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Genomics, Proteomics & Bioinformatics 2022年第3期20卷 524-535页

作者： Qichao Lian Yamao Chen Fang Chang Ying Fu Ji Qi State Key Laboratory of Genetic Engineering Institute of Plant BiologySchool of Life SciencesFudan UniversityShanghai 200433China

Accurately identifying DNA polymorphisms can bridge the gap between phenotypes and genotypes and is essential for molecular marker assisted genetic studies.Genome complexities,including large-scale structural variations,bring great challenges to bioinformatic analysis for obtaining high-confidence genomic variants,as sequence differences between non-allelic loci of two or more genomes can be misinterpreted as polymorphisms.It is important to correctly filter out artificial variants to avoid false genotyping or estimation of allele frequencies.Here,we present an efficient and effective framework,inGAP-family,to discover,filter,and visualize DNA polymorphisms and structural variants(SVs)from alignment of short reads.Applying this method to polymorphism detection on real datasets shows that elimination of artificial variants greatly facilitates the precise identification of meiotic recombination points as well as causal mutations in mutant genomes or quantitative trait loci.In addition,inGAP-family provides a user-friendly graphical interface for detecting polymorphisms and SVs,further evaluating predicted variants and identifying mutations related to genotypes.It is accessible at https://***/projects/ingap-family/.

关键词： inGAP-family Genomic variation Structural variation Meiotic analysis genetic mapping Causal mutation

PIWI-specific insertion module: a newly identified regulatory element essential for longer pi RNAs loading and male fertility

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Science China(Life Sciences) 2023年第7期66卷 1708-1710页

作者： Chunyu Liu Feng Zhang Obstetrics and Gynecology Hospital State Key Laboratory of Genetic EngineeringInstitute of Reproduction and DevelopmentFudan UniversityShanghai200011China

Small noncoding RNAs (sn RNAs) such as short interfering RNAs (si RNAs), micro RNAs (mi RNAs), and PIWI-interacting RNAs (pi RNAs) play important roles in diverse cellular processes. These small regulatory RNA molecules exert key regulatory functions by forming complexes with different Argonaute proteins, including the Argonaute(AGO) and PIWI subfamilies (Peters and Meister, 2007).AGO subfamily proteins are ubiquitously expressed and interact with mi RNAs or si RNAs, while PIWI subfamily proteins are expressed mainly in germline cells and interact specifically with pi RNAs (Bartel, 2018).

关键词： insertion fertility element

Exome sequencing identifies rare mutations of LDLR and QTRT1 conferring risk for early-onset coronary artery disease in Chinese

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National Science Review 2022年第8期9卷 22-25页

作者： Kang Yao Yuxiang Dai Juan Shen Yi Wang Huanjie Yang Runda Wu Qijun Liao Hongyi Wu Xiaodong Fang Shalaimaiti Shali Lili Xu Meng Hao Chenhao Lin Zhonghan Sun Yilian Liu Mengxin Li Zhen Wang Qiang Gao Shuning Zhang Chenguang Li Wei Gao Lei Ge Yunzeng Zou Aijun Sun Juying Qian Li Jin Shangyu Hong Yan Zheng Junbo Ge Department of Cardiology Zhongshan HospitalFudan University Shanghai Institute of Cardiovascular Disease BGI Genomics BGI-Shenzhen State Key Laboratory of Genetic Engineering School of Life Sciences and Human PhenomeInstituteFudan University BGI-Shenzhen State Key Laboratory of Genetic Engineering School of Life Sciences and Human Phenome InstituteFudan University

Despite the advances made over the past decades, the known loci for coronary artery disease(CAD) still only explain<20% of the genetic variation in risk[1,2]. The known loci with the strongest effects usually confer a...

Despite the advances made over the past decades, the known loci for coronary artery disease(CAD) still only explaingenetic variation in risk[1,2]. The known loci with the strongest effects usually confer a 20%–37% increased CAD risk and the most loci modulate risk by ≤10% [1]. While most of the current data are from European populations, the use of trans-ethnic analyses could be helpful to identify additional loci. genetic inheritance may impose a high burden on early-onset coronary artery disease(EOCAD).

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SHANK1 and autism spectrum disorders

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Science China(Life Sciences) 2015年第10期58卷 985-990页

作者： GONG XiaoHong WANG HongYan MOE key laboratory of Contemporary Anthropology and State Key Laboratory of Genetic Engineering School of Life SciencesFudan University

Autism spectrum disorders(ASD) are highly heterogeneous pediatric developmental disorders with estimated heritability more than 70%. Although the genetic factors in ASD are mainly unknown, a large number of gene mutations have been found, especially in genes involved in neurogenesis. The Neurexin-Neuroligin-Shank(NRXN-NLGN-SHANK) pathway plays a key role in the formation, maturation and maintenance of synapses, consistent with the hypothesis of neurodevelopmental abnormality in ASD. Presynaptic NRXNs interact with postsynaptic NLGNs in excitatory glutamatergic synapses. SHANK proteins function as core components of the postsynaptic density(PSD) by interacting with multiple proteins. Recently, deletions and point mutations of the SHANK1 gene have been detected in ASD individuals, indicating the involvement of SHANK1 in ASD. This review focuses on the function of SHANK1 protein, Shank1 mouse models, and the molecular genetics of the SHANK1 gene in human ASD.

关键词：自闭蛋白质相互作用谱系基因突变神经再生 ASD 突触前基因点突变

Facile suspension culture protocol of the liver biliary organoids

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Bio-Design and Manufacturing 2023年第1期6卷 74-81页

作者： Jin Chen Jiting Zhang Li Yang Bing Zhao State Key Laboratory of Genetic Engineering School of Life SciencesHuman Phenome InstituteZhongshan HospitalFudan UniversityShanghai 200438China

Introduction Why do we focus on human liver biliary organoids?The three-dimensional(3D)organoid approach is emerging as a powerful tool for basic study and biomedical applications due to its excellent recapitulation of the structure and functions of the primary tissues[1-3].Liver biliary organoids are derived from the biliary tree,which includes the intrahepatic bile duct(IHBD)and extrahepatic bile duct(EHBD).

关键词： biliary liver Liver

Transfer of disulfide bond formation modules via yeast artificial chromosomes promotes the expression of heterologous proteins inKluyveromyces marxianus

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mLife 2024年第1期3卷 129-142页

作者： Pingping Wu Wenjuan Mo Tian Tian Kunfeng Song Yilin Lyu Haiyan Ren Jungang Zhou Yao Yu Hong Lu State Key Laboratory of Genetic Engineering School of Life SciencesFudan UniversityShanghaiChina Shanghai engineering Research Center of Industrial Microorganisms ShanghaiChina

Kluyveromyces marxianus is a food-safe yeast with great potential for producing heterologous proteins.Improving the yield in K.marxianus remains a challenge and incorporating large-scale functional modules poses a technical obstacle in engineering.To address these issues,linear and circular yeast artificial chromosomes of K.marxianus(KmYACs)were constructed and loaded with disulfide bond formation modules from Pichia pastoris or K.marxianus.These modules contained up to seven genes with a maximum size of 15 kb.KmYACs carried telomeres either from K.marxianus or Tetrahymena.KmYACs were transferred successfully into K.marxianus and stably propagated without affecting the normal growth of the host,regardless of the type of telomeres and configurations of KmYACs.KmYACs increased the overall expression levels of disulfide bond formation genes and significantly enhanced the yield of various heterologous proteins.In high-density fermentation,the use of KmYACs resulted in a glucoamylase yield of 16.8 g/l,the highest reported level to date in K.marxianus.Transcriptomic and metabolomic analysis of cells containing KmYACs suggested increased flavin adenine dinucleotide biosynthesis,enhanced flux entering the tricarboxylic acid cycle,and a preferred demand for lysine and arginine as features of cells overexpressing heterologous proteins.Consistently,supplementing lysine or arginine further improved the yield.Therefore,KmYAC provides a powerful platform for manipulating large modules with enormous potential for industrial applications and fundamental research.Transferring the disulfide bond formation module via YACs proves to be an efficient strategy for improving the yield of heterologous proteins,and this strategy may be applied to optimize other microbial cell factories.

关键词： disulfide bond formation expression of heterologous proteins Kluyveromyces marxianus telomere yeast artificial chromosome

Generation of liver bipotential organoids with a small-molecule cocktail

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Journal of Molecular Cell Biology 2020年第8期12卷 618-629页

作者： Xin Wang Chao Ni Ning Jiang Jinsong Wei Jianqing Liang Bing Zhao Xinhua Lin State Key Laboratory of Genetic Engineering School of Life SciencesZhongshan HospitalFudan UniversityShanghai 200438China

Understanding the mechanism of how cholangiocytes(liver ductal cells)are activated upon liver injury and specified to hepatocytes would permit liver regenerative medicine.Here we achieved long-term in vitro expansion of mouse liver organoids by modulating signaling pathways with a combination of three small-molecule compounds.CHIR-99021,blebbistatin,and forskolin together maintained the liver organoids in bipotential stage with both cholangiocyte-and hepatocyte-specific gene expression profiles and enhanced capacity for further hepatocyte differentiation.By employing a chemical approach,we demonstrated that Wnt/β-catenin,NMII-Rac,and PKA-ERK are core signaling pathways essential and sufficient for mouse liver progenitor expansion.Moreover,the advanced small-molecule culture of bipotential organoids facilitates the ex vivo investigation of liver cell fate determination and the application of organoids in liver regenerative medicine.

关键词： liver bipotential organoid small-molecule cocktail long-term expansion progenitor cell hepatocyte differentiation liver regeneration

Amino acids TORC (talk) to anabolism through uncharged tR NA

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Science China Life Sciences 2024年

作者： Zhen-Zhen Ma Shi-Min Zhao State Key Laboratory of Genetic Engineering The Obstetrics & Gynecology Hospital of Fudan University Shanghai key laboratory of Metabolic Remodelling and Health

Anabolism is essential for proliferation as well as to replenish dysfunctional macromolecules in cells. Due to that both substantial building blocks and energy are required for anabolism, cells must double check whether these prerequisites are met before deciding to start anabolism. Amino acids are building blocks of protein synthesis, their sufficiency in cells is closely monitored by several mechanisms, which all are linked to protein synthesis.

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Prediction of lipid nanoparticles for mRNA vaccines by the machine learning algorithm

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Acta Pharmaceutica Sinica B 2022年第6期12卷 2950-2962页

作者： Wei Wang Shuo Feng Zhuyifan Ye Hanlu Gao Jinzhong Lin Defang Ouyang state key laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical SciencesUniversity of MacaoMacao 999078China State Key Laboratory of Genetic Engineering School of Life SciencesZhongshan HospitalFudan UniversityShanghai 200438China

Lipid nanoparticle(LNP) is commonly used to deliver mRNA vaccines.Currently,LNP optimization primarily relies on screening ionizable lipids by traditional experiments which consumes intensive cost and time.Current study attempts to apply computational methods to accelerate the LNP development for mRNA vaccines.Firstly,325 data samples of mRNA vaccine LNP formulations with IgG titer were collected.The machine learning algorithm,lightGBM,was used to build a prediction model with good performance(R^(2)>0.87).More importantly,the critical substructures of ionizable lipids in LNPs were identified by the algorithm,which well agreed with published results.The animal experimental results showed that LNP using DLin-MC3-DMA(MC3) as ionizable lipid with an N/P ratio at 6:1 induced higher efficiency in mice than LNP with SM-102,which was consistent with the model prediction.Molecular dynamic modeling further investigated the molecular mechanism of LNPs used in the experiment.The result showed that the lipid molecules aggregated to form LNPs,and mRNA molecules twined around the LNPs.In summary,the machine learning predictive model for LNP-based mRNA vaccines was first developed,validated by experiments,and further integrated with molecular modeling.The prediction model can be used for virtual screening of LNP formulations in the future.

关键词： Lipid nanoparticle Ionizable lipid mRNA Vaccine Formulation prediction Machine learning LightGBM Molecular modeling

engineering stable heterosis

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Journal of genetics and Genomics 2019年第1期46卷 1-3页

作者： Yingxiang Wang State Key Laboratory of Genetic Engineering and Ministry of Education key laboratory of Biodiversity Sciences and Ecological engineering Institute of Plant Biology School of Life Sciences Fudan University

The ability to fix heterosis or hybrid vigor in crops without crossing holds great potential for crop yield improvement and global food security. Recent studies in Nature and Nature Biotechnology from two independent groups demonstrate the feasibility of clonal propagation of hybrids by engineering changes in meiosis and embryogenesis. These synthetic apomixis technologies represent a watershed moment for both understanding the fundamental basis of heterosis and plant breeding.

关键词： heterosis independent groups technologies represent