Role of rare damaging mutations in aging

衰老与有害变化的持续积累、相应的功能丧失以及 与年龄有关的疾病的发展。生物体的寿命是一个复杂的特征，受遗传因素的影响， 环境和随机过程。为了定义寿命的遗传基础，人们付出了大量的努力 变种。然而，常见的遗传变异的效应大小很低，并且只对一小部分 人类寿命的变化。另一方面，人类基因组也含有极具破坏性的变异，例如 以重要基因的功能丧失变异为代表的高度有害的等位基因。这些破坏性的突变 稀有或超稀有，但它们往往有很强的效果大小。虽然这些变种通过基因分型而被遗漏， 通过外显子组测序可以很容易地检测到它们，这为量化它们在年龄相关中的作用提供了机会 疾病、死亡率和寿命，如果这些表型的信息与exome一起提供的话 序列。我们假设，罕见破坏性变异的负担会影响寿命，而且这种影响可以 被量化。这将意味着长寿的人，特别是百岁老人，平均而言会耗尽 这些突变，而中年死亡率可能与他们增加的负担有关。为了测试这一点 假设，我们提出如下建议：(1)量化罕见破坏性突变对人类的影响 死亡率和健康寿命。我们将研究更高的破坏性突变负担是否与增加相关 死亡率和与年龄有关的疾病的早期发病。为了测试这种可能性，我们将确定更长的寿命是否 与导致终止或开始密码子增减、移码和剪接的稀有变异的较低负担相关 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，决定它们对各种年龄相关疾病发病率的影响 疾病以及对健康寿命的影响，评估突变频率的影响，并确定基因和 受破坏性突变影响的通路。我们将进一步确定百岁老人和其他长寿人士 个体的破坏性突变耗尽，而更早的死亡与他们相关。(二)审查 罕见破坏性变异的负担与小鼠寿命的关系。我们将利用基因优势 已知死亡年龄的异种UM-HET3小鼠。我们将对它们的外显子进行测序，并确定 罕见的破坏性突变对寿命的影响。和人类一样，我们假设这些变种的负担 对老鼠寿命有负面影响。对人类和老鼠破坏性突变的比较分析将使我们能够 以揭示突变、基因和途径水平上的共同特征。我们将进一步描述外星人的特征 接受延长寿命的干预措施的小鼠。使用此数据集，我们将确定是否针对 突变负担为这些干预措施的观察效果提供了更好的统计支持。

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.