GEMS: Genomic approach to connecting Elevated germline Mutation rates with male infertility and Somatic health

GEMS：将种系突变率升高与男性不育和躯体健康联系起来的基因组方法

• 批准号: 10478160
• 负责人: Kenneth Ivan Aston
• 金额: $ 76.23万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10478160
• 关键词: Age; Andrology; Automobile Driving; Autopsy; Blood; Cadaver; Cardiovascular Diseases; Cause of Death; Childhood Leukemia; Clinic; Colon; Colon Carcinoma; Complex; Consensus; DNA; DNA sequencing; Data; Data Set; Electronic Health Record; Environment; Etiology; Family; Family member; Fertility; Follow-Up Studies; Foundations; Generations; Genetic; Genomic Instability; Genomic approach; Germ-Line Mutation; Goals; Health; Hereditary Malignant Neoplasm; Heritability; Human; Incidence; Individual; Infertility; Life Style; Link; Longevity; Male Infertility; Malignant Childhood Neoplasm; Malignant neoplasm of prostate; Malignant neoplasm of testis; Malignant neoplasm of thyroid; Maps; Measures; Mosaicism; Mutation; Organ; Organ Donor; Paternal Age; Population; Population Database; Prostate; Reproduction; Research; Risk; Sampling; Somatic Cell; Somatic Mutation; Sperm Banks; Sperm Count Procedure; Subfertile Men; Testing; Testis; Tissue Banks; Tissue Donors; Tissues; Utah; Work; assisted reproduction; cancer risk; cohort; congenital anomaly; de novo mutation; deep sequencing; disorder risk; epidemiologic data; genetic pedigree; genome sequencing; genomic epidemiology; high risk; high risk men; human tissue; leukemia/lymphoma; men; offspring; prostate cancer risk; reproductive; sperm cell; stem cells; subfertility

PROJECT SUMMARY / ABSTRACT Male infertility impacts up to 7% of all men and has been shown to be associated with poor somatic health and elevated individual and familial cancer risk. Significant epidemiological data links male infertility to poorer somatic health compared with fertile men, manifesting as increased individual risks for prostate cancer, testis cancer, colon cancer, cardiovascular disease and reduced life span. Recent work by our group has also demonstrated that family members of infertile men are at higher risk of testis cancer and both major congenital anomalies and pediatric cancer. Specifically, much of this work found different associations in men with severe oligozoospermia (reduced sperm counts) compared with those with azoospermia, suggesting that their etiologies are fundamentally different. In a follow up study that mined age and cause of death information from the Utah Population Database (UPDB), we found that individuals with the highest quartile of age-adjusted germline mutation rates live for five fewer years than those in the lowest quartile. This project aims to study a unique population to measure mutations in the testis, mature sperm, and somatic tissue to test the hypotheses that genomic instability underlies reduced fertility, and that genome instability in one’s germline is connected to increased somatic mutation and mosaicism. We will test this through two aims. 1.) Assessment of whether subfertile men have higher germline mutation rates than fertile men by examining complex pedigree data to identify familial associations between male infertility and cancer risk and determine mutation rates in the germline and somatic cells of 20 oligozoospermic men and 20 hyperzoospermic men. 2.) We will test whether higher germline mutation rates are predictive of elevated somatic mutation rates and lower sperm counts by using cadaveric organ donor tissue from testis, sperm, prostate, blood and colon to assess mutation rates. These two aims will provide foundational datasets for the field and will be able to answer whether higher de-novo mutation rates are the mechanistic link underlying both male infertility and poor somatic health.

项目摘要 /摘要 男性不育症最多影响7％的男性，并且已被证明与躯体健康不良有关 升高的个体和家庭癌症风险。大量的流行病学数据将男性不育症与较差联系起来 与肥沃的男性相比，体细胞健康，表现为前列腺癌的个体风险增加，睾丸 癌症，结肠癌，心血管疾病和寿命降低。我们小组最近的工作也 证明不育男性的家庭成员患睾丸癌的风险较高，主要先天性 异常和小儿癌。具体而言，这项工作的大部分都发现严重的男性有不同的关联 与具有azoospermia的寡质体（精子数量减少），表明其病因 根本不同。在一项随访研究中，该研究旨在挖掘犹他州的年龄和死因信息 人口数据库（UPDB），我们发现具有年龄最高的种系的四分位数 突变率比最低四分位数的年龄少五年。该项目旨在研究独特的 测量睾丸，成熟精子和体细胞组织突变的种群，以检验假设 基因组不稳定性降低了生育能力，并且种系中的基因组不稳定性与 增加体细胞突变和镶嵌。我们将通过两个目标进行测试。 1.）评估是否 通过检查复杂的谱系数据到 确定男性不育症和癌症风险之间的家庭联系，并确定种系中的突变率 以及20个低氮杂男性和20个超化酶体男性的体细胞。 2.）我们将测试是否更高 生殖线突变率可预测升高的体细胞突变率和通过使用的精子计数降低 来自睾丸，精子，前列腺，血液和结肠的尸体器官供体组织，以评估突变率。这两个 AIMS将为该领域提供基础数据集，并能够回答更高的De-Novo突变 率是男性不育症和躯体健康不良的基础机械联系。