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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.

SUBMITTER: Forsberg LA

PROVIDER: S-EPMC3276669 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Age-related somatic structural changes in the nuclear genome of human blood cells.

Forsberg Lars A LA Rasi Chiara C Razzaghian Hamid R HR Pakalapati Geeta G Waite Lindsay L Thilbeault Krista Stanton KS Ronowicz Anna A Wineinger Nathan E NE Tiwari Hemant K HK Boomsma Dorret D Westerman Maxwell P MP Harris Jennifer R JR Lyle Robert R Essand Magnus M Eriksson Fredrik F Assimes Themistocles L TL Iribarren Carlos C Strachan Eric E O'Hanlon Terrance P TP Rider Lisa G LG Miller Frederick W FW Giedraitis Vilmantas V Lannfelt Lars L Ingelsson Martin M Piotrowski Arkadiusz A Pedersen Nancy L NL Absher Devin D Dumanski Jan P JP

American journal of human genetics 20120202 2

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 aberration ...[more]

PMID: 22305530

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Project description:Age-related hearing loss is a chronic degenerative disorder affecting one in two individuals above the age of 75. Current population projections predict a steady climb in the number of older individuals making the search for interventions to prevent or reverse this disorder even more critical. There is growing acceptance that aberrant activity of resident or infiltrating immune cells, such as macrophages, is a major factor contributing to the onset and progression of age-related degenerative diseases. However, how macrophage populations and their functionally-driven morphological characteristics change with age in the human cochlea remains largely unknown. In this study, we employed immunohistochemical approaches along with confocal and super-resolution imaging, three-dimensional reconstructions, and quantitative analysis to determine age-related changes in macrophage numbers and morphology as well as interactions with other cell-types and structures of the auditory nerve and lateral wall in the human cochlea. In the cochlea of human ears from young and middle aged adults those macrophages in the auditory nerve assumed a worm-like structure in contrast to those in the spiral ligament or associated with the dense microvascular network in the stria vascularis which exhibited a highly ramified morphology. Macrophages in both the auditory nerve and cochlear lateral wall showed morphological alterations with age. The population of activated macrophages in the auditory nerve increased in cochleas obtained from older donors. Dual-immunohistochemical staining with macrophage, myelin, and neuronal markers revealed increased interactions of macrophages with the glial and neuronal components of the aged auditory nerve. These findings implicate the involvement of abnormal macrophage-glia interactions in age-related physiological and pathological alterations in the human cochlea. There is clearly a need to further investigate the contribution of macrophage-associated inflammatory dysregulation in human presbyacusis.

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Age-related somatic structural changes in the nuclear genome of human blood cells.

Publications

Age-related somatic structural changes in the nuclear genome of human blood cells.

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