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

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学方法来识别隐性遗传性软骨发育不良（影响颅面、中轴和四肢骨骼的疾病）的基因座和疾病基因，从而揭示新的疾病机制。该项目将测试以下假设：首先，祖先血统身份可用于识别小型近亲家庭中隐性遗传疾病的基因座。其次，识别软骨中选择性表达的基因是筛选连锁区间基因并快速识别疾病基因的有效方法。第三，对连锁区间内的所有基因进行大规模平行序列分析可用于识别不在软骨中选择性表达的骨骼发育不良疾病基因。这些假设将在两个具体目标下进行测试： I. 使用祖先血统同一性作图来识别隐性遗传的骨骼发育不良表型的位点。利用少量的近亲家庭，一种新颖的数学祖先血统同一性方法将应用于全基因组单核苷酸多态性数据，以确定与未知病因的骨骼发育不良相关的基因组区间，从而定位这些表型的疾病基因。二.结合软骨选择性基因表达和大规模并行序列分析来鉴定新型骨骼发育不良疾病基因。在目标 I 下确定的关联区间内的基因将通过软骨选择性基因表达优先进行突变分析。对于组织选择性基因表达无法识别的疾病基因，将使用定制阵列捕获连锁区间内每个基因的每个外显子，并使用大规模并行序列分析进行突变分析。预计结果将揭示以前未知的正常骨骼发育所必需的机制和途径。公共健康相关性：拟议的工作将定义人类骨骼发育疾病、影响颅面、中轴和四肢骨骼的疾病的遗传基础。该研究将揭示并提供在此过程中重要的基因的临床背景。研究结果的转化应用将包括为家庭提供 DNA 诊断机会，以及基于确定的特定基因和途径的潜在新疗法。

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.