通过广泛比较孩子和老人的DNA,基因研究者们已经确定了影响寿命的基因变异,包括了可以增加疾病风险的变异以及能避免疾病的变异.
这项新研究的领导者是费城儿童医院应用基因组学中心的主管Hakon Hakonarson博士,他说:“这篇文章首次报道了一项与人类寿命有关的、基因拷贝数变异的群体全基因组研究.”相关结果发表在PLOS ONE杂志上.
基因拷贝数变异(Copy number variations, CNVs)是指缺少或多出了某段DNA序列,这些序列通常是稀有的,但常常发挥重要的作用,可以提高或降低疾病的发生风险.
该研究小组比较了儿童医院资料库中7313名年轻受试者(18岁或以下)与冰岛心脏协会招募的2701冰岛年老受试者(67岁或以上)的CNVs比率.研究人员利用基因芯片对他们进行了全基因组CNV分析.
Hakonarson说:“我们的假设是,在儿童中出现而在老人中没有出现的CNVs更可能是致病的,而那些在老年人中成比例提高的CNVs很可能具有保护作用,可以使他们活得更久.”
同时,该研究小组还在美国进行了一个平行的研究,受试者为2079名儿童和4692名老人,并利用了统计调整来解决人口分层.最终,他们发现了7个重要的CNVs,其中3个是缺失DNA序列的,而另外4个是加倍的.
CNVs影响的基因大部分都存在可变剪接.可变剪接是一个重要的生物学机制,不同于一个基因简单地表达一种蛋白质,mRNA的变型导致产生了基于同一DNA密码的不同蛋白质产物.
“我们的结果暗示,CNVs和其它的基因突变体可能通过调控生物学功能的基因网络和信号通路来发挥它们的影响,例如通过可变剪接机制.”Hakonarson说,“这种方式的作用或许比之前认为的更加广泛,这些CNVs中的一些可能发挥了有利的作用,而另一些可能对你是有害的,让你更容易生病.”
Hakonarson补充到,尽管我们还有许多工作要做,但是就目前的情况来看,在儿童中过多的CNVs或许代表了能预测短寿命的新靶标.如果这种CNVs检测纳入早期临床筛查,那么它们的存在就可成为预后的标志物,指示哪些患者应该进行个性化的预防性健康措施.(生物谷Bioon.com)
doi: 10.1371/journal.pone.0053846
PMC:
PMID
Copy Number Variations in Alternative Splicing Gene Networks Impact Lifespan Joseph T. Glessner
Albert Vernon Smith,Saarene Panossian,Cecilia E. Kim,Nagahide Takahashi,Kelly A. Thomas,Fengxiang Wang,Kallyn Seidler,Tamara B. Harris,Lenore J. Launer,Brendan Keating,John Connolly,Patrick M. A. Sleiman,Joseph D. Buxbaum,Struan F. A. Grant,Vilmundur Gudnason,Hakon Hakonarson
Longevity has a strong genetic component evidenced by family-based studies. Lipoprotein metabolism, FOXO proteins, and insulin/IGF-1 signaling pathways in model systems have shown polygenic variations predisposing to shorter lifespan. To test the hypothesis that rare variants could influence lifespan, we compared the rates of CNVs in healthy children (0–18 years of age) with individuals 67 years or older. CNVs at a significantly higher frequency in the pediatric cohort were considered risk variants impacting lifespan, while those enriched in the geriatric cohort were considered longevity protective variants. We performed a whole-genome CNV analysis on 7,313 children and 2,701 adults of European ancestry genotyped with 302,108 SNP probes. Positive findings were evaluated in an independent cohort of 2,079 pediatric and 4,692 geriatric subjects. We detected 8 deletions and 10 duplications that were enriched in the pediatric group (P = 3.33×10?8–1.6×10?2 unadjusted), while only one duplication was enriched in the geriatric cohort (P = 6.3×10?4). Population stratification correction resulted in 5 deletions and 3 duplications remaining significant (P = 5.16×10?5–4.26×10?2) in the replication cohort. Three deletions and four duplications were significant combined (combined P = 3.7×10?4?3.9×10?2). All associated loci were experimentally validated using qPCR. Evaluation of these genes for pathway enrichment demonstrated ~50% are involved in alternative splicing (P = 0.0077 Benjamini and Hochberg corrected). We conclude that genetic variations disrupting RNA splicing could have long-term biological effects impacting lifespan.