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

X 染色体的基因组完整性

• 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
• 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' 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

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）：原始卵泡池衰竭是大多数女性原发性卵巢功能不全（POI）的原因。1-2%的女性患有POI，而遗传因素对POI的影响高达70%。除不育外，POI妇女患骨质疏松症、心血管疾病和死亡率的风险也增加。目前只有核型和FMR1突变前检测提供给POI妇女。对于有卵巢功能丧失风险的女性来说，保留生育能力目前是可行的，但是对于能够预测卵巢功能不全的强大和更好的生物标志物的需求很大。我们感兴趣的是识别与POI相关的遗传生物标志物。长期以来，基因敲除动物模型中涉及的X染色体和候选常染色体基因在人类POI病因学中的作用一直被假设，但在基因水平上几乎没有证据。我们构建了一个新的高分辨率基因组阵列，询问X染色体和134个候选常染色体基因拷贝数。我们表明，该阵列可以检测到小至500个碱基对的基因组失衡，并且优于商业阵列。我们假设病理性基因组失衡涉及X染色体和候选常染色体位点，将存在于10%以上的女性POI患者中。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，以确定致病性突变对POI的贡献。我们的建议将测试我们的靶向方法在识别POI女性致病性突变中的相关性，并将刺激进一步研究这种靶向方法预测卵巢衰竭的可行性。拟议的研究可能会发现新的途径，并为与人类POI相关的基础科学研究提供未来的方向。