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Aging as Accelerated Accumulation of Somatic Variants: Whole-Genome Sequencing of Centenarian and Middle-Aged Monozygotic Twin Pairs

  • Kai Ye (a1), Marian Beekman (a1) (a2), Eric-Wubbo Lameijer (a1), Yanju Zhang (a1), Matthijs H. Moed (a1), Erik B. van den Akker (a1) (a3), Joris Deelen (a1) (a2), Jeanine J. Houwing-Duistermaat (a4), Dennis Kremer (a1), Seyed Yahya Anvar (a5), Jeroen F. J. Laros (a5), David Jones (a6), Keiran Raine (a6), Ben Blackburne (a7), Shobha Potluri (a8), Quan Long (a9), Victor Guryev (a10), Ruud van der Breggen (a1), Rudi G. J. Westendorp (a11), Peter A. C. ‘t Hoen (a12), Johan den Dunnen (a12), Gert Jan B. van Ommen (a12), Gonneke Willemsen (a13), Steven J. Pitts (a8), David R. Cox (a8), Zemin Ning (a6), Dorret I. Boomsma (a13) and P. Eline Slagboom (a1) (a2)...
Abstract

It has been postulated that aging is the consequence of an accelerated accumulation of somatic DNA mutations and that subsequent errors in the primary structure of proteins ultimately reach levels sufficient to affect organismal functions. The technical limitations of detecting somatic changes and the lack of insight about the minimum level of erroneous proteins to cause an error catastrophe hampered any firm conclusions on these theories. In this study, we sequenced the whole genome of DNA in whole blood of two pairs of monozygotic (MZ) twins, 40 and 100 years old, by two independent next-generation sequencing (NGS) platforms (Illumina and Complete Genomics). Potentially discordant single-base substitutions supported by both platforms were validated extensively by Sanger, Roche 454, and Ion Torrent sequencing. We demonstrate that the genomes of the two twin pairs are germ-line identical between co-twins, and that the genomes of the 100-year-old MZ twins are discerned by eight confirmed somatic single-base substitutions, five of which are within introns. Putative somatic variation between the 40-year-old twins was not confirmed in the validation phase. We conclude from this systematic effort that by using two independent NGS platforms, somatic single nucleotide substitutions can be detected, and that a century of life did not result in a large number of detectable somatic mutations in blood. The low number of somatic variants observed by using two NGS platforms might provide a framework for detecting disease-related somatic variants in phenotypically discordant MZ twins.

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Corresponding author
address for correspondence: Eline Slagboom, Molecular Epidemiology, Medical Statistics and Bioinformatics, Leiden University Medical Center, 2333 ZC, Leiden, the Netherlands. E-mail: P.Slagboom@lumc.nl
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