Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Mech Ageing Dev. 2013 Oct;134(10):478-85. doi: 10.1016/j.mad.2013.01.005. Epub 2013 Feb 1.
Despite evidence of a substantial genetic component, the genetic factors that underlie longevity in humans remain to be identified. Previous genome-wide linkage and association studies have not found strong evidence for the contribution of common variants besides the APOE gene, suggesting the role of rare variants in human longevity. To discover rare variants that might contribute to longevity, we selected 988 candidate genes and performed a pilot study to identify novel non-synonymous variants in 6 Ashkenazi Jewish centenarians older than 105. Our candidate genes act in pathways implicated in aging and longevity, including neurodegeneration, cognitive function, lipid metabolism, DNA repair, and genome maintenance. By implementing custom-designed Agilent SureSelect target capture and next-generation sequencing, we discovered a total of 89 novel non-synonymous SNPs (nsSNPs) and validated 51 nsSNPs by iPLEX MassArray assays. Genotyping analysis of these novel SNPs in 410 Ashkenazi Jewish controls and 390 centenarians showed significant enrichment (5.3 fold, p = 0.02) of the p.Y318C variant in PMS2 and significant depletion (7.5 fold, p = 0.04) of the p.V465A variant in GABRR3 in centenarians compared to controls. Our study presents the potential of targeted next-generation sequencing for discovery of rare but functional genetic variation which may lead to exceptional longevity in humans.
尽管有大量遗传因素的证据，但人类长寿的遗传因素仍有待确定。之前的全基因组连锁和关联研究除了 APOE 基因外，没有发现常见变异对长寿的贡献有很强的证据，这表明稀有变异在人类长寿中的作用。为了发现可能导致长寿的稀有变异，我们选择了 988 个候选基因，并进行了一项初步研究，以鉴定 6 名年龄超过 105 岁的阿什肯纳兹犹太百岁老人中的新非同义变异。我们的候选基因作用于与衰老和长寿相关的途径，包括神经退行性变、认知功能、脂质代谢、DNA 修复和基因组维护。通过实施定制的安捷伦 SureSelect 靶向捕获和下一代测序，我们总共发现了 89 个新的非同义 SNP（nsSNP），并通过 iPLEX MassArray 测定验证了 51 个 nsSNP。对 410 名阿什肯纳兹犹太对照者和 390 名百岁老人中的这些新 SNP 进行基因分型分析显示，PMS2 中的 p.Y318C 变异和 GABRR3 中的 p.V465A 变异在百岁老人中与对照相比显著富集（5.3 倍，p = 0.02）和显著缺失（7.5 倍，p = 0.04）。我们的研究表明，靶向下一代测序具有发现稀有但功能遗传变异的潜力，这些变异可能导致人类的非凡长寿。
