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: 10290013
• 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/10290013
• 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.

项目总结/摘要 男性不育症影响高达7%的男性，并已被证明与身体健康状况差有关， 个人和家族癌症风险增加。重要的流行病学数据将男性不育症与贫穷 与有生育能力的男性相比，身体健康，表现为前列腺癌、睾丸癌和前列腺癌的个体风险增加。 癌症、结肠癌、心血管疾病和寿命缩短。我们小组最近的工作也 研究表明，不育男性的家庭成员患睾丸癌的风险较高， 畸形和儿童癌症具体来说，这项工作的大部分发现，在男性严重 与无精子症患者相比，少精子症（精子计数减少），这表明他们的病因 是完全不同的在一项追踪研究中，从犹他州挖掘了年龄和死亡原因的信息， 人口数据库（CIMB），我们发现，具有最高四分位数的年龄调整生殖系的个体， 突变率比最低四分位数的人少活五年。该项目旨在研究一种独特的 群体来测量睾丸、成熟精子和体细胞组织中的突变，以检验以下假设： 基因组的不稳定性是生育能力降低的基础，而一个人的生殖系中的基因组不稳定性与以下因素有关： 增加体细胞突变和嵌合现象。我们将通过两个目标来检验这一点。1.）的人。评估是否 通过检查复杂的家系数据， 确定男性不育和癌症风险之间的家族联系，并确定生殖系中的突变率 20例少精子症和20例多精子症患者的体细胞。2.）的情况。我们将测试是否更高 生殖细胞突变率可以预测体细胞突变率的升高和精子数量的降低， 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 aims将为该领域提供基础数据集，并将能够回答更高的从头突变是否 生育率是造成男性不育和身体健康不良的机械联系。