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.

CNV Concordance in 1,097 MZ Twin Pairs

“…with age, as (1) blood-derived samples were predominantly adult as opposed to buccal-derived samples, (2) carriers of putative de novo CNVs from both blood and buccal epithelium showed a higher average age than the rest of the samples from the same tissue (although non-significant), and (3) previous studies have shown that de novo mutations increase with age (Forsberg et al, 2012, Kong et al, 2012, Ye et al, 2013.…”

The Three Genetics (Nuclear DNA, Mitochondrial DNA, and Gut Microbiome) of Longevity in Humans Considered as Metaorganisms

“…The advent of next-generation sequencing (NGS) has renewed interest and hopes of the researchers in the study of the genetics of longevity, as this technology allows a previously unattainable systematic discovery of low frequency variants in thousands of samples. In the context of longevity, NGS has been applied to assess whether ageing is accompanied by an accelerated accumulation of somatic DNA mutations that affects the primary structure of proteins, ultimately compromising organismal functions [38]. Ye et al performed whole genome sequencing of two pairs of monozygotic twins aged 40 and 100 years old, by using two independent NGS platforms and validating potentially discordant single-base substitutions by Sanger, Roche 454, and Ion Torrent sequencing.…”

Epigenetic Variation in Monozygotic Twins: A Genome-Wide Analysis of DNA Methylation in Buccal Cells

“…Because MZ twins derive from a single zygote and, therefore, have (nearly) identical DNA sequences (see, for example, Ye et al , 2013 [20]), the comparison of DNA methylation patterns of MZ twins allows one to examine the extent to which differences in methylation between human individuals are related to environmental and stochastic events. Previous studies have highlighted that various tissues of MZ twins already show differences in DNA methylation at birth [21,22] and that differences between twins for average genome-wide DNA methylation, total histone acetylation levels and methylation at certain loci increase with age (referred to as “epigenetic drift”) [23].…”