The EMBO Journal (2009) 28, 2532–2540 | & 2009 European Molecular Biology Organization | Some Rights Reserved 0261-4189/09 www.embojournal.org THE EMBO JOURNAL Focus Review Telomeres and disease Peter M Lansdorp1,2,* 1Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia, Canada and 2Department of Medicine, Division of Hematology, University of British Columbia, Vancouver, British Columbia, Canada The telomeres of most eukaryotes are characterized by guanine-rich repeats synthesized by the reverse transcrip- tase telomerase. Complete loss of telomerase is tolerated for several generations in most species, but modestly reduced telomerase levels in human beings are implicated in bone marrow failure, pulmonary ﬁbrosis and a spec- trum of other diseases including cancer. Differences in telomerase deﬁciency phenotypes between species most likely reﬂect a tumour suppressor function of telomeres in long-lived mammals that does not exist as such in short- lived organisms. Another puzzle provided by current observations is that family members with the same genetic defect, haplo-insufﬁciency for one of the telomerase genes, can present with widely different diseases. Here, the crucial role of telomeres and telomerase in human (stem cell) biology is discussed from a Darwinian perspective. It is proposed that the variable phenotype and penetrance of heritable human telomerase deﬁciencies result from additional environmental, genetic and stochastic factors or combinations thereof. The EMBO Journal (2009) 28, 2532–2540. doi:10.1038/ emboj.2009.172; Published online 23 July 2009 Subject Categories: molecular biology of disease Keywords: cancer; dyskeratosis; mutations; telomerase Introduction Several recent studies have highlighted the tremendous im- portance of telomeres in clinical medicine (Yamaguchi et al, 2005; Armanios et al, 2007; Calado et al, 2009). These advances provide an opportunity to revisit some of the concepts and data that provide a link between telomeres, the turnover of various (stem) cells and the diverse pathology that is now linked to telomere dysfunction. This aim of this essay is not to provide a comprehensive review of the many papers that have implicated telomeres in human disease. Instead, I hope to provide some insight into this broad and complex topic by reviewing ideas and data from selected publications in very diverse areas. *Corresponding author. Terry Fox Laboratory, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia, Canada V5Z 1L3. Tel.: þ 1 604 675 8135; Fax: þ 1 604 877 0712; E-mail: plansdor@bccrc.ca Received: 24 April 2009; accepted: 3 June 2009; published online: 23 July 2009 2532 The EMBO Journal VOL 28 | NO 17 | 2009 The chicken or the egg? The Russian evolutionary biologist Theodosius Dobzhansky, wrote ‘Nothing in Biology Makes Sense Except in the Light of Evolution’ (Dobzhansky, 1973).1 The essential truth in this statement is in my view exempliﬁed by a remarkable differ- ence in telomere function between human beings and most other eukaryotes. This difference is illustrated by the con- sequences of complete and partial telomerase deﬁciencies. Strikingly, complete loss of telomerase is tolerated for several generations in yeast, worms, plants and mice (Table I). In each of these species, the loss of telomerase results in a measurable and predictable decline in average telomere length with each subsequent generation. After four or more generations without major changes in growth or develop- ment, telomeres become too short to protect chromosome ends and problems start to occur. Chromosome ends without sufﬁcient telomere repeats typically are prone to fusion and the resulting dicentric chromosomes compromise the ability of cells to continue cell division.2 Chromosome fusions and other molecular changes in cells of late generation telomer- ase-null mutant animals or plants result in a plethora of phenotypes. Most typical are a failure to reproduce, variable growth defects, accelerated ‘ageing’ in some tissues and failed or delayed responses to tissue injury. In stark contrast to these consequences in late generation telomerase-null animals or plants are the often severe and life-threatening clinical phenotypes observed in patients with a modest, two- fold reduction in telomerase levels (e.g. resulting from haplo- insufﬁciency for one of the two essential telomerase genes) (Table I). What could be the explanation for these phenotypic differences? In evolutionary terms, the cells of the germline are the most important cells: only the gametes produced by the cells of the germline have the potential to cross generations, whereas somatic cells are inevitably lost with each generation (Figure 1). The disposable soma theory provides a useful paradigm to think about reproduction, somatic cells and ageing (Kirkwood and Holliday, 1979). Cells of the germline and soma are of course highly integrated. All somatic cells and tissues, including our brain, reﬂect an evolutionary strategy to propagate germline DNA. Most people do not (like to) see themselves as the mortal carriers of precious, highly selected DNA contained in cells of the germline. However, the notion that our soma serves to propagate germline DNA and is ‘disposable’ in the bigger scheme of things is useful in considering possible differences in 1American Biology Teacher, volume 35, pages 125–129. 2The consequences of fused and broken chromosomes in cells differ greatly between species. For example, multiple anaphase bridges were observed in late generation telomerase-null Arabidopsis plants. This level of genomic instability is not tolerated by mammalian cells (see Riha et al, 2001). & 2009 European Molecular Biology Organization