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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要 Coffin-Siris 综合征 (CSS)、Nicolaides-Baraitser 综合征 (NCBRS) 和 Cornelia de Lange 综合征 (CdLS) 是罕见的染色质修饰遗传性疾病，其特征是不同程度的智力障碍，癫痫发作、肌张力低下以及面部和手指异常。同一基因中与 CSS 相关的突变不会必然存在相同的表型，表明存在自然发生的遗传变异在改变疾病表现的患者遗传背景内。该提案检验了假设候选遗传修饰因子导致 CSS、NCBRS 和 CdLS 的不同严重程度，并寻求使用黑腹果蝇来识别此类修饰剂。没有足够的 CSS 患者来提供足够的使用人类数据识别这些修饰符的统计能力。然而，与 CSS 和相关基因相关的基因疾病在各个分类群中高度保守，促进了模型生物（例如果蝇）的使用黑腹果蝇，阐明可能的遗传修饰因子和发病机制。苍蝇可以在受控遗传背景下经济上大量饲养并表现出可量化的变化 CSS、NCBRS 和 CdLS 相关基因的果蝇直系同源物受到扰动后的行为。飞行与 CSS、NCBRS 和 CdLS 相关果蝇扰动时共同调节的基因表达减少将评估直向同源物的行为变化和上位遗传相互作用的存在。结果遗传相互作用或行为变化表明基因可能是候选遗传修饰剂。影响 CSS 果蝇表型的遗传背景将在具有正常或突变拷贝的转基因果蝇上进行评估人类 ARID1B（CSS 中最常见的突变基因）以及果蝇的表达降低 osa，ARID1B 的果蝇直系同源物。全基因组关联分析将用于识别潜在的遗传修饰符，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作用 CSS 疾病发展中的作用。这些基因修饰剂将作为进一步研究的合理目标 CSS 及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接受与其长期职业目标相关领域的培训，包括生物信息学、统计分析和复杂性状方法通过动物模型的使用。除了实验室培训之外，实验室提供的环境和资源克莱姆森人类遗传学中心将为候选人提供额外的机会参与临床医生并参与遗传学教育和外展活动。