The Dynamics of Somatic Mutagenesis During Life in Humans

Abstract

From conception to death, human cells accumulate somatic mutations in their genomes. These mutations can contribute to the development of cancer and non-malignant diseases and have also been associated with aging. Rapid technological developments in sequencing approaches in the last few years and their application to normal tissues have greatly advanced our knowledge about the accumulation of these mutations during healthy aging. Whole genome sequencing studies have revealed that there are significant differences in mutation burden and patterns across tissues, but also that the mutation rates within tissues are surprisingly constant during adult life. In contrast, recent lineage-tracing studies based on whole-genome sequencing have shown that the rate of mutation accumulation is strongly increased early in life before birth. These early mutations, which can be shared by many cells in the body, may have a large impact on development and the origin of somatic diseases. For example, cancer driver mutations can arise early in life, decades before the detection of the malignancy. Here, we review the recent insights in mutation accumulation and mutagenic processes in normal tissues. We compare mutagenesis early and later in life and discuss how mutation rates and patterns evolve during aging. Additionally, we outline the potential impact of these mutations on development, aging and disease.

Individual Genetic Heterogeneity

“…Human somatic mutation rates vary for different types of cells. Germline cells have the lowest rates, while kidney tubules and appendiceal crypts have tens of times higher rate [ 96 ]. It has been estimated that at the age of over 60, for example, human intestinal epithelial cells that divide in every week or two have generated a variation in every position in the genome [ 92 ].…”

“…Human body consists on average of about 3.72 × 10 13 cells [ 123 ], which are the outcome of about 10 16 mitoses [ 124 ]. The accumulation of somatic variants has been assumed to be constant during life [ 96 ]. Most of these variants do not have effect or major phenotype, as they are just normal genetic variation and thus tolerated.…”

Individual Genetic Heterogeneity

“…Human somatic mutation rates vary for different types of cells. Germline cells have the lowest rates, while kidney tubules and appendiceal crypts have tens of times higher rate (Manders et al, 2021). It has been estimated that at the age of over 60, for example human intestinal epithelial cells that divide in every week or two, have generated a variation in every position in the genome (Lynch, 2010).…”

“…Human body consists on average of about 3.72 x 10 13 cells (Bianconi et al, 2013), which are the outcome of about 10 16 mitoses (Iourov et al, 2010). The accumulation of somatic variants has been assumed to be constant during life (Manders et al, 2021). Most of these variants do not have effect or major phenotype, they are just normal genetic variation and thus tolerated.…”

“…As discussed above, somatic mutation rate is substantially higher than germline rate, varying according to cell type. The rate in kidney tubules and appendiceal crypts is about 50 times higher than in sperms and oocytes (Manders et al, 2021). Despite the high-fidelity of DNA replication and DNA repair mechanisms, some new variants are introduced in every cell generation.…”