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

描述（由申请人提供）：本项目的目标是使用新的数学和遗传学方法来识别隐性遗传的软骨发育不良，影响颅面，轴骨和尾骨的疾病的位点和疾病基因，从而揭示疾病的新机制。该项目将测试以下假设：首先，祖先血统身份可以用于识别小型近亲家庭中隐性疾病的基因位点。其次，识别软骨中选择性表达的基因是一种有效的方法，可以在关联区间内过滤基因，快速识别疾病基因。第三，在一个关联区间内对所有基因进行大规模平行序列分析，可用于识别在软骨中没有选择性表达的骨骼发育不良疾病基因。这些假设将在两个特定目的下进行测试：1 .使用祖先血统鉴定图确定隐性遗传骨骼发育不良表型的位点。利用少量的近亲家庭，一种新的数学祖先血统识别方法将应用于全基因组单核苷酸多态性数据，以识别与未知病因的骨骼发育不良相关的基因组间隔，从而定位这些表型的疾病基因。2。利用软骨选择性基因表达和大规模平行序列分析相结合的方法鉴定新的骨骼发育不良疾病基因。在Aim I下确定的连接间隔内的基因将优先进行软骨选择性基因表达的突变分析。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接区间内每个基因的每个外显子，并将大规模并行序列分析用于突变分析。研究结果有望揭示以前未知的正常骨骼发育的机制和途径。公共卫生相关性：拟议的工作将确定人类骨骼发育疾病的遗传基础，影响颅面、轴骨和尾骨的疾病。这项研究将揭示并提供在这一过程中重要的基因的临床背景。这些发现的转化应用将包括为家庭提供DNA诊断机会，以及基于已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.