Role of rare damaging mutations in aging

衰老伴随着有害变化的持续积累，随之而来的功能丧失， 与年龄有关的疾病的发展。生物体生存时间的长短是一个复杂的特征，受遗传， 环境和随机过程。许多努力都放在定义寿命的遗传基础 变化量然而，常见的遗传变异具有较低的效应大小，并且仅对一小部分基因突变负责。 人类寿命的变化。另一方面，人类基因组也含有高度破坏性的变异，如 高度有害的等位基因，由重要基因中的功能丧失变体代表。这些破坏性的突变 是罕见或超罕见的，但它们通常具有很强的效应量。虽然这些变异被基因分型遗漏， 它们可以很容易地通过外显子组测序检测，提供了一个机会来量化它们在年龄相关的 疾病，死亡率和寿命，如果这些表型的信息与外显子组一起可用， 序列的我们假设，罕见的破坏性变异的负担影响寿命，这种影响可以 要量化。这意味着长寿的人，特别是百岁老人，平均来说， 这些突变，而中年死亡率可能与他们的负担增加有关。为了验证这一 假设，我们提出了以下建议：（1）量化的负担，罕见的破坏性突变对人类的影响 死亡率和健康寿命。我们将研究是否更高的破坏性突变负担与增加的 死亡率和与年龄有关的疾病的早发。为了测试这种可能性，我们将确定更长的寿命是否 与导致终止或起始密码子获得/丢失、移码和剪接的罕见变异的负担较低相关 畸变我们将把我们在初步研究中开发的方法应用到更大的队列中， 罕见突变负荷在男性和女性中的作用，确定其对各种年龄相关疾病发生率的影响。 疾病以及对健康的影响，评估突变频率的影响，并确定基因和 受到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的人 个体的破坏性突变被耗尽，而早期死亡与它们有关。(2)审查 罕见的破坏性变异的负担与小鼠寿命的关联。我们将从基因上 具有已知死亡年龄的异质UM-HET 3小鼠。我们将对它们的外显子组进行测序， 罕见的破坏性突变对寿命的影响。在人类中，我们假设这些变异的负担 对小鼠寿命有负面影响。对人类和小鼠的破坏性突变进行比较分析， 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显子组 对老鼠进行干预以延长寿命。使用此数据集，我们将确定是否调整 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.