Telomere Length as a Quantitative Trait: Genome-Wide Survey and Genetic Mapping of Telomere Length-Control Genes in Yeast

Tonibelle Gatbonton,Joshua M Akey,Julian A Simon,Douglas M Ruderfer,Maria Imbesi,Leonid Kruglyak,Melisa Nelson,Antonio Bedalov,Michael Snyder

doi:10.1371/journal.pgen.0020035

Abstract

Telomere length-variation in deletion strains of Saccharomyces cerevisiae was used to identify genes and pathways that regulate telomere length. We found 72 genes that when deleted confer short telomeres, and 80 genes that confer long telomeres relative to those of wild-type yeast. Among identified genes, 88 have not been previously implicated in telomere length control. Genes that regulate telomere length span a variety of functions that can be broadly separated into telomerase-dependent and telomerase-independent pathways. We also found 39 genes that have an important role in telomere maintenance or cell proliferation in the absence of telomerase, including genes that participate in deoxyribonucleotide biosynthesis, sister chromatid cohesion, and vacuolar protein sorting. Given the large number of loci identified, we investigated telomere lengths in 13 wild yeast strains and found substantial natural variation in telomere length among the isolates. Furthermore, we crossed a wild isolate to a laboratory strain and analyzed telomere length in 122 progeny. Genome-wide linkage analysis among these segregants revealed two loci that account for 30%–35% of telomere length-variation between the strains. These findings support a general model of telomere length-variation in outbred populations that results from polymorphisms at a large number of loci. Furthermore, our results laid the foundation for studying genetic determinants of telomere length-variation and their roles in human disease.

Highlights

Telomeres are complex structures at the ends of linear chromosomes composed of DNA, proteins, and ribonuclear protein complexes [1]
The magnitude of the telomere length-alteration was scored on a 1–3 scale: (1) in short telomere strains corresponding to the reduction of the telomere length by 200, (2) 200–50, or (3) less than 50 bp; and in long telomere strains, (1) an increase by more than 300, (2) 50–300 bp, or (3) less than 50 bp
A trait that is controlled by a large number of genes has the potential to exhibit phenotypic variation in genetically diverse populations, and when we analyzed variation in telomere length in 13 Saccharomyces cerevisiae strains isolated from the wild [23], we found that the size of the terminal restriction fragment varied significantly among different strains (Figure 6A)

Summary

Introduction

Telomeres are complex structures at the ends of linear chromosomes composed of DNA, proteins, and ribonuclear protein complexes [1]. Telomeric DNA is composed of highly repetitive sequences (T2AG3)n in humans and (C1–3A/TG1–3)n in yeast [2]. Telomerase is a highly specialized ribonuclear reverse transcriptase enzyme that catalyzes extension of 59-ends of the lagging DNA strand using an RNA template [4]. In most human cells telomeres shorten as a function of cellular division and serve as a genetic and biochemical clock of cellular replication [10]. Additional pathways involved in telomere lengthregulation in yeast include telomere- or telomerase-interacting proteins (Rap1p, Rif1p, Rif2p, and Pif1p), the Ku70/Ku80 end-capping complex [13], the nonsense-mediated RNA decay (NMD) pathway (Nmd2p, Upf3p, and Nam7p) [14], and the RMX (Rad50p, Mre11p, Xrs2p) DNA-strand break repair complex [15]. The genetic and functional relationships among these diverse pathways are under active investigation

Methods

Results

Conclusion