provide dense inputs to or receive dense inputs from PVN BDNF neurons, including several known weight control regions and several novel regions that might be functionally important for the BDNF-mediated regulation of energy homeostasis. Interestingly, several regions show very dense reciprocal connections with PVN BDNF neurons, including the lateral septum, the preoptic area, the ventromedial hypothalamic nucleus, the paraventricular thalamic nucleus, the zona incerta, the lateral parabrachial nucleus, the subiculum, the raphe magnus nucleus, and the raphe pallidus nucleus. These strong anatomical connections might be indicative of important functional connections. Therefore, we provide an outline of potential neural circuitry mediated by PVN BDNF neurons, which might be helpful to resolve the complex obesity network.

    更新日期:2019-01-28
  • OsSPL18 controls grain weight and grain number in rice
    J. Genet. Genomics (IF 4.650) Pub Date : 2019-01-23
    Hua Yuan, Peng Qin, Li Hu, Shijie Zhan, Shifu Wang, Peng Gao, Jing Li, Mengya Jin, Zhengyan Xu, Qiang Gao, Anping Du, Bin Tu, Weilan Chen, Bingtian Ma, Yuping Wang, Shigui Li

    Grain weight and grain number are two important traits directly determining grain yield in rice. To date, a lot of genes related to grain weight and grain number have been identified; however, the regulatory mechanism underlying these genes remains largely unknown. In this study, we studied the biological function of OsSPL18 during grain and panicle development in rice. Knockout (KO) mutants of OsSPL18 exhibited reduced grain width and thickness, panicle length and grain number, but increased tiller number. Cytological analysis showed that OsSPL18 regulates the development of spikelet hulls by affecting cell proliferation. qRT-PCR and GUS staining analyses showed that OsSPL18 was highly expressed in developing young panicles and young spikelet hulls, in agreement with its function in regulating grain and panicle development. Transcriptional activation experiments indicated that OsSPL18 is a functional transcription factor with activation domains in both the N-terminus and C-terminus, and both the activation domains are indispensable for its biological functions. Quantitative expression analysis showed that DEP1, a major grain number regulator, was significantly down-regulated in OsSPL18 KO lines. Both yeast one-hybrid and dual-luciferase (LUC) assays showed that OsSPL18 could bind to the DEP1 promoter, suggesting that OsSPL18 regulates panicle development by positively regulating the expression of DEP1. Sequence analysis showed that OsSPL18 contains the OsmiR156k complementary sequence in the third exon; 5ʹ RLM-RACE experiments indicated that OsSPL18 could be cleaved by OsmiR156k. Taken together, our results uncovered a new OsmiR156k-OsSPL18-DEP1 pathway regulating grain number in rice.

    更新日期:2019-01-23
  • Identification and characterization of rice blast resistance gene Pid4 by a combination of transcriptomic profiling and genome analysis
    J. Genet. Genomics (IF 4.650) Pub Date : 2018-12-31
    Zhixiong Chen, Wen Zhao, Xiaobo Zhu, Chengdong Zou, Junjie Yin, Mawsheng Chern, Xiaogang Zhou, Heng Ying, Xin Jiang, Yongzhen Li, Haicheng Liao, Mengping Cheng, Weitao Li, Min He, Jing Wang, Jichun Wang, Bingtian Ma, Jirui Wang, Xuewei Chen

    Map-based cloning of plant disease resistance (R) genes is time-consuming. Here, we reported the isolation of blast R gene Pid4 using comparative transcriptomic profiling and genome-wide sequence analysis. Pid4 encodes a coiled-coil nucleotide-binding site leucine-rich repeat (CC-NBS-LRR) protein and is constitutively expressed at diverse developmental stages in the rice variety Digu. The Pid4 protein is localized in both the nucleus and cytoplasm. Introduction of Pid4 into susceptible rice cultivars confers race-specific resistance to leaf and neck blast. Amino acid sequence comparison and blast resistance spectrum tests showed that Pid4 is a novel R gene, different from the previously reported R genes located in the same gene cluster. A Pid4 Indel marker was developed to facilitate the identification of Pid4 in different rice varieties. We demonstrated that a plant R gene can be quickly isolated using transcriptomic profiling coupled with genome-wide sequence analysis.

    更新日期:2019-01-01
  • Drosophila homolog of the intellectual disability-related long-chain acyl-CoA synthetase 4 is required for neuroblast proliferation
    J. Genet. Genomics (IF 4.650) Pub Date : 2018-12-26
    Mingyue Jia, Danqing Meng, Mo Chen, Tingting Li, Yong Q. Zhang, Aiyu Yao

    Mutations in long-chain acyl-CoA synthetase 4 (ACSL4) are associated with non-syndromic X-linked intellectual disability (ID). However, the neural functions of ACSL4 and how loss of ACSL4 leads to ID remain largely unexplored. We report here that mutations in Acsl, the Drosophila ortholog of human ACSL3 and ACSL4, result in developmental defects of the mushroom body (MB), the center of olfactory learning and memory. Specifically, Acsl mutants show fewer MB neuroblasts (Nbs) due to reduced proliferation activity and premature differentiation. Consistently, these surviving Nbs show reduced expression of cyclin E, a key regulator of the G1-to S-phase cell cycle transition, and nuclear mislocalization of the transcriptional factor Prospero, which is known to repress self-renewal genes and activate differentiating genes. Furthermore, RNA-seq analysis reveals downregulated Nb– and cell-cycle-related genes and upregulated neuronal differentiation genes in Acsl mutant Nbs. As Drosophila Acsl and human ACSL4 are functionally conserved, our findings provide novel insights into a critical and previously unappreciated role of Acsl in neurogenesis and the pathogenesis of ACSL4-related ID.

    更新日期:2018-12-28
  • Loss of miR-83 extends lifespan and affects target gene expression in an age-dependent manner in Caenorhabditis elegans
    J. Genet. Genomics (IF 4.650) Pub Date : 2018-12-09
    Emmanuel Enoch Dzakah, Ahmed Waqas, Shuai Wei, Bin Yu, Xiaolin Wang, Tao Fu, Lei Liu, Ge Shan

    MicroRNAs (miRNAs) are short non-coding RNAs that are involved in the post-transcriptional regulation of protein-coding genes. miRNAs modulate lifespan and the aging process in a variety of organisms. In this study, we identified a role of miR-83 in regulating lifespan of Caenorhabditis elegans. mir-83 mutants exhibited extended lifespan, and the overexpression of miR-83 was sufficient to decrease the prolonged lifespan of the mutants. We observed upregulation of the expression levels of a set of miR-83 target genes in young mir-83 mutant adults; while different sets of genes were upregulated in older mir-83 mutant adults. In vivo assays showed that miR-83 regulated expression of target genes including din-1, spp-9 and col-178, and we demonstrated that daf-16 and din-1 were required for the extension of lifespan in the mir-83 mutants. The regulation of din-1 by miR-83 during aging resulted in the differential expression of din-1 targets such as gst-4 and gst-10. In daf-2 mutants, the expression level of miR-83 was significantly reduced compared to wild-type animals. We identified a role for miR-83 in modulating lifespan in C. elegans and provided molecular insights into its functional mechanism.

    更新日期:2018-12-10
  • WDR74 functions as a novel coactivator in TGF-β signaling
    J. Genet. Genomics (IF 4.650) Pub Date : 2018-11-27
    Jinquan Liu, Meiling Zhao, Bo Yuan, Shuchen Gu, Mingjie Zheng, Jian Zhou, Jianping Jin, Ting Liu, Xin-Hua Feng

    Smads are critical intracellular signal transducers for transforming growth factor-β (TGF-β) in mammalian cells. In this study, we have identified WD repeat-containing protein 74 (WDR74) as a novel transcriptional coactivator for Smads in the canonical TGF-β signaling pathway. Through direct interactions with Smad proteins, WDR74 enhances TGF-β-mediated phosphorylation and nuclear accumulation of Smad2 and Smad3. Consequently, WDR74 enables stronger transcriptional responses and more robust TGF-β-induced physiological responses. Our findings have elucidated a critical role of WDR74 in regulating TGF-β signaling.

    更新日期:2018-11-28
  • The molecular and evolutionary basis of reproductive isolation in plants
    J. Genet. Genomics (IF 4.650) Pub Date : 2018-11-05
    Yidan Ouyang, Qifa Zhang

    Reproductive isolation is defined as processes that prevent individuals of different populations from mating, survival or producing fertile offspring. Reproductive isolation is critical for driving speciation and maintaining species identity, which has been a fundamental concern in evolutionary biology. In plants, reproductive isolation can be divided into prezygotic reproductive barriers and postzygotic reproductive barriers, according to its occurrence at different developmental stages. Postzygotic reproductive isolation that caused by reduced fitness in hybrids is frequently observed in plants, which hinders gene flow between divergent populations and has substantial effects on genetic differentiation and speciation, and thus is a major obstacle for utilization of heterosis in hybrid crops. During the past decade, China had made tremendous progress in molecular and evolutionary basis of prezygotic and postzygotic reproductive barriers in plants. Present understandings in reproductive isolation especially with new data in the last several years well support three evolutionary genetic models, which represent a general mechanism underlying genomic differentiation and speciation. The updated understanding will offer new approaches for the development of wide-compatibility or neutral varieties, which facilitate breeding of hybrid rice as well as other hybrid crops.

    更新日期:2018-11-06
  • Conservation genetics and genomics of threatened vertebrates in China
    J. Genet. Genomics (IF 4.650) Pub Date : 2018-11-05
    Huizhong Fan, Yibo Hu, Qi Wu, Yonggang Nie, Li Yan, Fuwen Wei

    Conservation genetics and genomics are two independent disciplines that focus on using new techniques in genetics and genomics to solve problems in conservation biology. During the past two decades, conservation genetics and genomics have experienced rapid progress. Here, we summarize the research advances in the conservation genetics and genomics of threatened vertebrates (e.g., carnivoran, primates, ungulates, cetaceans, avians, amphibians and reptiles) in China. First, we introduce the concepts of conservation genetics and genomics and their development. Second, we review the recent advances in conservation genetics research, including noninvasive genetics and landscape genetics. Third, we summarize the progress in conservation genomics research, which mainly focuses on resolving genetic problems relevant to conservation such as genetic diversity, genetic structure, demographic history, and genomic evolution and adaptation. Finally, we discuss the future directions of conservation genetics and genomics.

    更新日期:2018-11-06
  • Retrospective and perspective of plant epigenetics in China
    J. Genet. Genomics (IF 4.650) Pub Date : 2018-11-06
    Cheng-Guo Duan, Jian-Kang Zhu, Xiao-Feng Cao

    Epigenetics refer to the study of heritable changes in gene function that do not involve changes in the DNA sequence. Such effects on cellular and physiological phenotypic traits may result from external or environmental factors or be part of normal developmental program. In eukaryotes, DNA wraps on a histone octamer (two copies of H2A, H2B, H3 and H4) to form nucleosome, the fundamental unit of chromatin. The structure of chromatin is subjected to a dynamic regulation through multiple epigenetic mechanisms, including DNA methylation, histone posttranslational modifications (PTMs), chromatin remodeling and noncoding RNAs. As conserved regulatory mechanisms in gene expression, epigenetic mechanisms participate in almost all the important biological processes ranging from basal development to environmental response. Importantly, all of the major epigenetic mechanisms in mammalians also occur in plants. Plant studies have provided numerous important contributions to the epigenetic research. For example, gene imprinting, a mechanism of parental allele-specific gene expression, was firstly observed in maize; evidence of paramutation, an epigenetic phenomenon that one allele acts in a single locus to induce a heritable change in the other allele, was firstly reported in maize and tomato. Moreover, some unique epigenetic mechanisms have been evolved in plants. For example, the 24-nt siRNA-involved RNA-directed DNA methylation (RdDM) pathway is plant-specific because of the involvements of two plant-specific DNA-dependent RNA polymerases, Pol IV and Pol V. A thorough study of epigenetic mechanisms is of great significance to improve crop agronomic traits and environmental adaptability. In this review, we make a brief summary of important progresses achieved in plant epigenetics field in China over the past several decades and give a brief outlook on future research prospects. We focus our review on DNA methylation and histone PTMs, the two most important aspects of epigenetic mechanisms.

    更新日期:2018-11-06
  • The forty years of medical genetics in China
    J. Genet. Genomics (IF 4.650) Pub Date : 2018-11-03
    Lei Cai, Lan Alice Zheng, Lin He

    Medical genetics is the newest cutting-edge discipline that focuses on solving medical problems using genetics knowledge and methods. In China, medical genetics research activities initiated from a poor inner basis but a prosperous genetics development outer environment. During the 40 years of reform and opening-up policy, Chinese scientists contributed significantly in the field of medical genetics, garnering considerable attention worldwide. In this review, we highlight the significant findings and/or results discovered by Chinese scientists in monogenic diseases, complex diseases, cancer, genetic diagnosis, as well as gene manipulation and gene therapy. Due to these achievements, China is widely recognized to be at the forefront of medical genetics research and development. However, the significant progress and development that has been achieved could not have been accomplished without sufficient funding and a well-constructed logistics network. The successful implementation of translational medicine or precise medicine sourced from medical genetics will depend on a strong foundation based on an open ethic policy and strong support at the Chinese national industry level.

    更新日期:2018-11-05
  • Fruit fly research in China
    J. Genet. Genomics (IF 4.650) Pub Date : 2018-11-03
    Ying Cheng, Dahua Chen

    Served as a model organism over a century, fruit fly has significantly pushed forward the development of global scientific research, including in China. The high similarity in genomic features between fruit fly and human enables this tiny insect to benefit the biomedical studies of human diseases. In the past decades, Chinese biologists have used fruit fly to make numerous achievements on understanding the fundamental questions in many diverse areas of biology. Here, we review some of the recent fruit fly studies in China, and mainly focus on those studies in the fields of stem cell biology, cancer therapy and regeneration medicine, neurological disorders and epigenetics.

    更新日期:2018-11-05
  • Retrospective and perspective of rice breeding in China
    J. Genet. Genomics (IF 4.650) Pub Date : 2018-11-03
    Shiwei Bai, Hong Yu, Bing Wang, Jiayang Li

    Breeding is the art and science of selecting and changing crop traits for the benefit of human beings. For several decades, tremendous efforts have been made by Chinese scientists in rice breeding in improving grain yield, nutrition quality, and environmental performance, achieving substantial progresses for global food security. Several generations of crop breeding technologies have been developed, for example, selection of better performance in the field among variants (conventional breeding), application of molecular markers for precise selection (molecular marker assisted breeding), and development of molecular design (molecular breeding by rational design). In this review, we briefly summarize the advances in conventional breeding, functional genomics for genes and networks in rice that regulate important agronomic traits, and molecular breeding in China with focuses on high yield, good quality, stress tolerance, and high nutrient-use efficiency. These findings have paved a new avenue for rational design of crops to develop ideal varieties with super performance and productivity.

    更新日期:2018-11-05
  • Gene diagnosis and targeted breeding for blast-resistant Kongyu 131 without changing regional adaptability
    J. Genet. Genomics (IF 4.650) Pub Date : 2018-10-22
    Xiangchun Zhou, Gonghao Jiang, Longwei Yang, Lei Qiu, Ping He, Chunxiao Nong, Yunyue Wang, Yuqing He, Yongzhong Xing

    The fungus Magnaporthe oryzae threatens the rice production of Kongyu 131 (KY131), a leading japonica variety in Northeast China. In this study, two rice lines, KP1 and KP2-Hd1, were obtained by introgressing the blast resistance genes Pi1 and Pi2 into KY131, respectively. However, both lines headed later than KY131. RICE60K SNP array analysis showed that Hd1 closely linked to Pi2 was introgressed into KP2-Hd1, and the linkage drag of Hd1 was broken by recombination. On the other hand, no known flowering genes were introgressed into KP1. Gene diagnosis by resequencing six flowering genes showed that KP1 carried functional Hd16 and Ghd8 alleles. Due to its suppression role in heading under long-day conditions, Ghd8 was chosen as the target for gene editing to disrupt its function. Four sgRNAs targeting different sites within Ghd8 were utilized to induce large deletion mutations, which were easy to detect via agarose gel electrophoresis. All the ghd8-mutated KP1 lines were resistant to rice blast disease and headed earlier than the control KP1, even than KY131, under natural long-day conditions, which ensures its growth in Northeast China. This study confirmed that a combination of gene diagnosis and targeted gene editing is a highly efficient way to quickly eliminate undesired traits in a breeding line.

    更新日期:2018-10-23
  • The present and future of whole-exome sequencing in studying and treating human reproductive disorders
    J. Genet. Genomics (IF 4.650) Pub Date : 2018-10-22
    Wei Guo, Xiaohui Zhu, Liying Yan, Jie Qiao

    The causes of recurrent spontaneous abortion (RSA) and fetal malformations are multifactorial and unclear in most cases. Environmental, maternal, and genetic factors have been shown to contribute to these defects. Whole exome sequencing (WES) is widely used to detect genetic variations associated with human diseases and has recently been successfully applied to unveil genetic causes of unexplained recurrent spontaneous abortion (URSA) and fetal malformations. Here, we review the current discovery and diagnosis strategies to identify the underlying pathogenic mutations of URSA and fetal malformations using WES technology and propose to further develop WES, both to advance our understanding of these diseases and to eventually lead to targeted therapies for reproductive disorders.

    更新日期:2018-10-22
  • Genomic landscapes of Chinese sporadic autism spectrum disorders revealed by whole-genome sequencing
    J. Genet. Genomics (IF 4.650) Pub Date : 2018-10-21
    Jinyu Wu, Ping Yu, Xin Jin, Xiu Xu, Jinchen Li, Zhongshan Li, Mingbang Wang, Tao Wang, Xueli Wu, Yi Jiang, Wanshi Cai, Junpu Mei, Qingjie Min, Qiong Xu, Bingrui Zhou, Hui Guo, Ping Wang, Wenhao Zhou, Zhong Sheng Sun

    Autism spectrum disorder (ASD) is a neurodevelopmental disorder with considerable clinical and genetic heterogeneity. In this study, we identified all classes of genomic variants from whole-genome sequencing (WGS) dataset of 32 Chinese trios with ASD, including de novo mutations, inherited variants, copy number variants (CNVs) and genomic structural variants. A higher mutation rate (Poisson test, P < 2.2×10-16) in exonic (1.37×10-8) and 3′-UTR regions (1.42×10-8) were revealed in comparison with that of whole genome (1.05×10-8). Using an integrated model, we identified 87 potentially risk genes (P < 0.01) from 4 832 genes harboring various rare deleterious variants, including CHD8 and NRXN2, implying that the disorders may be in favor to multiple-hit. In particular, frequent rare inherited mutations of several microcephaly-associated genes (ASPM, WDR62, and ZNF335) were found in ASD. In chromosomal structure analyses, we found four de novo CNVs and one de novo chromosomal rearrangement event, including a de novo duplication of UBE3A-containing region at 15q11.2-q13.1, which causes Angelman syndrome and microcephaly, and a disrupted TNR due to de novo chromosomal translocation t(1;5)(q25.1;q33.2). Taken together, our results suggest that abnormalities of centrosomal function and chromatin remodeling of the microcephaly-associated genes may be implicated in pathogenesis of ASD. Adoption of WGS as a new yet efficient technique to illustrate the full genetic spectrum in complex disorders, such as ASD, could provide novel insights into pathogenesis, diagnosis and treatment.

    更新日期:2018-10-22
  • Tel1 and Rif2 oppositely regulate telomere protection at uncapped telomeres in Saccharomyces cerevisiae
    J. Genet. Genomics (IF 4.650) Pub Date : 2018-09-19
    Ling-Li Zhang, Zhenfang Wu, Jin-Qiu Zhou

    It has been well documented that Tel1 positively regulates telomere-end resection by promoting Mre11-Rad50-Xrs2 (MRX) activity, while Rif2 negatively regulates telomere-end resection by inhibiting MRX activity. At uncapped telomeres, whether Tel1 or Rif2 plays any role remains largely unknown. In this work, we examined the roles of Tel1 and Rif2 at uncapped telomeres in yku70Δ and/or cdc13-1 mutant cells cultured at non-permissive temperature. We found that deletion of TEL1 exacerbates the temperature sensitivity of both yku70Δ and cdc13-1 cells. Further epistasis analysis indicated that MRX and Tel1 function in the same pathway in telomere protection. Consistently, TEL1 deletion increases accumulation of Exo1-dependent telomeric single-stranded DNA (ssDNA) at uncapped telomeres, which stimulates checkpoint-dependent cell cycle arrest. Moreover, deletion of TEL1 in yku70Δ and yku70Δ tlc1Δ cells facilitates Rad51-dependent Y′ recombination, allowing yku70Δ tlc1Δ cells to bypass senescence. In contrast, RIF2 deletion in yku70Δ cells decreases the accumulation of telomeric ssDNA after 8 h of incubation at the non-permissive temperature of 37°C and suppresses the temperature sensitivity of yku70Δ cells, likely due to the increase of Mre11 association at telomeres. Collectively, our findings indicate that Tel1 and Rif2 regulate telomere protection at uncapped telomeres via their roles in balancing MRX activity in telomere resection.

    更新日期:2018-09-20
  • CGPS: A machine learning-based approach integrating multiple gene set analysis tools for better prioritization of biologically relevant pathways
    J. Genet. Genomics (IF 4.650) Pub Date : 2018-09-13
    Chen Ai, Lei Kong

    Gene set enrichment (GSE) analyses play an important role in the interpretation of large-scale transcriptome datasets. Multiple GSE tools can be integrated into a single method as obtaining optimal results is challenging due to the plethora of GSE tools and their discrepant performances. Several existing ensemble methods lead to different scores in sorting pathways as integrated results; furthermore, it is difficult for users to choose a single ensemble score to obtain optimal final results. Here, we develop an ensemble method using a machine learning approach called CGPS that integrates the results provided by nine prominent GSE tools into a single ensemble score (R score) to sort pathways as integrated results. Moreover, to the best of our knowledge, CGPS is the first GSE ensemble method built based on a priori knowledge of pathways and phenotypes. Compared with 10 widely used individual methods and five types of ensemble scores from two ensemble methods, we demonstrate that sorting pathways based on the R score can better prioritize relevant pathways, as established by an evaluation of 120 simulated datasets and 45 real datasets. Additionally, CGPS is applied to expression data involving the drug panobinostat, which is an anticancer treatment against multiple myeloma. The results identify cell processes associated with cancer, such as the p53 signaling pathway (hsa04115); by contrast, according to two ensemble methods (EnrichmentBrowser and EGSEA), this pathway has a rank higher than 20, which may cause users to miss this pathway in their analyses. We show that this method, which is based on a priori knowledge, can capture valuable biological information from numerous types of gene set collections, such as KEGG pathways, GO terms, Reactome, and BioCarta. CGPS is publicly available as a standalone source code at ftp://ftp.cbi.pku.edu.cn/pub/CGPS_download/cgps-1.0.0.tar.gz.

    更新日期:2018-09-13
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