Similar burden of pathogenic coding variants in exceptionally long-lived individuals and individuals without exceptional longevity
| Autor: | Joris Deelen, Claudia Gonzaga-Jauregui, Patrick Sin-Chan, Tina Gao, Nir Barzilai, Gil Atzmon, A. R. Shuldiner, Danielle Gutman, Gabriel Lidzbarsky, Sofiya Milman |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Aging Offspring media_common.quotation_subject Population Longevity Biology 03 medical and health sciences 0302 clinical medicine Humans education Exome sequencing media_common Genetics Aged 80 and over education.field_of_study Genetic Variation Cell Biology Original Articles Ashkenazi jews 030104 developmental biology Case-Control Studies Cohort Mutation (genetic algorithm) Female Original Article 030217 neurology & neurosurgery Founder effect |
| Zdroj: | Aging Cell |
| Popis: | 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. The burden of disease‐causing mutation is similar among exceptionally long‐lived individuals, their offspring, and people with no familial exceptional longevity. Our results suggest the favorable longevity phenotype is an outcome of genetic buffers. |
| Databáze: | OpenAIRE |
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