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遗传学报
遗传学报

薛勇彪

月刊

1673-8527

jgg@genetics.ac.cn

010-64889354

100101

北京市朝阳区北辰西路1号院2号,遗传与发育生物学研究所

遗传学报/Journal Journal of Genetics and GenomicsCSCD北大核心CSTPCDSCI
查看更多>>本刊是中国遗传学会和中国科学院遗传与发育生物学研究所主办、科学出版社出版的高级学术刊物，全国优秀期刊、中国自然科学核心期刊、中国期刊方阵双百期刊，最近入围国家期刊奖重点期刊行列。已被美国化学文摘（CA）、生物学文摘（BA）和医学索引（MED）等国内外30余种重要检索系统和数据库收录。
正式出版
收录年代

    Exploring noncoding variants in genetic diseases:from detection to functional insights

    Ke WuFengxiao BuYang WuGen Zhang...
    111-132页
    查看更多>>摘要：Previous studies on genetic diseases predominantly focused on protein-coding variations,overlooking the vast noncoding regions in the human genome.The development of high-throughput sequencing technologies and functional genomics tools has enabled the systematic identification of functional noncoding variants.These variants can impact gene expression,regulation,and chromatin conformation,thereby contributing to disease pathogenesis.Understanding the mechanisms that underlie the impact of noncoding variants on genetic diseases is indispensable for the development of precisely targeted therapies and the implementation of personalized medicine strategies.The intricacies of noncoding regions introduce a multitude of challenges and research opportunities.In this review,we introduce a spectrum of noncoding variants involved in genetic diseases,along with research strategies and advanced technologies for their precise identification and in-depth understanding of the complexity of the noncoding genome.We will delve into the research chal-lenges and propose potential solutions for unraveling the genetic basis of rare and complex diseases.
      原文链接:
    • 万方数据
    • 维普

    Gene therapy for monogenic disorders:challenges,strategies,and perspectives

    Yi ZhangZhi-Ying Wu
    133-143页
    查看更多>>摘要：Monogenic disorders refer to a group of human diseases caused by mutations in single genes.While disease-modifying therapies have offered some relief from symptoms and delayed progression for some monogenic diseases,most of these diseases still lack effective treatments.In recent decades,gene therapy has emerged as a promising therapeutic strategy for genetic disorders.Researchers have developed various gene manipulation tools and gene delivery systems to treat monogenic diseases.Despite this progress,concerns about inefficient delivery,persistent expression,immunogenicity,toxicity,capacity limitation,genomic integration,and limited tissue specificity still need to be addressed.This review gives an overview of commonly used gene therapy and delivery tools,along with the challenges they face and potential strategies to counter them.
      原文链接:
    • 万方数据

    Unraveling the complexity of polycystic ovary syndrome with animal models

    Huanju LiuMixue TuZhiyong YinDan Zhang...
    144-158页
    查看更多>>摘要：Polycystic ovary syndrome(PCOS)is a highly familial and heritable endocrine disorder.Over half of the daughters born to women with PCOS may eventually develop their own PCOS-related symptoms.Progress in the treatment of PCOS is currently hindered by the complexity of its clinical manifestations and incomplete knowledge of its etiopathogenesis.Various animal models,including experimentally induced,naturally occurring,and spontaneously arising ones,have been established to emulate a wide range of phenotypical and pathological traits of human PCOS.These studies have led to a paradigm shift in un-derstanding the genetic,developmental,and evolutionary origins of this disorder.Furthermore,emerging evidence suggests that animal models are useful in evaluating state-of-the-art drugs and treatments for PCOS.This review aims to provide a comprehensive summary of recent studies of PCOS in animal models,highlighting the power of these disease models in understanding the biology of PCOS and aiding high-throughput approaches.
      原文链接:
    • 万方数据
    • 维普

    Current therapies for osteoarthritis and prospects of CRISPR-based genome,epigenome,and RNA editing in osteoarthritis treatment

    Yuxi ChenXiao LuoRui KangKaixin Cui...
    159-183页
    查看更多>>摘要：Osteoarthritis(OA)is one of the most common degenerative joint diseases worldwide,causing pain,disability,and decreased quality of life.The balance between regeneration and inflammation-induced degradation results in multiple etiologies and complex pathogenesis of OA.Currently,there is a lack of effective therapeutic strategies for OA treatment.With the development of CRISPR-based genome,epi-genome,and RNA editing tools,OA treatment has been improved by targeting genetic risk factors,acti-vating chondrogenic elements,and modulating inflammatory regulators.Supported by cell therapy and in vivo delivery vectors,genome,epigenome,and RNA editing tools may provide a promising approach for personalized OA therapy.This review summarizes CRISPR-based genome,epigenome,and RNA editing tools that can be applied to the treatment of OA and provides insights into the development of CRISPR-based therapeutics for OA treatment.Moreover,in-depth evaluations of the efficacy and safety of these tools in human OA treatment are needed.
      原文链接:
    • 万方数据
    • 维普

    CGG repeat expansion in LOC642361/NUTM2B-AS1 typically presents as oculopharyngodistal myopathy

    Yan ShiChunyan CaoYiheng ZengYuanliang Ding...
    184-196页
    查看更多>>摘要：CGG repeat expansions in LOC642361/NUTM2B-AS1 have recently been identified as a cause of oculo-pharyngeal myopathy with leukoencephalopathy.However,since only three patients from a single family were reported,it remains unknown whether their clinicopathological features are typical for CGG repeat expansions in LOC642361/NUTM2B-AS1.Here,using repeat-primed-polymerase chain reaction and long-read sequencing,we identify 12 individuals from 3 unrelated families With CGG repeat expansions in LOC642361/NUTM2B-AS1,typically presenting with oculopharyngodistal myopathy.The CGG repeat ex-pansions range from 161 to 669 repeat units.Most of the patients present with ptosis,restricted eye movements,dysphagia,dysarthria,and diffuse limb muscle weakness.Only one patient shows T2-weighted hyperintensity in the cerebellar white matter surrounding the deep cerebellar nuclei on brain magnetic resonance imaging.Muscle biopsies from three patients show a myopathic pattern and rimmed vacuoles.Analyses of muscle biopsies suggest that CGG repeat expansions in LOC642361/NUTM2B-AS1 may deleteriously affect aggrephagic capacity,suggesting that RNA toxicity and mitochondrial dysfunction may contribute to pathogenesis.Our study thus expands the phenotypic spectrum for the CGG repeat expansion of LOC642361/NUTM2B-AS1 and indicates that this genetic variant typically manifests as oculopharyngodistal myopathy with chronic myopathic changes with rimmed vacuoles and filamentous intranuclear inclusions in muscle fibers.
      原文链接:
    • 万方数据
    • 维普

    Correction of a CADASIL point mutation using adenine base editors in hiPSCs and blood vessel organoids

    Jingwen WangLei ZhangGuanglan WuJinni Wu...
    197-207页
    查看更多>>摘要：Cerebral autosomal dominant arterlopathy with subcortical infarcts and leukoencephalopathy(CADASIL)is a monogenic small vessel disease caused by mutations in the NOTCH3 gene.However,the pathogenesis of CADASIL remains unclear,and patients have limited treatment options.Here,we use human induced pluripotent stem cells(hiPSCs)generated from the peripheral blood mononuclear cells of a patient with CADASIL carrying a heterozygous NOTCH3 mutation(c.1261C＞T,p.R421C)to develop a disease model.The correction efficiency of different adenine base editors(ABEs)is tested using the HEK293T-NOTCH3 reporter cell line.ABEmax is selected based on its higher efficiency and minimization of predicted off-target effects.Vascular smooth muscle cells(VSMCs)differentiated from CADASIL hiPSCs show NOTCH3 deposition and abnormal actin cytoskeleton structure,and the abnormalities are recovered in corrected hiPSC-derived VSMCs.Furthermore,CADASIL blood vessel organoids generated for in vivo modeling show altered expression of genes related to disease phenotypes,including the downregulation of cell adhesion,extracellular matrix organization,and vessel development.The dual adeno-associated virus(AAV)split-ABEmax system is applied to the genome editing of vascular organoids with an average editing efficiency of 8.82％.Collectively,we present potential genetic therapeutic strategies for patients with CADASIL using blood vessel organoids and the dual AAV split-ABEmax system.
      原文链接:
    • 万方数据

    The m6A reader YTHDC2 maintains visual function and retinal photoreceptor survival through modulating translation of PPEF2 and PDE6B

    Yeming YangXiaoyan JiangJunyao ChenLu Liu...
    208-221页
    查看更多>>摘要：Inherited retinal dystrophies(IRDs)are major causes of visual Impairment and Irreversible blindness worldwide,while the precise molecular and genetic mechanisms are still elusive.N6-methyladenosine(m6A)modification is the most prevalent internal modification in eukaryotic mRNA.YTH domain containing 2(YTHDC2),an m6A reader protein,has recently been identified as a key player in germline development and human cancer.However,its contribution to retinal function remains unknown.Here,we explore the role of YTHDC2 in the visual function of retinal rod photoreceptors by generating rod-specific Ythdc2 knockout mice.Results show that Ythdc2 deficiency in rods causes diminished scotopic ERG responses and progressive retinal degeneration.Multi-omics analysis further identifies Ppef2 and Pde6b as the potential targets of YTHDC2 in the retina.Specifically,via its YTH domain,YTHDC2 recognizes and binds m6A-modified Ppef2 mRNA at the coding sequence and Pde6b mRNA at the 5'-UTR,resulting in enhanced translation efficiency without affecting mRNA levels.Compromised translation efficiency of Ppef2 and Pde6b after YTHDC2 depletion ultimately leads to decreased protein levels in the retina,impaired retinal function,and progressive rod death.Collectively,our finding highlights the importance of YTHDC2 in visual function and photoreceptor survival,which provides an unreported elucidation of IRD pathogenesis via epitranscriptomics.
      原文链接:
    • 万方数据

    Rare loss-of-function variants in FLNB cause non-syndromic orofacial clefts

    Wenbin HuangShiying ZhangJiuxiang LinYi Ding...
    222-229页
    查看更多>>摘要：Orofacial clefts(OFCs)are the most common congenital craniofacial disorders,of which the etiology is closely related to rare coding variants.Filamin B(FLNB)is an actin-binding protein implicated in bone formation.FLNB mutations have been identified in several types of syndromic OFCs and previous studies suggest a role of FLNB in the onset of non-syndromic OFCs(NSOFCs).Here,we report two rare heterozygous variants(p.P441T and p.G565R)in FLNB in two unrelated hereditary families with NSOFCs.Bioinformatics analysis suggests that both variants may disrupt the function of FLNB.In mammalian cells,p.P441T and p.G565R variants are less potent to induce cell stretches than wild type FLNB,suggesting that they are loss-of-function mutations.Immunohistochemistry analysis demon-strates that FLNB is abundantly expressed during palatal development.Importantly,Flnb-/-embryos display cleft palates and previously defined skeletal defects.Taken together,our findings reveal that FLNB is required for development of palates in mice and FLNB is a bona fide causal gene for NSOFCs in humans.
      原文链接:
    • 万方数据
    • 维普

    NCAD v1.0:a database for non-coding variant annotation and interpretation

    Xiaoshu FengSihan LiuKe LiFengxiao Bu...
    230-242页
    查看更多>>摘要：The application of whole genome sequencing is expanding in clinical diagnostics across various genetic disorders,and the significance of non-coding variants in penetrant diseases is increasingly being demonstrated.Therefore,it is urgent to improve the diagnostic yield by exploring the pathogenic mecha-nisms of variants in non-coding regions.However,the interpretation of non-coding variants remains a significant challenge,due to the complex functional regulatory mechanisms of non-coding regions and the current limitations of available databases and tools.Hence,we develop the non-coding variant annotation database(NCAD,http://www.ncawdb.net/),encompassing comprehensive insights into 665,679,194 var-iants,regulatory elements,and element interaction details.Integrating data from 96 sources,spanning both GRCh37 and GRCh38 versions,NCAD v1.0 provides vital information to support the genetic diagnosis of non-coding variants,including allele frequencies of 12 diverse populations,with a particular focus on the population frequency information for 230,235,698 variants in 20,964 Chinese individuals.Moreover,it offers prediction scores for variant functionality,five categories of regulatory elements,and four types of non-coding RNAs.With its rich data and comprehensive coverage,NCAD serves as a valuable platform,empowering researchers and clinicians with profound insights into non-coding regulatory mechanisms while facilitating the interpretation of non-coding variants.
      原文链接:
    • 万方数据

    PICOTEES:a privacy-preserving online service of phenotype exploration for genetic-diagnostic variants from Chinese children cohorts

    Xinran DongYulan LuLanting GuoChuan Li...
    243-251页
    查看更多>>摘要：The growth in biomedical data resources has raised potential privacy concerns and risks of genetic infor-mation leakage.For instance,exome sequencing aids clinical decisions by comparing data through web services,but it requires significant trust between users and providers.To alleviate privacy concems,the most commonly used strategy is to anonymize sensitive data.Unfortunately,studies have shown that anonym-ization is insufficient to protect against reidentification attacks.Recently,privacy-preserving technologies have been applied to preserve application utility while protecting the privacy of biomedical data.We present the PICOTEES framework,a privacy-preserving online service of phenotype exploration for genetic-diagnostic variants(https://birthdefectlab.cn:3000/).PICOTEES enables privacy-preserving queries of the phenotype spectrum for a single variant by utilizing trusted execution environment technology,which can protect the privacy of the user's query information,backend models,and data,as well as the final results.We demon-strate the utility and performance of PICOTEES by exploring a bioinformatics dataset.The dataset is from a cohort containing 20,909 genetic testing patients with 3,152,508 variants from the Children's Hospital of Fudan University in China,dominated by the Chinese Han population(＞99.9％).Our query results yield a large number of unreported diagnostic variants and previously reported pathogenicity.
      原文链接:
    • 万方数据
    • 维普