The pattern of chromosome-specific variations in telomere length in humans is determined by inherited, telomere-near factors and is maintained throughout life Jesper Graakjaer a , Claus Bischoff a , Lars Korsholm b , Søren Holstebroe c , Werner Vach b , Vilhelm A. Bohr d , Kaare Christensen e , Steen Kølvraa a, * a Institute of Human Genetics, University of Aarhus, Bartholin Building, Vilhelm Meyers Alle, 8000 Aarhus C, Denmark b Department of Statistics and Demography, University of Southern Denmark, Sdr. Boulevard 23A, 5000 Odense C Denmark c DAKO, Produktionsvej 42, 2600 Glostrup Denmark d Laboratory of Molecular Gerontology, National Institute on Aging, Baltimore, MD 21224, USA e Section for Epidemiology, Institute of Public Health, University of Southern Denmark, Srd. Boulevard 23A, 5000 Odense C Denmark Received 27 September 2002; received in revised form 12 February 2003; accepted 21 February 2003 Abstract In this study the telomere length distribution on individual chromosome arms in humans has been characterized. Using fluorescent in situ hybridisation (FISH) followed by computer-assisted analysis of digital images, we show that the distribution of telomere length on individual chromosome arms is not random, but that humans have a common telomere profile. This profile exists in both lymphocytes, amniocytes and fibroblasts, and is conserved during life until about the age of 100. We find that the length of the telomeres generally follows the length of the chromosomes and that the chromosome specific differences in telomere length are determined by factors located very distally on the chromosome arms. In addition to the common profile, we also find that each individual has specific characteristics. Based on analysis of both monozygotic and dizygotic twins, we find that these characteristics are partly inherited. For each chromosome, age-related chromosome loss correlates negatively with telomere length. This suggests that decrease in telomere length may be an element in age-related genome instability. # 2003 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Chromosome-specific variations; Telomere length; FISH 1. Introduction Telomeres are GC-rich repetitive structures located at the very end of chromosomes in higher organisms (Blackburn, 1994; Zakian, 1995). The monomeric unit of the telomeres in humans is TTAGGG (Moyzis et al., 1988; Lejnine et al., 1995), and tandem repeats of this unit results in a stretch of repetitions that varies from a few thousands to about 15.000 bp in size (Harley et al., 1990; Lindsey et al., 1991; Frenck et al., 1998). This DNA sequence is surrounded by a number of specific proteins (Chong et al., 1995; Bilaud et al., 1997; Broccoli et al., 1997; Smith et al., 1998; Kim et al., 1999), and the whole structure serves as a cap to protect the chromo- some ends (Shay, 1999), possibly by forming a telomere loop structure (Greider, 1999; Griffith et al., 1999). This function is clearly demonstrated by the fact that chromosomes without telomeres are highly unstable and are frequently lost during cell growth (Li et al., 1998). The telomere repeat sequences also represent a buffer of DNA sequence that appears to be dispensable with- out adverse effects. The cell needs such a buffer because a short stretch of DNA is lost during every replication cycle due to the well known ‘end replication problem’ (Olovnikov, 1973). In most somatic cells there is no system for compensating this telomere loss. However, in a few cell types, most notably in germ line cells, * Corresponding author. Present address: Institute of Human Genetics, University of Aarhus, Bartholin Building, Vilhelm Meyers Alle, Aarhus C 8000, Denmark. Tel.:  /45-89421677; fax:  /45- 86123173. E-mail address: steen@humgen.au.dk (S. Kølvraa). Mechanisms of Ageing and Development 124 (2003) 629  /640 www.elsevier.com/locate/mechagedev 0047-6374/03/$ - see front matter # 2003 Elsevier Science Ireland Ltd. All rights reserved. doi:10.1016/S0047-6374(03)00081-2