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的数学和遗传方法来确定遗传性软骨发育不良的基因座和疾病基因，影响颅面，中轴和无骨骨骼的疾病，从而揭示疾病的新机制。该项目将测试以下假设：第一，祖先身份的血统可以用来确定基因座的隐性疾病的小，血缘家庭。第二，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，在连锁区间内对所有基因进行大规模平行序列分析，可用于鉴定在软骨中不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检验：I.利用祖先血统定位法确定遗传性骨骼发育不良表型的基因位点。使用少量的血缘家庭，一种新的数学祖先身份的血统方法将应用于全基因组单核苷酸多态性数据，以确定与骨骼发育不良的病因不明的基因组间隔，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平行序列分析鉴定新的骨骼发育不良疾病基因。在目标I下鉴定的相关区间内的基因将优先用于通过软骨选择性基因表达进行突变分析。对于不能通过组织选择性基因表达识别的疾病基因，将使用定制阵列捕获链接区间中每个基因的每个外显子，并将使用大规模平行序列分析进行突变分析。这些结果有望揭示以前未知的机制和正常骨骼发育所必需的途径。公共卫生相关性：拟议的工作将确定人类骨骼发育障碍的遗传基础，这些障碍影响颅面、中轴和外骨骼。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家庭的DNA诊断机会和基于所确定的特定基因和途径的潜在新治疗方法。

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.