Role of rare damaging mutations in aging

罕见的破坏性突变在衰老中的作用

• 批准号: 10403519
• 负责人: Vadim N. Gladyshev
• 金额: $ 55.52万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10403519
• 关键词: Affect; Age; Aging; Alleles; Centenarian; Cessation of life; Complex; Consequentialism; Data Set; Development; Disease; Elderly; Exhibits; Frequencies; Future; Gender; Genes; Genetic; Genomics; Genotype; Genotype-Tissue Expression Project; Germ-Line Mutation; Human; Human Genome; Incidence; Individual; Initiator Codon; Intervention; Intervention Studies; Lead; Length; Life; Longevity; Methods; Mus; Mutation; Organism; Pathway interactions; Pattern; Phenotype; Proteins; RNA Splicing; Risk; Role; Sampling; Schedule; Stochastic Processes; Technology; Terminator Codon; Testing; Time; Twin Studies; Variant; Woman; age related; biobank; cohort; comparative; disorder risk; early onset; exome; exome sequencing; genetic variant; genome wide association study; healthspan; human mortality; improved; intervention effect; loss of function; men; middle age; mortality; mouse model; negative affect; programs; rare variant; trait

Aging is associated with a continuous accumulation of deleterious changes, consequential loss of function, and development of age-related diseases. The length of time organisms live is a complex trait, influenced by genetic, environmental and stochastic processes. Much effort has been placed at defining the genetic basis of lifespan variation. However, common genetic variants have low effect size and are responsible only for a fraction of human lifespan variation. On the other hand, human genomes also harbor highly damaging variants, such as highly deleterious alleles represented by loss-of-function variants in important genes. These damaging mutations are rare or ultra-rare, but they often have strong effect sizes. While these variants are missed by genotyping, they can be easily detected by exome sequencing, providing an opportunity to quantify their role in age-related diseases, mortality and longevity, if information on these phenotypes is available together with exome sequences. We hypothesize that burden of rare damaging variants influences lifespan and that this effect can be quantified. This would mean that long-lived individuals, especially centenarians, on average are depleted of these mutations, whereas mid-life mortality may be associated with their increased burden. To test this hypothesis, we propose the following: (1) Quantify the impact of burden of rare damaging mutations on human mortality and healthspan. We will examine if higher burden of damaging mutations is associated with increased mortality and an early onset of age-related diseases. To test this possibility, we will determine if longer life is associated with lower burden of rare variants that lead to stop or start codon gain/loss, frameshifting and splicing aberrations. We will apply the methods we developed in preliminary studies to larger cohorts, quantifying the role of rare mutation burden in men and women, determining their effect on the incidence of various age-related diseases as well as on healthspan, assessing the effect of mutation frequency, and identifying genes and pathways affected by damaging mutations. We will further determine if centenarians and other long-lived individuals are depleted of damaging mutations, whereas earlier mortality is associated with them. (2) Examine the association of burden of rare damaging variants with mouse lifespan. We will take advantage of genetically heterogeneous UM-HET3 mice with the known age at death. We will sequence their exomes and determine the effect of rare damaging mutations on longevity. As in humans, we hypothesize that burden of these variants negatively affects mouse lifespan. Comparative analysis of human and mouse damaging mutations will allow us to uncover common features at the level of mutations, genes and pathways. We will further characterize exomes of mice subjected to interventions that extend lifespan. Using this dataset, we will determine if adjusting for mutation burden offers a better statistical support for the observed effect of these interventions.

衰老与有害变化的持续积累、随之而来的功能丧失以及 与年龄相关的疾病的发展。生物体存活时间的长短是一个复杂的特征，受到遗传、 环境和随机过程。人们在定义寿命的遗传基础方面付出了很多努力 变化。然而，常见的遗传变异的影响较小，并且只对一小部分负责。 人类寿命的差异。另一方面，人类基因组也含有高度破坏性的变异，例如 以重要基因功能丧失变异为代表的高度有害的等位基因。这些破坏性突变 是罕见或极其罕见的，但它们通常具有很强的效应量。虽然基因分型漏掉了这些变异， 它们可以通过外显子组测序轻松检测到，从而提供了量化它们在与年龄相关的作用中的机会 疾病、死亡率和寿命（如果有关这些表型的信息与外显子组一起可用） 序列。我们假设罕见的破坏性变异的负担会影响寿命，并且这种效应可以 被量化。这意味着长寿的人，尤其是百岁老人，平均而言会耗尽 这些突变，而中年死亡率可能与其负担增加有关。为了测试这个 假设，我们提出以下建议：（1）量化罕见破坏性突变负担对人类的影响 死亡率和健康寿命。我们将检查破坏性突变的较高负担是否与增加有关 死亡率和与年龄相关的疾病的早发。为了测试这种可能性，我们将确定是否可以延长寿命 与导致终止或起始密码子增益/丢失、移码和剪接的稀有变异负担较低相关 像差。我们将把我们在初步研究中开发的方法应用于更大的队列，量化 罕见突变负担在男性和女性中的作用，确定其对各种与年龄相关的发病率的影响 疾病以及健康寿命，评估突变频率的影响，并识别基因和 受破坏性突变影响的途径。我们将进一步确定百岁老人和其他长寿者是否 个体的破坏性突变已被耗尽，而早期死亡也与之相关。 (2)检查 罕见破坏性变异的负担与小鼠寿命的关联。我们将利用基因优势 已知死亡年龄的异质 UM-HET3 小鼠。我们将对他们的外显子组进行测序并确定 罕见的破坏性突变对寿命的影响。与人类一样，我们假设这些变异的负担 对小鼠寿命产生负面影响。对人类和小鼠破坏性突变的比较分析将使我们能够 揭示突变、基因和途径水平的共同特征。我们将进一步表征外显子组 接受延长寿命干预措施的小鼠。使用此数据集，我们将确定是否进行调整 突变负担为这些干预措施观察到的效果提供了更好的统计支持。