Drosophila Models of Rare Mendelian Disorders of Chromatin Modification

罕见孟德尔染色质修饰疾病的果蝇模型

• 批准号: 10313572
• 负责人: Rebecca A MacPherson
• 金额: $ 4.6万
• 依托单位: CLEMSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2024-08-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10313572
• 关键词: Affect; Animal Model; Area; Behavior; Behavioral; Bioinformatics; Bruck-de Lange syndrome; CRISPR/Cas technology; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Coffin-Siris Syndrome; Collection; Complementary DNA; Complex; Controlled Environment; Data; Defect; Development; Diagnosis; Diagnostic; Diagnostic tests; Digit structure; Disease; Disease Management; Drosophila genus; Drosophila melanogaster; Dysmorphology; Education and Outreach; Environment; Exhibits; Face; Female; Gene Expression; Genes; Genetic; Genetic Epistasis; Genetic Transcription; Genome; Genomic approach; Genotype; Goals; Human; Human Genetics; Impairment; Inbreeding; Intellectual functioning disability; Lead; Locomotion; Maps; Mediating; Mendelian disorder; Metabolism; Modeling; Muscle hypotonia; Mutate; Mutation; Orthologous Gene; Pathogenesis; Patients; Phenotype; Play; Protein Biosynthesis; RNA Interference; Rare Diseases; Reporting; Resources; Role; SWI/SNF Family Complex; Seizures; Severities; Severity of illness; Sleep; Speech; Startle Reaction; Statistical Data Interpretation; Students; Syndrome; Testing; Training; Transgenic Organisms; Validation; Variant; behavioral phenotyping; brahma; brain morphology; candidate identification; career; chromatin modification; clinically relevant; cohesin; comparative genomics; differential expression; disease-causing mutation; fly; genetic architecture; genetic variant; genome wide association study; human data; human disease; improved; interest; knock-down; laboratory experience; male; member; mutant; neurodevelopment; novel; null mutation; protein complex; rare genetic disorder; sex; stem; tool; trait; transcriptome sequencing

PROJECT SUMMARY Coffin-Siris syndrome (CSS), Nicolaides-Baraitser syndrome (NCBRS) and Cornelia de Lange syndrome (CdLS) are rare genetic disorders of chromatin modification characterized by varying degrees of intellectual disability, seizures, hypotonia, and facial and digit abnormalities. CSS-associated mutations in the same gene do not necessarily present with identical phenotypes, suggesting that there exists naturally occurring genetic variants within the genetic background of the patient that modify disease presentation. This proposal tests the hypothesis that candidate genetic modifiers are responsible for the varied severity of CSS, NCBRS, and CdLS and seeks to identify such modifiers using D. melanogaster. There are not enough CSS patients to provide adequate statistical power to identify these modifiers using human data. However, genes associated with CSS and related disorders are highly conserved across taxa, facilitating the use of model organisms, such as the fruit fly Drosophila melanogaster, to elucidate possible genetic modifiers and mechanisms of pathogenesis. Flies can be economically reared in large numbers within a controlled genetic background and exhibit quantifiable changes in behavior upon perturbation of fly orthologs of CSS-, NCBRS-, and CdLS-associated genes. Flies with decreased expression of genes co-regulated upon perturbation of CSS-, NCBRS-, and CdLS-associated fly orthologs will be assessed for behavioral changes and the presence of epistatic genetic interactions. Resulting genetic interactions or changes in behavior indicate that gene may be a candidate genetic modifier. The impact of genetic background on CSS fly phenotypes will be assessed on transgenic flies with normal or mutant copies of human ARID1B, the most commonly mutated gene in CSS, as well as on flies with decreased expression of osa, the fly ortholog for ARID1B. Genome-wide association analysis will be used to identify potential genetic modifiers, and subsequent functional validation will provide evidence that these candidate modifiers likely play a role in CSS disease development. These genetic modifiers will serve as plausible targets for further study on the pathogenesis, diagnosis, treatment and management of CSS and related disorders. This proposal provides the opportunity for the candidate to receive training in areas related to her long-term career goals, including bioinformatics, statistical analyses, and a complex-trait approach to characterize Mendelian diseases through the use of animal models. In addition to laboratory training, the environment and resources available at the Clemson Center for Human Genetics will provide the candidate with additional opportunities to engage with clinicians and participate in genetics education and outreach activities.

项目摘要 Coffin-Siris综合征（CSS）、Nicolaides-Baraitser综合征（NCBRS）和科尔内利亚德兰格综合征（CdLS） 是罕见的染色质修饰遗传疾病，其特征是不同程度的智力残疾， 癫痫张力减退面部和手指畸形同一基因中的CSS相关突变不 必然存在相同的表型，这表明存在自然发生的遗传变异， 在患者的遗传背景内改变疾病表现。这一提议验证了 候选遗传修饰剂负责CSS，NCBRS和CdLS的不同严重程度，并寻求 用D.黑腹菌没有足够的CSS患者提供足够的 统计能力，以确定这些修改器使用人类数据。然而，与CSS相关的基因和相关的 疾病在分类群中高度保守，便于使用模式生物，如果蝇 果蝇，阐明可能的遗传修饰和发病机制。苍蝇可以 在受控的遗传背景下经济地大量饲养，并表现出可量化的变化 在CSS-、NCBRS-和CdLS-相关基因的果蝇直系同源物的扰动后的行为中。苍蝇 CSS、NCBRS和CdLS相关苍蝇受到干扰后共调节的基因表达减少 将评估直系同源物的行为变化和上位遗传相互作用的存在。所得 遗传相互作用或行为变化表明基因可能是一个候选的遗传修饰因子。的影响 将在具有正常或突变拷贝的转基因果蝇上评估CSS果蝇表型的遗传背景 人类ARID 1B，CSS中最常见的突变基因，以及在果蝇中表达减少， osa，ARID 1B的果蝇直系同源物。全基因组关联分析将用于确定潜在的遗传 修饰符，以及随后的功能验证将提供证据表明，这些候选修饰符可能发挥 在CSS疾病发展中的作用。这些遗传修饰剂将作为进一步研究的合理目标， CSS和相关疾病的发病机制、诊断、治疗和管理。该提案提供了 候选人有机会在与其长期职业目标有关的领域接受培训，包括 生物信息学，统计分析和复杂性状的方法来表征孟德尔疾病， 使用动物模型。除了实验室培训外， 克莱姆森人类遗传学中心将为候选人提供额外的机会， 临床医生和参与遗传学教育和推广活动。