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Systematic Exploration of Optimized Base Editing gRNA Design and Pleiotropic Effects with BExplorer

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Genomics, Proteomics & Bioinformatics 2023年第6期21卷 1237-1245页

作者： Gongchen Zhang Chenyu Zhu Xiaohan Chen Jifang Yan Dongyu Xue Zixuan Wei Guohui Chuai Qi Liu Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine Shanghai East HospitalBioinformatics DepartmentSchool of Life Sciences and TechnologyTongji UniversityShanghai 200092China

Base editing technology is being increasingly applied in genome engineering,but the current strategy for designing guide RNAs(gRNAs)relies substantially on empirical experience rather than a dependable and efficient in silico ***,the pleiotropic effect of base editing on disease treatment remains unexplored,which prevents its further clinical ***,we presented BExplorer,an integrated and comprehensive computational pipeline to optimize the design of gRNAs for 26 existing types of base editors in *** BExplorer,we described its results for two types of mainstream base editors,BE3 and ABE7.10,and evaluated the pleiotropic effects of the corresponding base editing *** revealed 524 and 900 editable pathogenic single nucleotide polymorphism(SNP)loci in the human genome together with the selected optimized gRNAs for BE3 and ABE7.10,*** addition,the impact of 707 edited pathogenic SNP loci following base editing on 131 diseases was systematically explored by revealing their pleiotropic effects,indicating that base editing should be carefully utilized given the potential pleiotropic ***,the systematic exploration of optimized base editing gRNA design and the corresponding pleiotropic effects with BExplorer provides a computational basis for applying base editing in disease treatment.

关键词： Gene editing Base editing pleiotropy CRISPR/Cas9 gRNAdesign

Hormones and phenotypic plasticity： Implications for the evolution of integrated adaptive phenotypes

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Current Zoology 2013年第4期59卷 506-525页

作者： Sean C. LEMA Jun KITANO Biological Sciences Department Center for Coastal Marine Sciences California Polytechnic State University San Luis Obispo CA 93407-0401 Ecological Genetics Laboratory National Institute of Genetics Mishima Shizuoka Japan

It is generally accepted that taxa exhibit genetic variation in phenotypic plasticity, but many questions remain unan- swered about how divergent plastic responses evolve under dissimilar ecological conditions. Hormones are signaling molecules that act as proximate mediators of phenotype expression by regulating a variety of cellular, physiological, and behavioral re- sponses. Hormones not only change cellular and physiological states but also influence gene expression directly or indirectly, thereby linking environmental conditions to phenotypic development. Studying how hormonal pathways respond to environ- mental variation and how those responses differ between individuals, populations, and species can expand our understanding of the evolution of phenotypic plasticity. Here, we explore the ways that the study of hormone signaling is providing new insights into the underlying proximate bases for individual, population or species variation in plasticity. Using several studies as exem- plars, we examine how a ＇norm of reaction＇ approach can be used in investigations of hormone-mediated plasticity to inform the following： 1） how environmental cues affect the component hormones, receptors and enzymes that comprise any endocrine sig- naling pathway, 2） how genetic and epigenetic variation in endocrine-associated genes can generate variation in plasticity among these diverse components, and 3） how phenotypes mediated by the same hormone can be coupled and decoupled via independent plastic responses of signaling components across target tissues. Future studies that apply approaches such as reaction norms and network modeling to questions concerning how hormones link environmental stimuli to ecologically-relevant phenotypic re- sponses should help unravel how phenotypic plasticity evolves

关键词： Hormone Endocrine Reaction norm Developmental plasticity pleiotropy Ecology Network

Identification of susceptibility loci and relevant cell type for IgA nephropathy in Han Chinese by integrative genome-wide analysis

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Frontiers of Medicine 2024年第5期18卷 862-877页

作者： Ming Li Xingjie Hao Dianchun Shi Shanshan Cheng Zhong Zhong Lu Cai Minghui Jiang Lin Ding Lanbo Ding Chaolong Wang Xueqing Yu Department of Nephrology Guangdong Provincial People’s HospitalGuangdong Academy of Medical SciencesGuangzhou 510080China Department of Nephrology The First Affiliated HospitalSun Yat-sen UniversityGuangzhou 510080China Guangdong-Hong Kong Joint Laboratory on Immunological and Genetic Kidney Diseases Guangzhou 510080China Department of Epidemiology and Biostatistics Ministry of Education Key Laboratory of Environment and HealthSchool of Public HealthTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China NHC Key Laboratory of Nephrology(Sun Yat-sen University) and Guangdong Provincial Key Laboratory of NephrologyGuangzhou 510080China

Although many susceptibility loci for IgA nephropathy(IgAN)have been identified,they only account for 11.0%of the overall IgAN *** performed a large genome-wide meta-analysis of IgAN in Han Chinese with 3616 cases and 10417 controls to identify additional genetic loci of *** that inflammatory bowel disease(IBD)and asthma might share an etiology of dysregulated mucosal immunity with IgAN,we performed cross-trait integrative analysis by leveraging functional annotations of relevant cell type and the pleiotropic information from IBD and *** 8669456 imputed variants,we identified a novel locus at 4p14 containing the long noncoding RNA *** type enrichment analysis based on annotations suggested that PMA-I-stimulated CD4+CD25–IL17+Th17 cell was the most relevant cell type for IgAN,which highlights the essential role of Th17 pathway in the pathogenesis of ***,we identified six more novel loci associated with IgAN,which included three loci showing pleiotropic effects with IBD or asthma(2q35/PNKD,6q25.2/SCAF8,and 22q11.21/UBE2L3)and three loci specific to IgAN(14q32.32/TRAF3,16q22.2/TXNL4B,and 21q21.3/LINC00113)in the pleiotropic *** findings support the involvement of mucosal immunity,especially T cell immune response and IL-17 signal pathway,in the development of IgAN and shed light on further investigation of IgAN.

关键词： IgA nephropathy(IgAN) genome-wide association study(GWAS) relevant cell types integrative analysis pleiotropy

Assortative mating and self-fertilization differ in their contributions to reinforcement, cascade speciation, and diversification

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Current Zoology 2016年第2期62卷 169-181页

作者： Dean M. CASTILLO Amanda K. GIBSON Leonie C. MOYLE Department of Biology 1001 East Third Street Indiana University Bloomington IN 47405 USA

Cascade speciation and reinforcement can evolve rapidly when traits are pleiotropic and act as both signal/cue in nonrandom mating. Here, we examine the contribution of two key traits-assortative mating and self-fertilization--to reinforcement and （by extension） cascade speciation. First, using a population genetic model of reinforcement we find that both assortative mating and self-fertilization can make independent contributions to increased reproductive isolation, consistent with reinforcement. Self-fertilization primarily evolves due to its 2-fold transmission advantage when inbreeding depression （d） is lower （d〈 0.45） but evolves as a function of the cost of hybridization under higher inbreeding depression （0.45 〈 d〈 0.48）. When both traits can evolve simultaneously, increased self-fertilization often prohibits the evolution of assortative mating. We infer that, under specific conditions, mating system transitions are more likely to lead to increased reproductive isolation and initiate cascade speciation, than assortative mating. Based on the results of our simulations, we hypothesized that transitions to self-fertilization could contribute to clade-wide diversification if reinforcement or cascade speciation is common. We tested this hypothesis with comparative data from two different groups. Consistent with our hypothesis, there was a trend towards uniparental reproduction being associated with increased diversification rate in the Nematode phylum. For the plant genus Mimulus, however, self-fertilization was associated with reduced diversification. Reinforcement driving speciation via transitions to self-fertilization might be short lived or unsustainable across macroevolutionary scales in some systems （some plants）, but not others （such as nematodes）, potentially due to differences in susceptibility to inbreeding depression and/or the ability to transition between reproductive modes.

关键词： speciation pleiotropy self-fertilization.

A Post-domestication Mutation, Dt2, Triggers Systemic Modification of Divergent and Convergent Pathways Modulating Multiple Agronomic Traits in Soybean

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Molecular Plant 2019年第10期12卷 1366-1382页

作者： Dajian Zhang Xutong Wang Shuo Li Chaofan Wang Michael JGosney Michael VMickelbart Jianxin Ma Department of Agronomy Purdue UniversityWest LafayetteIN 47907USA College of Agronomy Shandong Agricultural UniversityTai'anShandong 271018China School of Life Sciences Shandong UniversityQingdaoShandong 266237China Department of Botany and Plant Pathology Purdue UniversityWest LafayetteIN 47907USA Center for Plant Biology Purdue UniversityWest LafayetteIN 47907USA

The semi-determinate stem growth habit in leguminous crops,similar to the“green revolution”semi-dwarf trait in cereals,is a key plant architecture trait that affects several other traits determining grain *** soybean semi-determinacy is modulated by a post-domestication gain-of-function mutation in the gene,Dt2,which encodes an MADS-box transcription ***,its role in systemic modification of stem growth and other traits is *** this study,we show that Dt2 functions not only as a direct repressor of Dt1,which prevents terminal flowering,but also as a direct activator of putative floral integrator/identity genes including GmSOC1,GmAP1,and GmFUL,which likely promote *** also demonstrate that Dt2 functions as a direct repressor of the putative drought-responsive transcription factor gene GmDREB1D,and as a direct activator of GmSPCH and GmGRP7,which are potentially associated with asymmetric division of young epidermal cells and stomatal opening,respectively,and may affect the plant's water-use efficiency(WUE).Intriguingly,Dt2 was found to be a direct activator or repressor of the precursors of eight microRNAs targeting genes potentially associated with meristem maintenance,flowering time,stomatal density,WUE,and/or stress *** study thus reveals the molecular basis of pleiotropy associated with plant productivity,adaptability,and environmental resilience.

关键词： abiotic stress agronomic traits convergent pathways stem growth habit pleiotropy soybean

CCT family genes in cereal crops: A current overview

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The Crop Journal 2017年第6期5卷 449-458页

作者： Yipu Li Mingliang Xu National Maize Improvement Center of China China Agricultural University Beijing 100193 China

Control of flowering time is crucial for reproductive success of cereal crops, and has a significant impact on grain yield as well as adaptation to diverse environmental *** integrate signals from both environmental cues and endogenous regulatory pathways to fine-tune flowering time. The CCT domain originally described to a 43-amino acid sequence at the C-terminus of three Arabidopsis proteins, namely CONSTANS(CO),CO-LIKE, and TIMING OF CAB1(TOC1). The CCT domain-containing genes(CCT genes),which encode transcription co-factors, are the major genetic determinants that modulate flowering time, and this in turn enables plants to effectively expand their territory to take advantage of favorable habitats. Moreover, certain CCT genes have pleiotropic effects on morphological traits and confer resistance/tolerance to biotic/abiotic stresses. CCT genes can be classified into three families, namely COL(CONSTANS-like), PRR(Pseudo-response regulator), and CMF(CCT motif family),based on their non-CCT domains. During domestication, natural and artificial selection resulted in reduced nucleotide diversity of CCT genes in modern cultivated cereals than their wild types. Here, we review the features and functions of CCT genes in cereal crops and propose future research to focus on CCT genes and their utilization in crop breeding.

关键词： CCT domain Flowering time Photoperiod pleiotropy

Diabetes mellitus susceptibility with varied diseased phenotypes and its comparison with phenome interactome networks

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World Journal of Clinical Cases 2022年第18期10卷 5957-5964页

作者： Madhusmita Rout Bhumandeep Kour Sugunakar Vuree Sajitha S Lulu Krishna Mohan Medicherla Prashanth Suravajhala Department of Pediatrics University of Oklahoma Health Sciences CentreOklahoma CityOK 73104United States Department of Biotechnology and Bioinformatics Birla Institute of Scientific ResearchJaipur 302001RajasthanIndia Department of Biotechnology Lovely Professional UniversityPhagwara 144001PunjabIndia Department of Biotechnology Vellore Institute of TechnologyVellore 632014Tamil NaduIndia Amrita School of Biotechnology Amrita Vishwa VidyapeethamVallikavu POAmritapuriClappanaKollam 690525KeralaIndia

An emerging area of interest in understanding disease phenotypes is systems *** diseases such as diabetes have played an important role towards understanding the susceptible genes and mutations.A wide number of methods have been employed and strategies such as polygenic risk score and allele frequencies have been useful,but understanding the candidate genes harboring those mutations is an unmet *** this perspective,using systems genomic approaches,we highlight the application of phenome-interactome networks in diabetes and provide deep ***01128,which we previously described as candidate for diabetes,is shown as an example to discuss the approach.

关键词： Type 1 diabetes Gestational diabetes mellitus Prostate cancer Phenome Type 2 diabetes pleiotropy

The role of gene variants in the pathogenesis of neurodegenerative disorders as revealed by next generation sequencing studies:a review

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Translational Neurodegeneration 2017年第1期6卷 245-255页

作者： Shirley Yin-Yu Pang Kay-Cheong Teo Jacob Shujui Hsu Richard Shek-Kwan Chang Miaoxin Li Pak-Chung Sham Shu-Leong Ho Division of Neurology Department of MedicineQueen Mary HospitalUniversity of Hong KongHong KongPeople’s Republic of China Centre for Genomic Sciences University of Hong KongHong KongPeople’s Republic of China Department of Medical Genetics Zhongshan School of MedicineSun Yat-sen UniversityGuangzhouPeople’s Republic of China Key Laboratory of Tropical Disease Control(SYSU) Ministry of EducationGuangzhouPeople’s Republic of China

The clinical diagnosis of neurodegenerative disorders based on phenotype is difficult in heterogeneous conditions with overlapping *** does not take into account the disease etiology or the highly variable clinical course even amongst patients diagnosed with the same *** advent of next generation sequencing(NGS)has allowed for a system-wide,unbiased approach to identify all gene variants in the genome *** the plethora of new genes being identified,genetic rather than phenotype-based classification of Mendelian diseases such as spinocerebellar ataxia(SCA),hereditary spastic paraplegia(HSP)and Charcot-Marie-Tooth disease(CMT)has become widely *** has also become clear that gene variants play a role in common and predominantly sporadic neurodegenerative diseases such as Parkinson’s disease(PD)and amyotrophic lateral sclerosis(ALS).The observation of pleiotropy has emerged,with mutations in the same gene giving rise to diverse phenotypes,which further increases the complexity of phenotype-genotype *** mechanisms of pleiotropy include different downstream effects of different mutations in the same gene,presence of modifier genes,and oligogenic *** directions include development of bioinformatics tools and establishment of more extensive public genotype/phenotype databases to better distinguish deleterious gene variants from benign polymorphisms,translation of genetic findings into pathogenic mechanisms through in-vitro and in-vivo studies,and ultimately finding disease-modifying therapies for neurodegenerative disorders.

关键词： Next generation sequencing Neurodegenerative diseases Genetics pleiotropy

Developmental rate： A unifying mechanism for sympatric divergence in postglacial fishes？

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Current Zoology 2012年第1期58卷 21-34页

作者： Mcphee, Megan V. Noakes, David L. G. ALLendorf, Fred W. Fisheries Division University of Alaska Fairbanks Juneau Alaska 99801 USA Department of Fisheries and Wildlife and Oregon Hatchery Research Center Oregon State University Corvallis Oregon 97331-3803 USA Division of Biological Sciences University of Montana Missoula MT 59812 USA

Morphologically divergent ecotypes arise in fish populations on postglacial time scales, and resource polymorphisms are often invoked to explain their origin. However, genetic recombination can constrain the ability of divergent selection to pro- duce reproductive isolation in sympatry. Recombination breaks up favorable combinations of traits （＂adaptive suites＂） if indivi- dual traits are affected by different loci. Recombination also breaks up any association between traits under divergent selection and traits contributing to reproductive isolation. Thus, ecological speciation in the absence of preexisting barriers to gene flow is more likely when pleiotropy minimizes the number of loci involved. Here, we revisit research conducted by Carl Hubbs in the early 1900s on the effects of developmental rate on morphological traits in fishes. Hubbs＇ work provides a mechanism to explain how sympatric divergence by trophic polymorphism can occur despite the challenges of recombination. We consider the implica- tions of Hubbs＇ observations for ecological speciation with gene flow in fishes, as well as rapid evolution in captive fish popula- tions [Current Zoology 58 （1）： 21-34, 2012].

关键词： pleiotropy Resource polymorphism Selection-recombination antagonism