GENETIC ARCHITECTURE OF THE MAMMALIAN (CANID) SKELETON

哺乳动物（犬科动物）骨骼的遗传结构

• 批准号: 8055652
• 负责人: KARL Gordon LARK
• 金额: $ 16.65万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-15 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8055652
• 关键词: Addison' s disease; Age; Aging-Related Process; Animals; Architecture; Autopsy; Behavior; Biological Markers; Biological Models; Breeding; Canis familiaris; Cessation of life; Chemistry; Complex; Control Locus; DNA Sequence; Data; Databases; Degenerative Disorder; Diagnosis; Disease; Environment; Exhibits; Frequencies; Funding; Genes; Genetic; Genome; Genotype; Haplotypes; Health; Hereditary Disease; Histopathology; Human; Human Genetics; Inflammatory Bowel Diseases; Laboratories; Length; Life; Longevity; Mediation; Modeling; Molecular; Morphology; Organ; Pancreatitis; Pathology; Pattern; Phenotype; Physiological; Population; Predisposition; Procedures; Process; Recording of previous events; Records; Regulation; Reporting; Request for Proposals; Research; Resources; Risk; Secure; Serum; Severity of illness; Shapes; Site; Skeleton; System; Thyroid Diseases; Time; Tissues; United States National Institutes of Health; Utah; Variant; Veterinary Medicine; Water; Work; disorder control; dog genome; genetic analysis; interest; life history; man; molecular marker; performance site; public health relevance; skeletal; soft tissue; tool; trait

DESCRIPTION (provided by applicant): This proposal builds on previous research that developed the dog as a model for the genetic analysis of complex traits. A working relationship with owners and breeders of Portuguese Water dogs (PW dogs) has led to a database of more than 1000 animals that have been genotyped with molecular markers and more than half of these have been phenotyped for skeletal morphology. Results from that genetic analysis were instrumental in securing the necessary priority leading to the sequencing of the canine genome. Most recent research on this project demonstrated that conclusions from this database could be validated using other breeds of dogs leading to haplotype sequences of reduced length, focused on specific genes. In the current proposal, genetic analysis focuses on disease related phenotypes: Genetic loci will be identified that regulate the serum chemistry of healthy dogs (biomarkers related to disease states) and that regulate the state of health of PW dogs at time of death determined by autopsy. The latter analysis should provide genetic data on degenerative diseases that occur as part of the aging process. Autopsy data also provides analysis of the genetic regulation of organs and soft tissues avoiding invasive procedures performed on living animals. Genetic analysis will utilize two approaches developed in the last three years: Analysis of segregating haplotypes within a single breed (PW dog) in which heritable variation has been documented; and analysis of fixed haplotypes that differ between breeds (genetic isolates) that exhibit different breed-wide fixed phenotypes. In PW dog sera, various aspects of serum chemistry are heritable and segregating loci have been demonstrated for several biomarkers. Differences between breeds (fixed phenotypes) also have been demonstrated for mean values of serum biomarkers. Values of serum biomarkers as well as frequency of diseases are available from extensive public databases. Autopsy data are obtained on PW dogs sent to the Utah performance site. More than 100 such autopsies have been carried out demonstrating the viability of this approach. Approximately 50 organ and tissue phenotypes are obtained from gross autopsy and a similar number from histopathology of tissue sections. Genotyping is carried out using the Affymetrix SNP chip. The analysis of this increasing database is a collaborative effort between the Utah site and the NIH laboratory of Dr. Elaine Ostrander. PUBLIC HEALTH RELEVANCE: Dogs share more than 200 genetic diseases in common with man, which are diagnosed with similar serum biomarkers and present most of the same histopathologies as in humans. This research will identify genetic loci that regulate variation in serum biomarkers of the dog and that control disease pathology. Results will be directly applicable to the diagnosis of human genetic diseases and the predisposition to genetic disease.

描述（由申请人提供）：该提案建立在先前的研究基础上，该研究发展为复杂性状遗传分析的模型。与葡萄牙水犬（PW Dogs）的所有者和育种者的工作关系导致了一个数据库，该数据库已有1000多只动物，这些动物已被分子标记物进行了基因型，其中一半以上已被表型用于骨骼形态。该遗传分析的结果对确保必要的优先级有助于导致犬类基因组测序的必要优先级。对该项目的最新研究表明，该数据库的结论可以使用其他犬种，导致长度降低的单倍型序列，重点介绍了特定基因。在当前的提案中，遗传分析的重点是与疾病相关的表型：将确定遗传基因座调节健康狗的血清化学（与疾病状态有关的生物标志物），并在尸检确定死亡时调节PW狗的健康状况。后一种分析应提供有关衰老过程一部分发生的退化性疾病的遗传数据。尸检数据还提供了避免对活动物进行的侵入性手术的器官和软组织的遗传调节。遗传分析将利用过去三年中开发的两种方法：单个品种（PW Dog）内的分离单倍型的分析，其中已记录了可遗传的变异；分析固定单倍型，这些固定型在均表现出不同品种固定表型的品种（遗传分离株）之间有所不同。在PW狗血清中，血清化学的各个方面都是遗传性的，并且已经证明了几种生物标志物的分离基因座。还已经证明了品种之间的差异（固定表型）对于血清生物标志物的平均值。血清生物标志物的值以及疾病的频率可从广泛的公共数据库中获得。尸检数据是在发送到犹他州性能站点的PW狗上获得的。已经进行了100多个此类尸检，以证明这种方法的生存能力。大约50个器官和组织表型是从组织切片的组织病理学中获得的。使用Affymetrix SNP芯片进行基因分型。对这一增加数据库的分析是犹他州网站与Elaine Ostrander博士的NIH实验室之间的合作努力。 公共卫生相关性：狗有200多种与人共同的遗传疾病，这些遗传疾病被诊断出患有类似的血清生物标志物，并表现出与人类相同的大多数组织病理学。这项研究将确定调节狗血清生物标志物和控制疾病病理的遗传基因座。结果将直接适用于人类遗传疾病的诊断和对遗传疾病的易感性。