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:
- 金额:$ 51.98万
- 依托单位:
- 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:
- 关键词:AffectAgeAneuploidyAutomobile DrivingBiological AssayBiological MarkersBiological ModelsBiologyBiopsyCaenorhabditis elegansCandidate Disease GeneCellsChromosome SegregationChromosomesClinicClustered Regularly Interspaced Short Palindromic RepeatsConceptionsCouplesDataData SetDiseaseEmbryoEmbryo TransferEtiologyEvaluationFemaleFertilityFrequenciesGenesGeneticGenetic MarkersGenetic ModelsGenetic RiskGenomeGerm CellsGoalsGrantHigh Risk WomanHomologous GeneHumanIn VitroIncidenceIndividualInfertilityKnock-in MouseKnowledgeMammalsMaternal AgeMeiosisMethodsMolecularMolecular AbnormalityMusMutationOocytesOutcomePathway interactionsPhenotypePreimplantation DiagnosisPrevalenceProcessPublic HealthRegulatory PathwayReproductionResearchResearch PersonnelRiskRisk MarkerRoleSpontaneous abortionSystemTestingTreatment FailureUnited StatesValidationVariantWomanWorkaneuploidy analysisbiobankbiomarker identificationblastocystcandidate identificationcandidate validationcausal variantclinical careeggempowermentexomeflygenetic analysisgenetic resourcegenetic risk factorgenetic variantgenome editinggenome sequencinghuman femalein vivoinfertility treatmentinnovationmaternal riskmethod developmentmodel organismmouse geneticsmouse modelnoveloocyte qualitypotential biomarkerpreimplantationpreservationpreventprogramsrisk predictionsuccessvariant of interestwhole 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/摘要
由于不孕不育是一个日益严重的公共卫生问题,我们必须了解
基本机制,并确定导致这种疾病的遗传风险因素。最
导致流产的常见遗传异常是非整倍体,即胚胎具有不适当的
染色体数目尽管非整倍体风险的增加与
随着母亲年龄的增加,在任何给定的年龄,非整倍体率都存在显着变化,
年龄本身不足以作为产生非整倍体妊娠风险的生物标志物。因此,我们认为,
我们假设,那些产生高于平均水平的着床前阶段的妇女,
在特定年龄的非整倍体具有基因中的因果变异,
产生非整倍体受孕的风险。为了验证这一假设,我们将开发一些方法,
使用从胚泡获得的低覆盖度全基因组序列鉴定致病基因
接受了植入前非整倍体基因检测(PGT-A)。PGT-A测序是
通常用于临床护理以指导单个整倍体胚胎移植,因此,
大量的序列要分析方法开发的成功可能会产生深远影响
使诊所能够进行自己的基于遗传学的评估。候选基因
通过本项目中的PGT-A分析和先前分析的数据集识别,
通过使用蠕虫和苍蝇模式生物测试和验证因果关系。高级
候选生物和没有模式生物同源物的候选生物将进行一次最终确认
在建立含有遗传基因的小鼠模型之前,
在人体内无法进行的体内研究的目标变体。这些
这些方法将揭示控制减数分裂染色体的分子机制
雌性配子的分离。最终,这项研究可能会导致识别产妇
遗传标记的风险产生一个非整倍体的概念,并帮助避免不孕不育,
为妇女提供必要的个性化信息,
个体生育力
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:
- 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:
- 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:
- 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.
- DOI:10.1038/s41374-020-00498-x
- 发表时间:2021-04
- 期刊:
- 影响因子:0
- 作者:Tyc KM;Wong A;Scott RT Jr;Tao X;Schindler K;Xing J
- 通讯作者:Xing J
Origins and mechanisms leading to aneuploidy in human eggs.
- DOI:10.1002/pd.5927
- 发表时间:2021-04
- 期刊:
- 影响因子:3
- 作者:Wartosch L;Schindler K;Schuh M;Gruhn JR;Hoffmann ER;McCoy RC;Xing J
- 通讯作者:Xing J
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Karen A Schindler其他文献
Karen A Schindler的其他文献
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{{ truncateString('Karen A Schindler', 18)}}的其他基金
Signaling Mechanisms that Control Chromosome Segregation during Female Meiosis
女性减数分裂过程中控制染色体分离的信号机制
- 批准号:
10683357 - 财政年份:2020
- 资助金额:
$ 51.98万 - 项目类别:
Signaling Mechanisms that Control Chromosome Segregation during Female Meiosis
女性减数分裂过程中控制染色体分离的信号机制
- 批准号:
10332058 - 财政年份:2020
- 资助金额:
$ 51.98万 - 项目类别:
Signaling Mechanisms that Control Chromosome Segregation during Female Meiosis
女性减数分裂过程中控制染色体分离的信号机制
- 批准号:
10455188 - 财政年份:2020
- 资助金额:
$ 51.98万 - 项目类别:
Signaling Mechanisms that Control Chromosome Segregation during Female Meiosis
女性减数分裂过程中控制染色体分离的信号机制
- 批准号:
10457384 - 财政年份:2020
- 资助金额:
$ 51.98万 - 项目类别:
Signaling Mechanisms that Control Chromosome Segregation during Female Meiosis (Equipment Administrative Supplement)
女性减数分裂过程中控制染色体分离的信号机制(设备管理补充)
- 批准号:
10405164 - 财政年份:2020
- 资助金额:
$ 51.98万 - 项目类别:
Signaling Mechanisms that Control Chromosome Segregation during Female Meiosis
女性减数分裂过程中控制染色体分离的信号机制
- 批准号:
10581965 - 财政年份:2020
- 资助金额:
$ 51.98万 - 项目类别:
Signaling Mechanisms that Control Chromosome Segregation during Female Meiosis
女性减数分裂过程中控制染色体分离的信号机制
- 批准号:
10682324 - 财政年份:2020
- 资助金额:
$ 51.98万 - 项目类别:
Signaling Mechanisms that Control Chromosome Segregation during Female Meiosis
女性减数分裂过程中控制染色体分离的信号机制
- 批准号:
10265406 - 财政年份:2020
- 资助金额:
$ 51.98万 - 项目类别:
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
- 批准号:
10307609 - 财政年份:2017
- 资助金额:
$ 51.98万 - 项目类别:
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
- 批准号:
10063883 - 财政年份:2017
- 资助金额:
$ 51.98万 - 项目类别:
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