Elsevier

The Lancet

Volume 363, Issue 9408, 14 February 2004, Pages 507-510
The Lancet

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Telomere length and possible link to X chromosome

https://doi.org/10.1016/S0140-6736(04)15535-9Get rights and content

Summary

Background

Because telomeres are eroded during mitosis, telomere length indicates the replicative history of human somatic cells. Clinical markers of ageing—such as pulse pressure and survival—are associated with telomere length. On the basis of findings of studies in twins, telomere length seems to be familial, but little is known about its mode of inheritance. We aimed to investigate the inheritance of telomere length.

Methods

We measured terminal restriction fragment (TRF) length in white-blood-cell DNA taken from individuals from the family-based cohort of the Flemish Study on Environment, Genes, and Health Outcomes.

Findings

We recorded no correlation in sex and age adjusted TRF length between spouses (r=−0·05; p=0·70) nor between fathers and sons (r=−0·16; p=0·35). By contrast, we noted robust correlations in TRF length between fathers and daughters (r=0·60; p<0·0001); between mothers and sons (r=0·41; p=0·0017) and daughters (r=0·59; p<0·0001); and among siblings (r=⩾0·61; p⩽0·0004).

Interpretation

X-linked inheritance of TRF length is the most probable explanation for our findings. Pending confirmation, our observations suggest that the process of ageing might be an X-linked trait.

Introduction

Telomeres consist of TTAGGG tandem repeats and telomere binding proteins that cap chromosomes and shield them from DNA-damage repair pathways.1 Telomeres undergo progressive attrition in cultured somatic cells because of the so-called end-replication problem. In utero, telomere length is similar in most tissues,2, 3 but during extrauterine life, telomeres progressively shorten in proliferative somatic cells and their length diminishes with age.4, 5, 6, 7 Telomere length is established by many factors, including cellular replicative history and telomerase—a reverse transcriptase consisting of an RNA component (hTR) and a catalytic protein component (hTERT) that has the ability to add telomere repeats to the ends of chromosomes.8 Based on studies in twins, telomere length seems to be familial, but little is known about its mode of inheritance.6, 7 We aimed to investigate the inheritance of telomere length.

Section snippets

Methods

We enrolled into our study a random sample of families living in a geographically defined area of northern Belgium, who were part of the family-based cohort of the Flemish Study on Environment, Genes, and Health Outcomes.9 We undertook our study according to the principles outlined in the Helsinki declaration for investigation of human participants. The ethics committee of the University of Leuven approved the study, and participants gave written informed consent.

We took blood samples from all

Results

Our multigeneration pedigrees spanned one (n=13), two (10), or three (8) generations and included 128 parents and 199 offspring (83 sons and 116 daughters). Mean age of parents and offspring was 51·7 years (SD 12·2) and 30·2 years (10·9), respectively. From the pedigrees, we identified 34 father-son pairs, 47 father-daughter pairs, 51 mother-son pairs, and 71 mother-daughter pairs. On the basis of ABO blood group and rhesus phenotypes, we did not detect any cases of false paternity.

TRF length

Discussion

The most plausible mechanism accounting for the high concordance of TRF length we noted between mothers and offspring and between fathers and daughters—but not between fathers and sons and between spouses—is an X-linked mechanism of inheritance. Findings of sensitivity analyses, with outliers excluded or including fictive parent-offspring pairs, suggested that our results were not attributable to chance, but did not completely exclude this possibility.

The X chromosome harbours the DKC1 gene

References (19)

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    Citation Excerpt :

    Therefore, future studies considering a larger sample size can provide us with better statistical power to compare between men and women. Several previous studies argued that at birth the TL is similar between the sexes, but with aging, women have longer telomeres than men and their annual shortening rate is lower.3–6,14–17 A systematic review and meta-analysis corroborate these sex-specific differences in the telomere attrition.18

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