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Title: Segregating YKU80 and TLC1 Alleles Underlying Natural Variation in Telomere Properties in Wild Yeast}
Article:
Abstract:
In yeast, as in humans, telomere length varies among individuals and is controlled by multiple loci. In a quest to define the extent of variation in telomere length, we screened 112 wild-type Saccharomyces sensu stricto isolates. We found extensive telomere length variation in S. paradoxus isolates. This phenotype correlated with their geographic origin: European strains were observed to have extremely short telomeres( <150 bp), whereas American isolates had telomeres approximately three times as long( >400 bp). Insertions of a URA3 gene near telomeres allowed accurate analysis of individual telomere lengths and telomere position effect( TPE). Crossing the American and European strains resulted in F1 spores with a continuum of telomere lengths consistent with what would be predicted if many quantitative trait loci( QTLs) were involved in length maintenance. Variation in TPE is similarly quantitative but only weakly correlated with telomere length. Genotyping F1 segregants indicated several QTLs associated with telomere length and silencing variation. These QTLs include likely candidate genes but also map to regions where there are no known genes involved in telomeric properties. We detected transgressive segregation for both phenotypes. We validated by reciprocal hemizygosity that YKU80 and TLC1 are telomere-length QTLs in the two S. paradoxus subpopulations. Furthermore, we propose that sequence divergence within the Ku heterodimer generates negative epistasis within one of the allelic combinations( American-YKU70 and European-YKU80) resulting in very short telomeres.
Introduction:
Telomeres are active nucleo-protein sites that constitute the ends of chromosomes in most eukaryotic species[1]. Telomeric DNA is G-rich and highly species specific in sequence. The telomeric DNA is bound by a number of proteins that together form a tight structure that effectively hides chromosome ends from DNA repair enzymes. Telomeric sequences are elegantly replenished by telomerase, a specialized reverse transcriptase. This process compensates for the loss of DNA from chromosome ends during DNA replication. Telomere length is both species and chromosome specific and appears to play an important role in the normal functioning of a cell. In S. cerevisiae, the mean telomeric length is ∼350 bp, whilst in humans it is several kilobases[1]. Although telomere length is generally conserved and maintained under quite rigorous control, different isolates of S. cerevisiae display moderate variation[2],[3]. Similar evidence of variation has been documented between individuals of worm[4], mouse[5], plant[6] and human[1] species. In S. cerevisiae, analysis of a complete set of deletion mutants revealed over 150 genes that altered telomere length[2],[7]. Telomerase( including its RNA template TLC1), Rap1, yKu, and Mre11 complexes, Pif1p and Cdc13p are amongst the principal regulators of telomere length. In this study, we investigated variation in telomere length among 112 Saccharomyces isolates, mostly belonging to the S. cerevisiae and S. paradoxus species, previously characterised for their subtelomeric structure and Ty prevalence[8]. Although the two species share many features, their histories differ notably. S. cerevisiae has been used for thousands of years by humans. Selection and domestication issues have been previously invoked[9],[10] to argue that S. cerevisiae may not be a good model for studying natural variation of complex traits. In contrast, S. paradoxus has had no such interaction with humans. Sequence analysis in this species supports the presence of three major geographic subpopulations: European, Far Eastern and American[8],[11]–[14]. Subtelomeric structures are also highly variable between S. paradoxus subpopulations as illustrated by the documented paucity of the Y′ element in Far Eastern isolates[8]. The overall sequence variation found in S. paradoxus( up to 4. 5%) is much greater than in any S. cerevisiae analysed( ∼0. 7%)[14]. The results reported below describe the phenotypic telomeric differences among Saccharomyces strains and the genetic mechanisms underlying this variation.
Discussion:
Telomere length shows quantitative differences controlled by a large number of loci fulfilling the definition of a complex trait. Early reports have shown telomere length to vary among S. cerevisiae strains[2],[3]. To obtain a broad picture of the extent of variation of this trait within a natural population and to investigate the mechanisms behind telomere length regulation we screened 112 Saccharomyces strains. The initial screening indicated extreme telomere length variation between two geographic subpopulations of S. paradoxus. We selected two strains, CBS432 and YPS138 as representative of the European and American subpopulations respectively, and accurately measured telomere length at individual telomeres. We detected a massive 3-fold telomere length variation between the strains: ∼150 bp in CBS432 and ∼450 bp in YPS138. The high sequence divergence with the large majority of SNPs not shared between subpopulations makes genome-wide association studies impossible. We looked at specific candidates where mutations with telomere length effects were previously characterised. In Est2p, the catalytic subunit of telomerase, substitution within a highly conserved domain( glutamic acid residue 76 to lysine in S288c) results in a telomere length increase of 100 bp[34]. We observed a substitution in exactly the same position in the American S. paradoxus lineage( glutamic acid residue to glycine) that could partially explain the observed extra long telomeres( Figure S7). We further characterised the telomeric repeats in the CBS and YPS strains by sequencing individual telomeres, deleting genes involved in telomere maintenance as well as protection, and measuring the G-overhang in WT and mutant strains. One surprising finding in the CBS strain was that inactivation of the Ku heterodimer did not affect telomere length per se but increased the length of G-tail. These results indicate that there are natural variants of the Ku proteins, which affect only some of its functions. Similar separation of function mutants have been obtained in the laboratory[35]. To obtain candidate QTLs, we generated 84 segregants from a CBS/YPS cross and performed linkage analysis. We measured length at individual telomeres to obtain a robust phenotype dataset. We also phenotyped the segregants for an additional quantitative telomeric trait, TPE, that also exhibits extreme variation in the CBS( no TPE) and YPS( high TPE) strains. As predicted by the phenotype distribution, both telomere length and TPE variation seem to be controlled by multiple QTLs( Figure 4). Some of the QTLs, like YKU80, are shared between the two phenotypes but many others only affect one of the phenotypes explaining the weak correlation between the two traits. Indeed, several mutations within RAP1, SIR3, SIR4, YKU70 and TEL1 have been shown to affect either TPE or telomere length independently[31]. Other potential QTLs involved in the length variation and TPE were also detected( Table S2). It is surprising that many alleles from the CBS strain are associated with high TPE suggesting that other alleles in CBS might mask their effect. Although the CBS-YKU80 reduces TPE in most of the F1 CBS RVB1-SIR4 spores, it does not completely eliminate TPE( results not shown). We confirmed that part of the variation in telomere length among individuals is due to natural sequence variants within YKU80 and TLC1. We also show that high sequence divergence in the Ku heterodimer results in a negative epistatic interaction producing extremely short telomeres in one allele combination. A similar negative interaction has been recently documented for alleles of two mismatch repair genes[36],[37]. We have evidence that negative epistasis is widespread in progeny obtained from the highly diverged parental strains CBS and YPS explaining their low fitness when exposed to a multitude of conditions( Warringer J and Liti G, unpublished results). This widespread epistasis could prevent hybridization between the European and American population of S. paradoxus in geographic regions where the two populations coexist but do not interbreed[12]. Widespread genetic incompatibility between highly diverged C. elegans strains isolated in England and Hawaii has been previously documented[38]. The presence of negative epistasis between diverging subpopulations can represent a powerful tool in mapping novel gene interactions. Indeed, the two S. paradoxus strains used in this study to generate the F1 segregants have a level of sequence divergence almost 10-fold higher than in any other S. cerevisiae strains previously used in linkage analysis[22],[39], which is consequently likely to result in strong epistatic interactions. The high sequence divergence also has a dramatic impact on gamete viability resulting from the reduced number of CO. This reduction in CO also decreases the resolution of the linkage analysis, requiring a low number of markers to generate the initial genotypes and to map the recombination breakpoints. We analysed segregants from the same meiotic event to ensure that the gametes are genuine meiotic products, with no aneuploidies, and provide important information on phenotype inheritance. Why geographic subpopulations of the same species have evolved dramatic differences in telomeric properties remains unclear.
Telomere length is a complex trait that varies among individuals . Its regulation is critical to the process of aging , and altered length control can result in either senescence or immortalization . We detected extreme variation between different subpopulations of the wild yeast S . paradoxus , the closest relative to S . cerevisiae . By tagging individual telomeric ends in these two groups , we show that regardless of the total number of telomeric repeats , the critical length at which any telomere is replenished remains conserved . To detect the quantitative trait loci ( QTLs ) behind the length variation , we used the two sub-populations with the most polar distribution to generate progeny and perform linkage analysis . Further , we validated that naturally occurring sequence variations in YKU80 and TLC1 , two genes previously shown to be important for telomere length maintenance , can explain part of the variation . We also identified other loci that influence both telomere length and gene silencing . Further investigation will provide more insights into the underlying genetic mechanism behind normal telomere regulation , potentially relevant in aging and aging-related disease such as cancer .