Human Genetic Variation and Disease

人类遗传变异与疾病

• 批准号: 10431948
• 负责人: Lynn Jorde
• 金额: $ 58.3万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-22 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10431948
• 关键词: Adult; Age; Amyotrophic Lateral Sclerosis; Blood; Blood specimen; Chronic Childhood Arthritis; Collection; DNA; DNA Insertion Elements; DNA Repair; DNA Repair Gene; Data; Detection; Disease; Event; Family; Funding; Generations; Genes; Genetic Diseases; Genetic Variation; Genome; Germ-Line Mutation; Human; Human Genetics; In Vitro; Longevity; Longitudinal Studies; Measurement; Measures; Methods; Mosaicism; Mutation; Participant; Pattern; Phenotype; Population Database; Premature Menopause; RNA Sequences; Resources; Sampling; Sequence Analysis; Somatic Mutation; System; Testing; Time; Utah; Variant; Whole Blood; Work; analytical tool; de novo mutation; genetic information; genetic pedigree; improved; in vivo; member; public repository; transcriptome sequencing; transmission process; whole genome

In this renewal, we will continue our studies of the causes and disease consequences of human genetic variation. We have generated whole-genome sequence (WGS) data from the three-generation Utah CEPH pedigrees to longitudinally characterize rates and patterns of de novo mutations (DNMs). We showed significant differences in the rates of accumulation of mutations among families, and we demonstrated that 10% of apparent DNMs are actually postzygotic events that result in mosaicism. We also showed that a higher rate of age-adjusted germline DNM transmission is significantly associated with a shorter lifespan and earlier menopause. These results imply that one’s germline DNM rate, which increases with age, is associated with the somatic mutation rate. In the next funding period, we will test this hypothesis directly using blood-derived DNA samples collected at three different time points in the same CEPH pedigree members over a 35-year time period. To our knowledge, this is the first long-term longitudinal study of germline and somatic mutation rates in human pedigrees. We also hypothesize that DNA repair mechanisms influence variation in both germline and somatic mutation rates. We will test this hypothesis using whole-genome sequence data (supported by separate funding) and RNA-seq data from freshly collected whole blood samples. We predict that lower expression of critical DNA repair genes will result in higher germline and somatic mutation rates. To increase our power to detect patterns and disease associations, we will (under separate funding) expand the CEPH pedigree collection to include more than 700 members of the fourth generation, who are now adults. We will also resample generations 2 and 3 for a third time. We will undertake WGS and RNA-seq in these study participants, creating a unique, publicly available repository of genetic information spanning four generations. More than 180 phenotypic measurements were made for generations 2 and 3 of the CEPH pedigrees 20 years ago, and the same measurements will be made for generation 4. These resources will allow us to explore the effects of genetic variation, including mutation rates and DNA repair, on a broad assortment of phenotypes across several generations. In addition, we will continue our work to develop new and improved methods for genome sequence analysis, including the detection of mobile element insertions. We will analyze WGS and RNA-seq data from members of large Utah disease pedigrees obtained from the Utah Population Database, focusing on amyotrophic lateral sclerosis and juvenile idiopathic arthritis. These projects involve analysis of WGS and RNA-seq data as well as functional analysis in in vitro and in vivo systems.

在本次更新中，我们将继续研究人类疾病的原因和后果 我们已经生成了三代人的全基因组序列（WGS）数据。 犹他州 CEPH 谱系纵向描述新生突变 (DNM) 的速率和模式。 家庭之间突变积累率存在显着差异，我们 我们证明，10% 的明显 DNM 实际上是导致嵌合体的合子后事件。 还表明，较高的年龄调整种系 DNM 传播率与 更短的寿命和更早的绝经意味着一个人的生殖细胞 DNM 率。 随着年龄的增长，与体细胞突变率有关，我们将在下一个资助期内进行测试。 该假设直接使用在三个不同时间点收集的血液 DNA 样本 据我们所知，这是第一个长期的CEPH血统成员。 我们还对人类谱系中种系和体细胞突变率进行了纵向研究。 DNA 修复机制影响种系和体细胞突变率的变化。 该假设使用全基因组序列数据（由单独资助支持）和 RNA-seq 数据 我们预测，从新鲜采集的全血样本中，关键 DNA 修复的表达会降低。 基因将导致更高的种系和体细胞突变率。 为了增强我们检测模式和疾病关联的能力，我们将（根据单独的 资金）扩大 CEPH 谱系收藏，包括第四届的 700 多名成员 我们还将对第 2 代和第 3 代进行第三次重新采样。 对这些研究参与者进行 WGS 和 RNA-seq，创建一个独特的、公开可用的存储库 跨越四代的遗传信息进行了 180 多次表型测量。 对 20 年前的第 2 代和第 3 代 CEPH 谱系进行相同的测量 第四代。这些资源将使我们能够探索遗传变异的影响，包括突变 率和 DNA 修复，在几代人的各种表型上。 此外，我们将继续努力开发新的和改进的基因组方法 序列分析，包括移动元素插入的检测我们将分析 WGS 和 来自犹他州人口的大型犹他州疾病谱系成员的 RNA-seq 数据 数据库，重点关注肌萎缩侧索硬化症和幼年特发性关节炎这些项目。 涉及 WGS 和 RNA-seq 数据分析以及体外和体内系统的功能分析。