Similar burden of pathogenic coding variants in exceptionally long-lived individuals and individuals without exceptional longevity.,Aging Cell

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Similar burden of pathogenic coding variants in exceptionally long-lived individuals and individuals without exceptional longevity.
Aging Cell ( IF 8.0 ) Pub Date : 2020-08-29 , DOI: 10.1111/acel.13216
Danielle Gutman ₁ , Gabriel Lidzbarsky ₁ , Sofiya Milman ₂ , Tina Gao ₂ , Patrick Sin-Chan ₃ , Claudia Gonzaga-Jauregui ₃ , ₃ , Joris Deelen _{4,

5} , Alan R Shuldiner ₃ , Nir Barzilai _{2,

6} , Gil Atzmon _{1,

2,

6}

Affiliation

Centenarians (exceptionally long‐lived individuals—ELLI) are a unique segment of the population, exhibiting long human lifespan and healthspan, despite generally practicing similar lifestyle habits as their peers. We tested disease‐associated mutation burden in ELLI genomes by determining the burden of pathogenic variants reported in the ClinVar and HGMD databases using data from whole exome sequencing (WES) conducted in a cohort of ELLI, their offspring, and control individuals without antecedents of familial longevity (n = 1879), all descendent from the founder population of Ashkenazi Jews. The burden of pathogenic variants did not differ between the three groups. Additional analyses of variants subtypes and variant effect predictor (VEP) biotype frequencies did not reveal a decrease of pathogenic or loss‐of‐function (LoF) variants in ELLI and offspring compared to the control group. Case–control pathogenic variants enrichment analyses conducted in ELLI and controls also did not identify significant differences in any of the variants between the groups and polygenic risk scores failed to provide a predictive model. Interestingly, cancer and Alzheimer's disease‐associated variants were significantly depleted in ELLI compared to controls, suggesting slower accumulation of mutation. That said, polygenic risk score analysis failed to find any predictive variants among the functional variants tested. The high similarity in the burden of pathogenic variation between ELLI and individuals without familial longevity supports the notion that extension of lifespan and healthspan in ELLI is not a consequence of pathogenic variant depletion but rather a result of other genomic, epigenomic, or potentially nongenomic properties.

中文翻译：

在特别长寿的个体和没有特别长寿的个体中，致病性编码变异的负担类似。

百岁老人（特别长寿的人——ELLI）是人口中的一个独特部分，尽管他们的生活习惯通常与同龄人相似，但他们的寿命和健康寿命都很长。我们使用全外显子组测序 (WES) 的数据，确定 ClinVar 和 HGMD 数据库中报告的致病变异负担，测试了 ELLI 基因组中与疾病相关的突变负担，这些数据是在 ELLI、他们的后代和没有家族先例的对照个体中进行的。长寿 ( n = 1879），都是德系犹太人的始祖后裔。三组之间的致病变异负担没有差异。与对照组相比，对变异亚型和变异效应预测因子 (VEP) 生物型频率的额外分析并未显示 ELLI 和后代的致病性或功能丧失 (LoF) 变异减少。在 ELLI 和对照中进行的病例对照致病变异富集分析也未发现组间任何变异的显着差异，并且多基因风险评分未能提供预测模型。有趣的是，与对照相比，ELLI 中癌症和阿尔茨海默病相关的变异显着减少，表明突变的积累较慢。那说，多基因风险评分分析未能在测试的功能变异中发现任何预测变异。ELLI 和没有家族寿命的个体之间致病变异负担的高度相似性支持这样一种观点，即 ELLI 的寿命和健康寿命的延长不是致病性变异耗尽的结果，而是其他基因组、表观基因组或潜在的非基因组特性的结果。

更新日期：2020-10-23

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