Age-related somatic structural changes in the nuclear genome of human blood cells.
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.
Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Sweden.
Lars A
LA
Forsberg
Chiara
C
Rasi
Hamid R
HR
Razzaghian
Geeta
G
Pakalapati
Lindsay
L
Waite
Krista Stanton
KS
Thilbeault
Anna
A
Ronowicz
Nathan E
NE
Wineinger
Hemant K
HK
Tiwari
Dorret
D
Boomsma
Maxwell P
MP
Westerman
Jennifer R
JR
Harris
Robert
R
Lyle
Magnus
M
Essand
Fredrik
F
Eriksson
Themistocles L
TL
Assimes
Carlos
C
Iribarren
Eric
E
Strachan
Terrance P
TP
O'Hanlon
Lisa G
LG
Rider
Frederick W
FW
Miller
Vilmantas
V
Giedraitis
Lars
L
Lannfelt
Martin
M
Ingelsson
Arkadiusz
A
Piotrowski
Nancy L
NL
Pedersen
Devin
D
Absher
Jan P
JP
Dumanski
D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D001773:Blood Cells / Q000502:physiology*; D002648:Child; D015331:Cohort Studies; D056915:DNA Copy Number Variations / Q000235:genetics*; D005260:Female; D015894:Genome, Human; D006801:Humans; D007206:Individuality; D008137:Longitudinal Studies; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009190:Myelodysplastic Syndromes / Q000097:blood / Q000235:genetics; D014430:Twins, Monozygotic / Q000235:genetics; D055815:Young Adult