Segregating YKU80 and TLC1 alleles underlying natural variation in telomere properties in wild yeast.
Segregating YKU80 and TLC1 alleles underlying natural variation in telomere properties in wild yeast.
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DOI：
10.1371/journal.pgen.1000659
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发表时间：
2009-09
期刊：
影响因子：
4.5
通讯作者：
Louis EJ
中科院分区：
文献类型：
--
作者：
Liti G;Haricharan S;Cubillos FA;Tierney AL;Sharp S;Bertuch AA;Parts L;Bailes E;Louis EJ
在酵母中，如同在人类中一样，端粒长度在个体之间存在差异，并由多个基因座控制。为了确定端粒长度变异的程度，我们筛选了112株野生型狭义酿酒酵母菌株。我们发现奇异酵母菌株的端粒长度存在广泛变异。这种表型与其地理起源相关：观察到欧洲菌株的端粒极短（<150bp），而美洲菌株的端粒长度约为其三倍（>400bp）。在端粒附近插入URA3基因能够精确分析单个端粒长度和端粒位置效应（TPE）。将美洲菌株和欧洲菌株杂交，得到的F1孢子的端粒长度呈连续分布，这与如果有许多数量性状基因座（QTLs）参与长度维持所预测的情况相符。TPE的变异同样是数量性的，但与端粒长度仅呈弱相关。对F1分离株进行基因分型表明有几个与端粒长度和沉默变异相关的QTLs。这些QTLs包括可能的候选基因，但也定位到没有已知参与端粒特性的基因的区域。我们检测到两种表型都存在超亲分离。通过相互半合子验证，我们证实YKU80和TLC1是两个奇异酵母亚群中的端粒长度QTLs。此外，我们提出Ku异二聚体内部的序列差异在其中一种等位基因组合（美洲 - YKU70和欧洲 - YKU80）中产生负上位性，导致端粒极短。
端粒长度是一种个体间存在差异的复杂性状。其调控对衰老过程至关重要，长度控制的改变可能导致衰老或永生化。我们在野生酵母奇异酵母（与酿酒酵母亲缘关系最近）的不同亚群之间检测到极端变异。通过标记这两组中的单个端粒末端，我们表明无论端粒重复的总数如何，任何端粒进行补充的关键长度是保守的。为了检测长度变异背后的数量性状基因座（QTLs），我们使用分布差异最大的两个亚群产生后代并进行连锁分析。此外，我们证实YKU80和TLC1（先前已表明对端粒长度维持很重要的两个基因）中自然发生的序列变异可以解释部分变异。我们还确定了其他影响端粒长度和基因沉默的基因座。进一步的研究将为正常端粒调控背后的潜在遗传机制提供更多见解，这可能与衰老以及癌症等衰老相关疾病有关。
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. 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.
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