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Association of the Maternal Exome with Risk of an Aneuploid Conception

母体外显子组与非整倍体受孕风险的关联

基本信息

批准号：
10307609
负责人：
Karen A Schindler
金额：
$ 37.27万
依托单位：
RUTGERS, THE STATE UNIV OF N.J.
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-12-15 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10307609
关键词：
Achievement Affect Age Aneuploidy Animal Model Biological Biological Markers Biological Models Biology CRISPR/Cas technology Candidate Disease Gene Cells Chromosome Segregation Chromosomes Code Conceptions Couples DNA DNA Library Disease Embryo Embryonic Development Female Fertility Fertilization in Vitro Frequencies Funding Genes Genetic Genetic Markers Genome Germ Cells Goals Human In Vitro Incidence Individual Infertility Knock-in Mouse Knowledge Lead Light Maternal Age Mediating Meiosis Methods Modeling Molecular Molecular Abnormality Mus Mutation Oocytes Pathway interactions Patients Phenotype Pilot Projects Population Study Prevalence Process Proteins Public Health Regulatory Pathway Reproduction Research Research Design Research Personnel Resources Risk Risk Marker Role Sampling Sampling Studies Spontaneous abortion System Technology Testing United States Validation Variant Woman Work aurora kinase biological systems causal variant empowered exome exome sequencing gene function genetic risk factor genetic variant genome editing high risk human female in vivo mouse genome mouse model mutant potential biomarker preimplantation preservation prevent programs reproductive fitness risk prediction screening whole genome

项目摘要

Project Summary/Abstract Because infertility is a growing public health problem, it is imperative that we understand the basic mechanisms and identify the genetic risk factors that give rise to this disease. The most common genetic abnormality that causes miscarriage is aneuploidy, an embryo with an improper number of chromosomes. While increased risk of aneuploidy is strongly correlated with increasing maternal age, significant variation exists in aneuploidy rates at any given age, making age alone an inadequate biomarker for the risk of producing an aneuploid conception. Therefore, we hypothesize that women who produce higher than average levels of preimplantation stage aneuploidy at a given age possess causal variants in genes which predispose them to an early risk of producing an aneuploid conception. To test this hypothesis, we will sequence the exomes of women at the extremes of the preimplantation aneuploidy phenotype. This project requires a significant number of prior achievements, including the creation of a DNA bank from women who have undergone in vitro fertilization (IVF) and comprehensive chromosome screening (CCS) of IVF-derived embryos, and the development and validation of an accurate method of CCS. Both of these hurdles have now been overcome making this proposal feasible. To achieve statistical power to accurately identify disease-causing genes, this study will complete exome-sequencing efforts that were initiated with pilot project funds. Previously identified candidate genes and those identified by sequencing in this project will be evaluated for functional significance in an animal model, because studies involving introduction of mutant genes are not possible in humans. These approaches will shed light on the molecular mechanisms that control chromosome segregation in female gametes. Ultimately, this study could lead to the identification of maternal genetic markers for risk of producing an aneuploid conception, and help prevent infertility by empowering women with necessary and personalized information to better preserve their individual fertility.

项目总结/文摘