Genome-wide recombination profiles in oocytes with chromosome 21 nondisjunction

21 号染色体不分离卵母细胞的全基因组重组谱

• 批准号: 7531755
• 负责人: Stephanie L. Sherman
• 金额: $ 28.74万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-05 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7531755
• 关键词: Address; Age; Aging; Aneuploidy; Biological; Biological Models; Case-Control Studies; Chemicals; Chromosome Segregation; Chromosomes; Chromosomes, Human, Pair 21; Class; Clinical Data; Conceptions; Congenital Abnormality; Data; Down Syndrome; End Point; Ensure; Environment; Environmental Risk Factor; Event; Frequencies; Funding; Genetic; Genetic Nondisjunction; Genetic Recombination; Genome; Human; Human Chromosomes; Individual; Infant; Investigation; Location; Maternal Age; Meiosis; Meiotic Prophase I; Meiotic Recombination; Mental Retardation; Modeling; Molecular; Numbers; Oocytes; Oogenesis; Parents; Pattern; Phenotype; Population; Predisposition; Pregnancy loss; Process; Property; Public Health; Rate; Resources; Rest; Risk; Risk Factors; Sampling; Siblings; Site; Testing; Time; Trans-Activators; Transact; Trisomy; Variant; Work; advanced maternal age; age group; age related; base; bisphenol A; clinically significant; in utero; insight; young mother

DESCRIPTION (provided by applicant): Human chromosome nondisjunction leads to an extraordinary frequency of aneuploidy: an estimated 10-25% of all human conceptions have too many or too few chromosomes. This chromosome error is the leading cause of pregnancy loss, mental retardation and birth defects. Despite this clinical significance, little is known about the causes and associated risk factors for nondisjunction. For the past 15 years, we have investigated trisomy 21, the leading cause of Down syndrome (DS), as a model to understand human nondisjunction. We have built an unprecedented resource of infants with DS and their parents, including biological samples, epidemiological and clinical data. We have shown that altered recombination patterns along the nondisjoined chromosome are risks for nondisjunction, and for the first time, have shown such patterns differ significantly by the age of the oocyte. In this proposal, we will focus on the pattern of recombination among the rest of the chromosomes to determine whether the observed effect on chromosome 21 is due to transacting or cis-acting factors. We will examine two basic properties of inter-individual variation in recombination among oocytes with nondisjoined chromosomes 21 and their siblings: 1) rate of genome-wide recombination and 2) preferred sites of recombination throughout the genome. Results will provide insight into the cause of altered recombination, a risk factor that significantly increases susceptibility for nondisjunction in humans. For example, evidence for a transacting factor that influences recombination suggests either genetic factors or environmental factors that have their effect in-utero during early oogenesis. Based on these results, we will be able to focus/re-focus our search for risk factors in the context of maternal age and recombination patterns. Thus, we will increase the power to dissect the susceptibility of human nondisjunction into its individual liability factors. Once identified, we can determine if such factors can be altered to ensure proper chromosome segregation during oogenesis, one of the most significant processes in our species. PUBLIC HEALTH RELEVANCE: Human chromosome nondisjunction is the leading cause of pregnancy loss, mental retardation and birth defects. In this proposal, we will focus on one important molecular risk factor, altered recombination. We will test the hypothesis the altered recombination patterns observed along the nondisjoined chromosome in oocytes are dictated by trans-acting factors. If true, treatment endpoints can be considered to ensure proper chromosome segregation during oogenesis, one of the most significant processes in our species.

描述（由申请人提供）：人类染色体不分离导致非整倍体的异常频率：估计所有人类受孕的10-25%具有过多或过少的染色体。这种染色体错误是导致流产、智力迟钝和出生缺陷的主要原因。尽管有这种临床意义，但对不分离的原因和相关风险因素知之甚少。在过去的15年里，我们研究了21三体，唐氏综合征（DS）的主要原因，作为一个模型，以了解人类不分离。我们已经建立了一个前所未有的资源与DS的婴儿和他们的父母，包括生物样本，流行病学和临床数据。我们已经证明，沿着不分离的染色体改变重组模式沿着是不分离的风险，并首次表明，这种模式显着不同的卵母细胞的年龄。在这个建议中，我们将集中在其余的染色体之间的重组模式，以确定是否观察到的21号染色体上的影响是由于反式或顺式作用因子。我们将研究具有非分离的21号染色体的卵母细胞及其兄弟姐妹之间重组的个体间变异的两个基本性质：1）全基因组重组的速率和2）整个基因组中重组的优选位点。结果将提供深入了解改变重组的原因，这是一个显著增加人类不分离易感性的风险因素。例如，影响重组的反式作用因子的证据表明，在早期卵子发生期间，遗传因素或环境因素在子宫内产生影响。基于这些结果，我们将能够在母体年龄和重组模式的背景下集中/重新集中我们对风险因素的搜索。因此，我们将增加的权力，剖析人类不分离的易感性，其个人的责任因素。一旦确定，我们可以确定这些因素是否可以改变，以确保在卵子发生过程中正确的染色体分离，这是我们物种中最重要的过程之一。公共卫生相关性：人类染色体不分离是导致流产、智力低下和出生缺陷的主要原因。在这个建议中，我们将集中在一个重要的分子风险因素，改变重组。我们将检验这样一个假设，即在卵母细胞中沿沿着不分离的染色体观察到的改变的重组模式是由反式作用因子决定的。如果是真的，可以考虑治疗终点，以确保卵子发生过程中正确的染色体分离，这是我们物种中最重要的过程之一。