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

描述(申请人提供)：这个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性软骨发育不良的基因座和疾病基因，这些疾病影响到颅面、枢椎和附件骨骼，从而揭示新的疾病机制。该项目将检验以下假设：首先，可以使用祖先血统认同来确定小家庭中隐性疾病的基因座。其次，识别软骨中选择性表达的基因是在连锁区间筛选基因并快速识别疾病基因的有效方法。第三，对连锁区间中所有基因的大规模平行序列分析可以用来识别骨骼发育不良疾病基因，这些基因在软骨中没有选择性表达。这些假说将在两个特定的目标下进行检验：1.使用祖先身份-血统图谱确定隐性遗传性骨骼发育不良表型的基因座。利用少量血缘家庭，一种新的数学祖先血统识别方法将被应用于全基因组单核苷酸多态数据，以确定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。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寻找新的骨骼发育不良疾病基因。AIM I中确定的连锁区间内的基因将优先用于软骨选择性基因表达的突变分析。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连锁区间中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。这一结果有望揭示以前未知的对正常骨骼发育至关重要的机制和途径。公共卫生相关性：拟议的工作将定义人类骨骼发育障碍的遗传基础，即影响头面部、轴骨和附件骨骼的疾病。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。这些发现的翻译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.