title: Aging as accelerated accumulation of somatic variants: whole-genome sequencing of centenarian and middle-aged monozygotic twin pairs.
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.
authors.affiliation: Molecular Epidemiology, Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Kai
authors.initials: K
authors.lastname: Ye
authors.forename: Marian
authors.initials: M
authors.lastname: Beekman
authors.forename: Eric-Wubbo
authors.initials: EW
authors.lastname: Lameijer
authors.forename: Yanju
authors.initials: Y
authors.lastname: Zhang
authors.forename: Matthijs H
authors.initials: MH
authors.lastname: Moed
authors.forename: Erik B
authors.initials: EB
authors.lastname: van den Akker
authors.forename: Joris
authors.initials: J
authors.lastname: Deelen
authors.forename: Jeanine J
authors.initials: JJ
authors.lastname: Houwing-Duistermaat
authors.forename: Dennis
authors.initials: D
authors.lastname: Kremer
authors.forename: Seyed Yahya
authors.initials: SY
authors.lastname: Anvar
authors.forename: Jeroen F J
authors.initials: JF
authors.lastname: Laros
authors.forename: David
authors.initials: D
authors.lastname: Jones
authors.forename: Keiran
authors.initials: K
authors.lastname: Raine
authors.forename: Ben
authors.initials: B
authors.lastname: Blackburne
authors.forename: Shobha
authors.initials: S
authors.lastname: Potluri
authors.forename: Quan
authors.initials: Q
authors.lastname: Long
authors.forename: Victor
authors.initials: V
authors.lastname: Guryev
authors.forename: Ruud
authors.initials: R
authors.lastname: van der Breggen
authors.forename: Rudi G J
authors.initials: RG
authors.lastname: Westendorp
authors.forename: Peter A C
authors.initials: PA
authors.lastname: 't Hoen
authors.forename: Johan
authors.initials: J
authors.lastname: den Dunnen
authors.forename: Gert Jan B
authors.initials: GJ
authors.lastname: van Ommen
authors.forename: Gonneke
authors.initials: G
authors.lastname: Willemsen
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Pitts
authors.forename: David R
authors.initials: DR
authors.lastname: Cox
authors.forename: Zemin
authors.initials: Z
authors.lastname: Ning
authors.forename: Dorret I
authors.initials: DI
authors.lastname: Boomsma
authors.forename: P Eline
authors.initials: PE
authors.lastname: Slagboom
mesh_terms: D000328:Adult; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics*; D001773:Blood Cells / Q000502:physiology*; D005260:Female; D015894:Genome, Human; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D014430:Twins, Monozygotic / Q000235:genetics*