Twin Research and Human Genetics

Articles

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

Kai Yea1, Marian Beekmana1a2, Eric-Wubbo Lameijera1, Yanju Zhanga1, Matthijs H. Moeda1, Erik B. van den Akkera1a3, Joris Deelena1a2, Jeanine J. Houwing-Duistermaata4, Dennis Kremera1, Seyed Yahya Anvara5, Jeroen F. J. Larosa5, David Jonesa6, Keiran Rainea6, Ben Blackburnea7, Shobha Potluria8, Quan Longa9, Victor Guryeva10, Ruud van der Breggena1, Rudi G. J. Westendorpa11, Peter A. C. ‘t Hoena12, Johan den Dunnena12, Gert Jan B. van Ommena12, Gonneke Willemsena13, Steven J. Pittsa8, David R. Coxa8, Zemin Ninga6, Dorret I. Boomsmaa13 * and P. Eline Slagbooma1a2 c1 *

a1 Molecular Epidemiology, Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, the Netherlands

a2 Netherlands Consortium for Healthy Ageing, Leiden, the Netherlands

a3 The Delft Bioinformatics Lab, Delft University of Technology, Delft, the Netherlands

a4 Statistical Genetics, Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, the Netherlands

a5 Center for Human and Clinical Genetics and Leiden Genome Technology Center, Leiden University Medical Center, Leiden, the Netherlands

a6 The Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK

a7 Faculty of Life Sciences, University of Manchester, Manchester, UK

a8 Pfizer Inc., San Francisco, CA, USA

a9 Gregor Mendel Institute, Vienna, Austria

a10 Hubrecht Institute, Utrecht, the Netherlands

a11 Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands

a12 Human Genetics, Leiden University Medical Center, Leiden, the Netherlands

a13 Department of Biological Psychology, VU University, Amsterdam, the Netherlands

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.

(Received August 23 2013)

(Accepted September 17 2013)

(Online publication November 04 2013)

Keywords:

  • aging;
  • next gen sequencing;
  • somatic mutations;
  • twin discordances;
  • human genome

Correspondence

c1 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

Footnotes

*  Both are equal last authors.

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