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

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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. Telomere maintenance is of great importance to ensure genome stability in organisms with linear genomes. In humans, telomeres shorten as a function of age and serve as a marker of cell replication history. Understanding the genetic differences in telomere length-maintenance may help provide the insights into the basis for different rates of aging among individuals and differences in individuals' propensity for aging-associated diseases such as cancer. Studies in yeast and other model organisms have defined several pathways that ensure stability of chromosome ends. In order to capture full complement of genes that participate in telomere maintenance in yeast Saccharomyces cerevisiae, the authors undertook a comprehensive screen for genes that affect telomere length. Among 152 identified genes, the authors found 39 genes whose function is critical for telomere maintenance in the absence of telomerase. The authors extended their studies from laboratory yeast strains to outbred populations of yeast and discovered significant phenotypic variation in telomere length among the isolates. Telomere length-analysis of a cross between a wild yeast isolate and a laboratory strain support a general model of telomere length-variation in outbred populations that results from polymorphisms at a large number of loci. This finding provides a basis for genetic studies of telomere maintenance in human populations.