Drosophila Models of Rare Mendelian Disorders of Chromatin Modification

项目总结 棺材-西里斯综合征(CSS)、Nicolades-Baraitser综合征(NCBRS)和Cornelia de Lange综合征(CDLS) 染色质修饰是一种罕见的遗传性疾病，其特征是不同程度的智力残疾， 癫痫发作，低眼压，面部和手指畸形。同一基因中的css相关突变不会 必然具有相同的表型，这表明存在自然发生的遗传变异 在改变疾病表现的患者的遗传背景内。这项提议检验了这一假设 候选的遗传修饰者导致了不同的CS、NCBRS和CDL和SEESS 用黑腹葡萄球菌鉴定这种修饰物。没有足够的CS患者提供足够的 使用人类数据识别这些修饰语的统计能力。然而，与css相关的基因和相关的 在不同的分类群中，病态是高度保守的，便于使用模式生物，如果蝇 以阐明可能的遗传修饰物和发病机制。苍蝇可以 在受控的遗传背景下大量经济地饲养，并表现出可量化的变化 在css相关基因、NCBRS同源基因和CDLS相关基因的果蝇同源基因的扰动下的行为。带着苍蝇 Css、NCBRS和CDLS相关果蝇扰动后共调控基因表达减少 将评估直系同源基因的行为变化和上位性遗传交互作用的存在。结果 基因的相互作用或行为的改变表明该基因可能是一个候选的遗传修饰物。其影响 将在具有正常或突变拷贝的转基因果蝇上评估css果蝇的遗传背景 在CS中最常见的突变基因人类ARID1B，以及在表达降低的果蝇中 OSA，ARID1B的苍蝇直射同源基因。全基因组关联分析将被用来识别潜在的基因 修饰符，以及随后的功能验证将提供证据，证明这些候选修饰符可能起到 在慢性阻塞性肺疾病发展中的作用。这些遗传修饰物将成为进一步研究 CS及相关疾病的发病机制、诊断、治疗和管理。这项建议提供了 候选人有机会在与其长期职业目标相关的领域接受培训，包括 通过生物信息学、统计分析和复杂特征方法来表征孟德尔疾病 动物模型的使用。除了实验室培训外，环境和可用资源 克莱姆森人类遗传学中心将为候选人提供更多参与的机会 并参与遗传学教育和外展活动。

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.