GENETIC AND MOLECULAR ANALYSES OF MUTATIONS

描述：p基因座在许多方面都是非凡的，包括 具有不同表型效应的各种突变， 一个特殊的等位基因，经常回复到野生型，几乎完全 小鼠和相应区域的遗传和物理图谱 在生物学上很有趣，在医学上也很重要 与人类基因组的这个区域对应的疾病。的关键 解剖这个区域是申请人的发现， 突变是一种基因组重复，经常恢复为野生型， 类型.这一发现很快导致了p基因的克隆， 在这个基因座上的许多等位基因之间进行测试， 表型效应（生长迟缓、雄性不育、雌性半 不育、腭裂、神经系统疾病、行为 异常和产前致死性）的特定缺失部分， 基因定位、基因图谱和物理图谱的开发， 其他特定疾病的候选基因映射到该基因座， 以及使用这些试剂评估疾病（Prader-Willi， Angelman，酪氨酸酶阳性眼皮肤白化病），映射到 人类基因组的相应区域。申请人做出了卓越的 上一个供资期间的进展。此次更新的重点 应用是为了了解非分子基础， 色素沉着表型的p缺失，并确定，克隆和 描述负责的基因。 具体目标1是完成遗传和物理图谱的p 基因座这些地图基本上是完整的， Brilliant将能够更快地识别和评估候选人 基因.这些图谱和试剂也将有助于分析 位于人类基因组相应区域的疾病基因。 具体目的2是评估生长障碍的候选基因， 神经功能，行为和生育能力与独立 p基因座的突变。Brilliant和他的合作者使用了 三个p等位基因的互补测试来证明一个基因 影响生长、行为、生育能力和神经系统 功能已经克隆了来自关键区域的候选基因， 特征化和部分测序。 具体目标3是确定腭裂的分子基础， 与五氯苯酚突变有关的异常神经功能

DESCRIPTION: The p locus is extraordinary in many ways, including the variety of mutations with diverse phenotypic effects, instability of a particular allele with frequent reversions to wild-type, nearly complete genetic and physical maps of both the mouse and the corresponding region of the human genome, biologically interesting and medically important diseases that map to this region of the human genome. The key to dissecting this region was the applicant's discovery that the pun mutation was a genomic duplication that frequently reverted to wild- type. This discovery soon led to cloning the p gene, to complementation tests among the many alleles at this locus, the assignment of various phenotypic effects (growth retardation, male sterility, female semi- sterility, cleft palate, neurological disorders, behavioral abnormalities, and prenatal lethality) to specific deleted portions of the locus, the development of genetic and physical maps for locating other candidate genes for particular diseases that map to this locus, and the use of these reagents to evaluate diseases (Prader-Willi, Angelman, tyrosinase positive oculocutaneous albinism) that map to the corresponding region of the human genome. The applicant made remarkable progress during the previous funding period. The focus of this renewal application is to understand the molecular basis for the non- pigmentation phenotypes of p deletions and to identify, clone and characterize the responsible genes. Specific Aim 1 is to complete the genetic and physical map of the p locus. The maps are largely complete and by filling in the gaps Brilliant will be able to more quickly identify and evaluate candidate genes. These maps and reagents will also facilitate analysis of diseases genes located in the corresponding region of the human genome. Specific Aim 2 is to evaluate a candidate gene for disorders in growth, neurological function, behavior and fertility associated with independent mutations at the p locus. Brilliant and his collaborators used complementation tests with three p alleles to argue that a single gene in this region affects growth, behavior, fertility and neurological function. A candidate gene from the critical region has been cloned, characterized and partially sequenced. Specific Aim 3 is to identify the molecular basis for cleft palate and the abnormal neurological function associated with the pcp mutation.