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Trisomy 21: Risk Factors for Chromosome Non-disjunction

21 三体：染色体不分离的危险因素

基本信息

批准号：
8301482
负责人：
Eleanor Feingold
金额：
$ 61.36万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-06-22 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8301482
关键词：
Age Aneuploidy Architecture Biological Biological Models Biology Birth Candidate Disease Gene Child Chromosome Mapping Chromosome Segregation Chromosomes Chromosomes, Human, Pair 21 Clinical Data Commit Conceptions Congenital Abnormality Contraceptive Usage Data Data Set Down Syndrome Economics Ensure Environmental Exposure Environmental Risk Factor Epidemiology Event Family Family Planning Female Folic Acid Deficiency Frequencies General Population Genes Genetic Genetic Nondisjunction Genetic Predisposition to Disease Genetic Recombination Genomics Genotype Germ Cells Human Human Chromosomes Individual Infant Intellectual functioning disability Intervention Lead Length Longevity Maternal Age Meiosis Meiotic Recombination Methylation Modeling Molecular Mothers Oocytes Oogenesis Oral Contraceptives Outcome Parents Paternal Age Pattern Phenotype Play Population Positioning Attribute Predisposition Pregnancy loss Process Recombinants Reporting Reproduction Research Research Personnel Resources Risk Risk Factors Role Sampling Sampling Studies Smoking Susceptibility Gene System Testing Time Trisomy Variant Woman Work advanced maternal age age related base case control clinically significant cohort epigenomics genome wide association study genome-wide insight male programs public health relevance repository reproductive social telomere

项目摘要

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, intellectual disabilities and birth defects. We propose to continue the study of trisomy 21, the cause of Down syndrome (DS), as a model to understand 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 a risk for nondisjunction, and for the first time, have shown that the position of susceptible recombinants differ by the age of the oocyte. Our data have generated new hypotheses that focus on the importance of the genetic architecture of meiotic recombination. We will harness the use of the public genotyping data from genome-wide association studies (GWAS) and our DS repository to gain insight into mechanisms that lead to nondisjunction. First, we will narrow possible mechanism of recombination-based nondisjunction by better understanding recombination patterns in normal meiosis. Second, we will determine the interaction between recombination patterns and environmental and genomic/epigenomic factors that have been associated with nondisjunction, and 3) conduct a GWAS study to identify susceptibility genes for nondisjunction of chromosome 21. Our strategy will ensure progress toward understanding nondisjunction and its consequent impact on the length of woman's reproductive life span. PUBLIC HEALTH RELEVANCE: Human chromosome nondisjunction is the leading cause of pregnancy loss, intellectual disabilities and birth defects. In this competitive renewal, we will focus on uncovering the genetic architecture of meiotic recombination, one important molecular risk factor for nondisjunction. Our strategy to identify recombination-related susceptibility genes will ensure progress toward understanding nondisjunction and its consequent impact on the length of woman' s reproductive life span.

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、智力残疾和出生缺陷的主要原因。我们建议继续研究21三体，唐氏综合征（DS）的原因，作为一个模型，以了解不分离。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，改变重组模式沿着不分离的染色体是不分离的风险，并为第一次，已经表明，敏感的重组体的位置不同的年龄的卵母细胞。我们的数据产生了新的假设，重点关注减数分裂重组的遗传结构的重要性。我们将利用来自全基因组关联研究（GWAS）和我们的DS库的公共基因分型数据来深入了解导致不分离的机制。首先，我们将通过更好地理解正常减数分裂中的重组模式来缩小基于重组的不分离的可能机制。其次，我们将确定重组模式与环境和基因组/表观基因组因素之间的相互作用，这些因素与不分离有关; 3）进行GWAS研究，以确定21号染色体不分离的易感基因。我们的策略将确保在了解不分离及其对女性生殖寿命长度的影响方面取得进展。公共卫生相关性：人类染色体不分离是导致流产、智力残疾和出生缺陷的主要原因。在这个竞争性的更新，我们将集中在揭示减数分裂重组的遗传结构，一个重要的分子风险因素不分离。我们的策略，以确定重组相关的易感基因，将确保在理解不分离及其对妇女的生殖寿命的长度随之产生的影响的进展。