By comparing DNA of children to that of elderly people, a multinational team of geneticists has identified rare gene variants that influence human lifespan.

The scientists analyzed copy number variations (CNVs) – losses or gains in DNA sequence that are usually rare, but which often play an important role in raising or lowering the risk of disease.

They compared the rates of CNVs in a sample of 7,313 young subjects (18 years old and below) from the Children’s Hospital network, to a group of 2,701 Icelandic subjects (67 years old or above) recruited by the Icelandic Heart Association. They also used microchip arrays to perform the whole-genome CNV analyses.

“This research is the first genome-wide, population-based study of copy number variations in children associated with human longevity,” said Dr Hakon Hakonarson of the Children’s Hospital of Philadelphia, lead author of a paper reporting the findings in the open-access journal PLoS ONE.

“Our assumption was that CNVs appearing in children but not in the elderly were more likely to be disease-causing, while CNVs that were proportionately higher in older people were more likely to be protective, allowing them to live longer.”

After performing a replication study in an independent U.S. cohort of 2,079 children and 4,692 older people and making statistical adjustments to address population stratification, the team found seven significant CNVs. Three of the CNVs were deletions of DNA sequence, while four were duplications.

The genes impacted by the CNVs were disproportionately involved in alternative splicing. This is an important biological mechanism in which, instead of one gene simply expressing one protein, modifications to messenger RNA result in different protein products based on the same underlying DNA code in a given gene.

“Our results suggest that CNVs and other genetic variants may exert their effects through gene networks and pathways that regulate biological functions through mechanisms such as alternative splicing. Possibly in a more global way than previously thought, some of these CNVs may have favorable effects, whereas others are bad for you and predispose you to diseases,” Dr Hakonarson said.

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Bibliographic information: Glessner JT et al. 2013. Copy Number Variations in Alternative Splicing Gene Networks Impact Lifespan. PLoS ONE 8(1): e53846; doi: 10.1371/journal.pone.0053846