Mapping of a major locus that determines telomere length in humans.
Telomere length is a crucial factor for both normal chromosomal function and senescence. Mean telomere length in humans shows considerable interindividual variation and strong genetic determination. To see if a locus (or loci) affecting telomere length in humans could be mapped, we performed a quantitative-trait linkage analysis of mean leukocyte telomere-restriction-fragment (TRF) lengths, measured by Southern blotting, in 383 adult subjects comprising 258 sib pairs. Heritability of mean (+/-SE) TRF was 81.9%+/-11.8%. There was significant linkage (LOD score 3.20) of mean TRF length to a locus on chromosome 12, which explained 49% of the overall variability in mean TRF length. We present preliminary analysis of a strong candidate gene in the region, the DNA helicase DDX11. In conclusion, we report mapping of the first locus that determines mean telomere length in humans. Identification of the gene involved and elucidation of its mechanism of action could have important implications for our understanding of chromosomal assembly, telomere biology, and susceptibility to age-related diseases.
Vasa-Nicotera
Mariuca
M
Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester LE3 9QP, United Kingdom.
Brouilette
Scott
S
Mangino
Massimo
M
Thompson
John R
JR
Braund
Peter
P
Clemitson
Jenny-Rebecca
JR
Mason
Andrea
A
Bodycote
Clare L
CL
Raleigh
Stuart M
SM
Louis
Edward
E
Samani
Nilesh J
NJ
D000293:Adolescent; D000328:Adult; D000368:Aged; D002874:Chromosome Mapping / Q000379:methods*; D002881:Chromosomes, Human, Pair 12; D003327:Coronary Disease / Q000235:genetics; D053487:DEAD-box RNA Helicases; D004265:DNA Helicases / Q000235:genetics*; D005260:Female; D006801:Humans; D007962:Leukocytes / Q000648:ultrastructure; D008126:Lod Score; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D040641:Quantitative Trait Loci; D016615:Telomere / Q000000981:diagnostic imaging*; D014463:Ultrasonography
D004265:DNA Helicases; C101830:DDX11 protein, human; D053487:DEAD-box RNA Helicases