Age-Related Somatic Structural Changes in the Nuclear Genome of Human Blood Cells

Abstract

Structural variations are among the most frequent interindividual genetic differences in the human genome. The frequency and distribution of de novo somatic structural variants in normal cells is, however, poorly explored. Using age-stratified cohorts of 318 monozygotic (MZ) twins and 296 single-born subjects, we describe age-related accumulation of copy-number variation in the nuclear genomes in vivo and frequency changes for both megabase- and kilobase-range variants. Megabase-range aberrations were found in 3.4% (9 of 264) of subjects ≥60 years old; these subjects included 78 MZ twin pairs and 108 single-born individuals. No such findings were observed in 81 MZ pairs or 180 single-born subjects who were ≤55 years old. Recurrent region- and gene-specific mutations, mostly deletions, were observed. Longitudinal analyses of 43 subjects whose data were collected 7-19 years apart suggest considerable variation in the rate of accumulation of clones carrying structural changes. Furthermore, the longitudinal analysis of individuals with structural aberrations suggests that there is a natural self-removal of aberrant cell clones from peripheral blood. In three healthy subjects, we detected somatic aberrations characteristic of patients with myelodysplastic syndrome. The recurrent rearrangements uncovered here are candidates for common age-related defects in human blood cells. We anticipate that extension of these results will allow determination of the genetic age of different somatic-cell lineages and estimation of possible individual differences between genetic and chronological age. Our work might also help to explain the cause of an age-related reduction in the number of cell clones in the blood; such a reduction is one of the hallmarks of immunosenescence.

Detection of leukemia-associated mutations in peripheral blood DNA of hematologically normal elderly individuals

“…Analysis of intensity data tracks from single nucleotide polymorphism (SNP) array analysis of peripheral blood DNA from older individuals (typically >60 years) in population cohorts has revealed large somatically-acquired chromosomal duplications, deletions and regions of acquired uniparental disomy (aUPD; also known as copy number neutral loss of heterozygosity) similar to those seen in individuals with a hematological malignancy [1][2][3][4] . Such variants are typically present in a proportion of peripheral blood cells at a specific time-point but their frequency can increase or decrease over time and even disappear, suggesting a dynamic pattern of clonal change 1 . Consistent with this data, mutations in genes that are often mutated in myeloid malignancy such as TET2, DNMT3A, ASXL1 and JAK2 have also been described in elderly individuals with no evidence of hematological malignancy [5][6][7][8] .…”

“…To investigate the presence of mutations in elderly populations further, we studied two independent cohorts, (i) the Uppsala Longitudinal Study of Adult Men (ULSAM), an ongoing epidemiologic study of all available men born between 1920-24 in Uppsala County, Sweden that have been analyzed by SNP arrays 1,4 and (ii) 56 elderly women with normal blood counts and paired DNA from both neutrophils and T cells 10 .…”

“…We have previously reported SNP array data showing that ULSAM-697 had readily apparent chromosome 4q aUPD in nucleated blood cells at the ages of 82, 88 and 90 but not at the age of 71. 1 Reinspection of the array data indicated that chromosome 4q aUPD was just visible at the age of 71, at a level of <10% nucleated cells. Overall, these data indicate that this individual thus had a large heterozygous mutant TET2 clone at the age of 71 but by the age of 82 a prominent homozygous mutant TET2 subclone had emerged.…”

“…1 Although it is difficult to accurately quantify deletions directly from sequence data, visual inspection of the mutant electropherograms suggests that the TET2 mutation level rose and fell in line with the changing aUPD (Figure 1). Cell fractionation studies at the age of 90…”

CIN and Aneuploidy: Different Concepts, Different Consequences

“…[103] In line with these findings, induced high-grade CIN has been found to accelerate aging in some mouse models. For instance decreased expression of the SAC protein BubR1 in vivo through a hypomorphic allele results in high-grade CIN, severe premature aging phenotypes and a significantly shorter lifespan.…”