Genomic integrity of the X chromosome & Ovary-Specific Autosomal Genes

X 染色体的基因组完整性

基本信息

批准号：
8840981
负责人：
ALEKSANDAR RAJKOVIC
金额：
$ 22.98万
依托单位：
MAGEE-WOMEN'S RES INST AND FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8840981
关键词：
Affect Age Animal Model BMP15 gene Base Pairing Basic Science Biological Markers Biological Preservation Candidate Disease Gene Cardiovascular Diseases Cardiovascular system Clinical Clinical Data Custom Cytogenetics Data Development Diagnosis Early Intervention Etiology FMR1 Failure Female Fertility Future Gene Dosage Genes Genetic Genetic Markers Genetic Predisposition to Disease Genomic Segment Genomics Guidelines Health Human Individual Infertility Investigation Karyotype Lead Longevity Massive Parallel Sequencing Medical Morbidity - disease rate Mosaicism Mutation Osteoporosis Ovarian Ovary Participant Pathologic Pathway interactions Personal Satisfaction Physiologic calcification Play Predisposition Premature Ovarian Failure Primordial Follicle Reproduction Research Resolution Risk Role Sex Chromosomes Structural defect Testing Time Turner&apos s Syndrome Variant Woman X Chromosome base body system cardiovascular health clinical practice cohort defined contribution design exome genome integrity interest knockout animal male microdeletion mortality novel ovarian failure premature primary ovarian insufficiency psychosocial reproductive targeted sequencing therapy design

项目摘要

DESCRIPTION (provided by applicant): Primordial follicle pool depletion is the cause of primary ovarian insufficiency (POI) in most women. POI afflicts 1-2% of women, and genetics contributes as much as 70% to POI. Besides infertility, women with POI are at increased risk for osteoporosis, cardiovascular morbidity and mortality. Currently only karyotype and FMR1 pre-mutation testing are offered to women with POI. Fertility preservation is currently feasible for women at risk for losing ovarian function, yet there is a great need for robust and better biomarkers capable of predicting ovarian insufficiency. We are interested in identifying genetic biomarkers that associate with POI. The role of the X chromosome and candidate autosomal genes implicated from knockout animal models has been hypothesized for a long time in the etiology of human POI, yet there is little to show at the gene level. We constructed a novel high-resolution genomic array that interrogates the X chromosome and 134 candidate autosomal gene copy numbers. We show that this array can detect genomic imbalances as small as 500 base pairs, and is superior to commercial arrays. We hypothesize that pathologic genomic imbalances involving the X chromosome and candidate autosomal loci, will be present in more than 10% of women who suffer POI. Moreover, we will sequence the X-chromosome exomes, as well as the exomes of 134 candidate autosomal genes to define contribution of pathogenic mutations to POI. Our proposal will test the relevance of our targeted approach in identifying pathogenic mutations in women with POI, and will stimulate further research into the feasibility of such targeted approaches to predict ovarian failure. Proposed studies may identify novel pathways, and provide future directions for basic science investigations relevant to human POI.

描述（由申请人提供）：原始卵泡池耗竭是大多数女性原发性卵巢功能不全（POI）的原因。 POI 困扰着 1-2% 的女性，而遗传因素对 POI 的影响高达 70%。除了不孕之外，患有 POI 的女性患骨质疏松症、心血管疾病和死亡的风险也会增加。目前仅向患有 POI 的女性提供核型和 FMR1 突变前检测。目前，对于面临卵巢功能丧失风险的女性来说，保留生育能力是可行的，但仍然非常需要能够预测卵巢功能不全的强大且更好的生物标志物。我们有兴趣识别与 POI 相关的遗传生物标志物。敲除动物模型中涉及的 X 染色体和候选常染色体基因的作用在人类 POI 的病因学中已经被假设了很长时间，但在基因水平上却几乎没有得到证实。我们构建了一种新型高分辨率基因组阵列，可检测 X 染色体和 134 个候选常染色体基因拷贝数。我们证明该芯片可以检测小至 500 个碱基对的基因组失衡，并且优于商业芯片。我们假设超过 10% 的 POI 女性会出现涉及 X 染色体和候选常染色体位点的病理性基因组失衡。此外，我们将对 X 染色体外显子组以及 134 个候选常染色体基因的外显子组进行测序，以确定致病突变对 POI 的贡献。我们的提案将测试我们的靶向方法在识别 POI 女性致病突变方面的相关性，并将刺激进一步研究这种靶向方法预测卵巢功能衰竭的可行性。拟议的研究可能会确定新的途径，并为与人类 POI 相关的基础科学研究提供未来方向。