Abstract：
The aging process, or senescence, is characterized by age-specific decline in physical and physiological function, and increased frailty and genomic changes, including mutation accumulation. However, the mechanisms through which changes in genomic architecture influence human longevity have remained obscure. Copy number variants (CNVs), an abundant class of genomic variants, offer unique opportunities for understanding age-related genomic changes. Here we report the spectrum of CNVs in a cohort of 670 Ashkenazi Jewish centenarians, their progeny, and unrelated controls. The average ages of these groups were 97.4 ± 2.8, 69.2 ± 9.2, and 66.5 ± 7.0 respectively. For the first time, we compared different size classes of CNVs, from 1 kB to 100 MB in size. Using a high-resolution custom Affymetrix array, targeting 44,639 genomic regions, we identified a total of 12,166, 22,188, and 10,285 CNVs in centenarians, their progeny, and control groups, respectively. Interestingly, the offspring group showed the highest number of unique CNVs, followed by control and centenarians. While both gains and losses were found in all three groups, centenarians showed a significantly higher average number of both total gains and losses relative to their controls (p < 0.0327, 0.0182, respectively). Moreover, centenarians showed a lower total length of genomic material lost, suggesting that they may maintain superior genomic integrity over time. We also observe a significance fold increase of CNVs among the offspring, implying greater genomic integrity and a putative mechanism for longevity preservation. Genomic regions that experienced loss or gains appear to be distributed across many sites in the genome and contain genes involved in DNA transcription, cellular transport, developmental pathways, and metabolic functions. Our findings suggest that the exceptional longevity observed in centenarians may be attributed to the prolonged maintenance of functionally important genes. These genes are intrinsic to specific genomic regions as well as to the overall integrity of the genomic architecture. Additionally, a strong association between longer CNVs and differential gene expression observed in this study supports the notion that genomic integrity could positively influence longevity.
摘要：
老化的过程，或者衰老，其特征是身体和生理功能的特定年龄下降，增加了脆弱和基因组的变化，包括突变积累。然而,基因组结构变化影响人类寿命的机制仍然不清楚。拷贝数变体（CNVs），丰富的基因组变异，为理解与年龄相关的基因组变化提供了独特的机会。在这里，我们报告了670名Ashkenazi犹太百岁老人的CNV光谱，他们的后代，和无关的控制。这些组的平均年龄分别为97.4±2.8、69.2±9.2和66.5±7.0。第一次,我们比较了不同大小的CNVs，大小从1kB到100MB。使用高分辨率的自定义Affymetrix阵列，靶向44,639个基因组区域，我们在百岁老人中确定了总共12,166,22,188和10,285CNV，他们的后代，和对照组，分别。有趣的是,后代群体显示出最高数量的独特CNV，其次是控制和百岁老人。虽然在所有三组中都发现了收益和损失，与对照组相比，百岁老人的总得失平均数明显更高（分别为p<0.0327，0.0182）。此外，百岁老人显示基因组材料丢失的总长度较低，表明它们可能随着时间的推移保持优越的基因组完整性。我们还观察到后代中CNVs的显著倍数增加，意味着更大的基因组完整性和推定的长寿保护机制。经历损失或增加的基因组区域似乎分布在基因组中的许多位点，并包含参与DNA转录的基因。细胞运输，发育途径,和代谢功能。我们的发现表明，在百岁老人中观察到的非凡寿命可能归因于功能重要基因的长期维持。这些基因对于特定基因组区域以及基因组结构的整体完整性是固有的。此外,本研究中观察到的较长CNVs与差异基因表达之间的强关联支持了基因组完整性可以积极影响寿命的观点.
