Identifying genes for recessive chondrodysplasias using ancestral identity-by-des

使用祖先身份鉴定隐性软骨发育不良的基因

• 批准号: 8250831
• 负责人: DANIEL H COHN
• 金额: $ 38.1万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-29 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8250831
• 关键词: Affect; Cartilage; Clinical; Custom; DNA; Data; Diagnosis; Disease; Etiology; Exons; Family; Gene Expression; Genes; Genetic; Genome; Genomics; Goals; Health; Hereditary Disease; Human; Inborn Genetic Diseases; Inherited; Link; Localized Disease; Maps; Methods; Modality; Modeling; Mutation Analysis; Other Genetics; Pathway interactions; Phenotype; Process; Recessive Genes; Sequence Analysis; Single Nucleotide Polymorphism; Skeletal Development; Skeleton; Testing; Tissues; Work; base; chondrodysplasia; craniofacial; new technology; novel; selective expression; skeletal dysplasia

DESCRIPTION (provided by applicant): The goals of this project are to use novel mathematical and genetic approaches to identify loci and disease genes for recessively inherited chondrodysplasias, disorders affecting the craniofacial, axial and appendicular skeleton, thereby revealing new mechanisms of disease. The project will test the following hypotheses: First, that ancestral identity-by-descent can be used to identify loci for recessive disorders in small, consanguineous families. Second, that identifying genes selectively expressed in cartilage is an efficient way to filter genes in a linked interval and quickly identify the disease gene. Third, that massively parallel sequence analysis of all genes in a linked interval can be used to identify skeletal dysplasia disease genes that are not selectively expressed in cartilage. These hypotheses will be tested under two Specific Aims: I. To identify loci for recessively inherited skeletal dysplasia phenotypes using ancestral identity-by-descent mapping. Using small numbers of consanguineous families, a novel mathematical ancestral identity-by-descent method will be applied to whole genome single nucleotide polymorphism data to identify genomic intervals associated with skeletal dysplasias of unknown etiology, thereby localizing the disease genes for these phenotypes. II. To identify novel skeletal dysplasia disease genes using a combination of cartilage selective gene expression and massively parallel sequence analysis. Genes within the linked intervals identified under Aim I will be prioritized for mutation analysis by cartilage- selective gene expression. For the disease genes not identifiable by tissue-selective gene expression, each exon of every gene in the linked interval will be captured using custom arrays, and massively parallel sequence analysis will be used for mutation analysis. The results are expected to reveal previously unknown mechanisms and pathways essential for normal skeletal development. PUBLIC HEALTH RELEVANCE: The proposed work will define the genetic basis for human disorders of skeletal development, disorders that affect the craniofacial, axial and appendicular skeleton. The study will reveal and provide clinical context for genes that are important in this process. Translational application of the findings will include DNA diagnosis opportunities for families and potential new treatments based on the specific genes and pathways identified.

描述（由申请人提供）：该项目的目标是使用新颖的数学和遗传方法来识别基因座和疾病基因，以遗传遗传遗传的软骨浮肿，影响颅面，轴向和阑尾骨骼的疾病，从而揭示出疾病的新机制。该项目将检验以下假设：首先，可以使用祖先的身份来识别小亲属家庭中隐性疾病的基因座。其次，在软骨中选择性表达的识别基因是在链接间隔中过滤基因并迅速识别疾病基因的有效方法。第三，在链接间隔中对所有基因的大规模平行序列分析可用于识别未在软骨中选择性表达的骨骼发育异常疾病基因。这些假设将在两个特定目的下进行测试：I。使用祖先的逐个映射鉴定隐性遗传遗传骨骼发育异常表型的基因座。使用少量的血统家族，将应用一种新型的数学祖先认同，将其应用于整个基因组单核苷酸多态性数据，以识别与未知病因的骨骼骨骼异常相关的基因组间隔，从而将这些表型的疾病基因定位。 ii。使用软骨选择性基因表达和大量平行序列分析的组合来鉴定新的骨骼发育不良基因。 AIM I下的链接间隔内的基因将通过软骨选择性基因表达优先进行突变分析。对于通过组织选择性基因表达无法鉴定的疾病基因，将使用自定义阵列捕获链接间隔中每个基因的每个外显子，并且将使用大规模平行的序列分析用于突变分析。预计该结果将揭示以前未知的机制和对正常骨骼发育必不可少的途径。公共卫生相关性：拟议的工作将定义骨骼发育的人类疾病的遗传基础，影响颅面，轴向和阑尾骨骼的疾病。该研究将揭示并提供在此过程中很重要的基因的临床环境。调查结果的翻译应用将包括基于确定的特定基因和途径的家庭的DNA诊断机会以及潜在的新疗法。