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Understanding genetic risk for aneuploid conception

了解非整倍体受孕的遗传风险

基本信息

批准号：
10585662
负责人：
Karen A Schindler
金额：
$ 51.98万
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 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10585662
关键词：
Affect Age Aneuploidy Automobile Driving Biological Assay Biological Markers Biological Models Biology Biopsy Caenorhabditis elegans Candidate Disease Gene Cells Chromosome Segregation Chromosomes Clinic Clustered Regularly Interspaced Short Palindromic Repeats Conceptions Couples Data Data Set Disease Embryo Embryo Transfer Etiology Evaluation Female Fertility Frequencies Genes Genetic Genetic Markers Genetic Models Genetic Risk Genome Germ Cells Goals Grant High Risk Woman Homologous Gene Human In Vitro Incidence Individual Infertility Knock-in Mouse Knowledge Mammals Maternal Age Meiosis Methods Molecular Molecular Abnormality Mus Mutation Oocytes Outcome Pathway interactions Phenotype Preimplantation Diagnosis Prevalence Process Public Health Regulatory Pathway Reproduction Research Research Personnel Risk Risk Marker Role Spontaneous abortion System Testing Treatment Failure United States Validation Variant Woman Work aneuploidy analysis biobank biomarker identification blastocyst candidate identification candidate validation causal variant clinical care egg empowerment exome fly genetic analysis genetic resource genetic risk factor genetic variant genome editing genome sequencing human female in vivo infertility treatment innovation maternal risk method development model organism mouse genetics mouse model novel oocyte quality potential biomarker preimplantation preservation prevent programs risk prediction success variant of interest 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. Although 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 develop methods to identify causal genes using low-coverage whole genome sequences obtained from blastocysts that underwent preimplantation genetic testing for aneuploidy (PGT-A). PGT-A sequencing is common for clinical care to guide single euploid embryo transfer, and therefore there is an abundance of sequences to analyze. Success in method development will likely have far reaching utility in enabling clinics to conduct their own genetics-based evaluations. Candidate genes identified by PGT-A analysis in this project and from previously analyzed datasets will be rapidly tested and validated for causation by using worm and fly model organisms. High-ranking candidates, and candidates without model organism homologs, will undergo one final validation pass in a mouse oocyte in vitro system, before creating mouse models that harbor the genetic variant of interest for in vivo studies that are not possible to conduct in humans. These approaches will shed light on the molecular mechanisms that control meiotic 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 avoid infertility by empowering women with necessary and personalized information to better preserve their individual fertility.

项目总结/文摘

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Sirtuins in female meiosis and in reproductive longevity.

DOI：
10.1002/mrd.23437
发表时间：
2020-12
期刊：
Molecular reproduction and development
影响因子：
2.5
作者：
Vazquez BN;Vaquero A;Schindler K
通讯作者：
Schindler K

Mathematical modeling of human oocyte aneuploidy.

人类卵母细胞非整倍性的数学模型。

DOI：
10.1073/pnas.1912853117
发表时间：
2020
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
Tyc,KatarzynaM;McCoy,RajivC;Schindler,Karen;Xing,Jinchuan
通讯作者：
Xing,Jinchuan

Human MLH1/3 variants causing aneuploidy, pregnancy loss, and premature reproductive aging.

DOI：
10.1038/s41467-021-25028-1
发表时间：
2021-08-18
期刊：
Nature communications
影响因子：
16.6
作者：
Singh P;Fragoza R;Blengini CS;Tran TN;Pannafino G;Al-Sweel N;Schimenti KJ;Schindler K;Alani EA;Yu H;Schimenti JC
通讯作者：
Schimenti JC

Analysis of DNA variants in miRNAs and miRNA 3'UTR binding sites in female infertility patients.