通過廣泛比較孩子和老人的DNA,基因研究者們已經(jīng)確定了影響壽命的基因變異,包括了可以增加疾病風(fēng)險(xiǎn)的變異以及能避免疾病的變異.
這項(xiàng)新研究的領(lǐng)導(dǎo)者是費(fèi)城兒童醫(yī)院應(yīng)用基因組學(xué)中心的主管Hakon Hakonarson博士,他說：“這篇文章首次報(bào)道了一項(xiàng)與人類壽命有關(guān)的,、基因拷貝數(shù)變異的群體全基因組研究.”相關(guān)結(jié)果發(fā)表在PLOS ONE雜志上.
基因拷貝數(shù)變異(Copy number variations, CNVs)是指缺少或多出了某段DNA序列,這些序列通常是稀有的,但常常發(fā)揮重要的作用,可以提高或降低疾病的發(fā)生風(fēng)險(xiǎn).
該研究小組比較了兒童醫(yī)院資料庫中7313名年輕受試者（18歲或以下）與冰島心臟協(xié)會(huì)招募的2701冰島年老受試者（67歲或以上）的CNVs比率.研究人員利用基因芯片對(duì)他們進(jìn)行了全基因組CNV分析.
Hakonarson說：“我們的假設(shè)是,在兒童中出現(xiàn)而在老人中沒有出現(xiàn)的CNVs更可能是致病的,而那些在老年人中成比例提高的CNVs很可能具有保護(hù)作用,可以使他們活得更久.”
同時(shí),該研究小組還在美國(guó)進(jìn)行了一個(gè)平行的研究,受試者為2079名兒童和4692名老人,并利用了統(tǒng)計(jì)調(diào)整來解決人口分層.最終,他們發(fā)現(xiàn)了7個(gè)重要的CNVs,其中3個(gè)是缺失DNA序列的,而另外4個(gè)是加倍的.
CNVs影響的基因大部分都存在可變剪接.可變剪接是一個(gè)重要的生物學(xué)機(jī)制,不同于一個(gè)基因簡(jiǎn)單地表達(dá)一種蛋白質(zhì),mRNA的變型導(dǎo)致產(chǎn)生了基于同一DNA密碼的不同蛋白質(zhì)產(chǎn)物.
“我們的結(jié)果暗示,CNVs和其它的基因突變體可能通過調(diào)控生物學(xué)功能的基因網(wǎng)絡(luò)和信號(hào)通路來發(fā)揮它們的影響,例如通過可變剪接機(jī)制.”Hakonarson說,“這種方式的作用或許比之前認(rèn)為的更加廣泛,這些CNVs中的一些可能發(fā)揮了有利的作用,而另一些可能對(duì)你是有害的,讓你更容易生病.”
Hakonarson補(bǔ)充到,盡管我們還有許多工作要做,但是就目前的情況來看,在兒童中過多的CNVs或許代表了能預(yù)測(cè)短壽命的新靶標(biāo).如果這種CNVs檢測(cè)納入早期臨床篩查,那么它們的存在就可成為預(yù)后的標(biāo)志物,指示哪些患者應(yīng)該進(jìn)行個(gè)性化的預(yù)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.
