Telomere length as a quantitative trait: genome-wide survey and genetic mapping of telomere length-control genes in yeast.
Telomere length as a quantitative trait: genome-wide survey and genetic mapping of telomere length-control genes in yeast.
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DOI：
10.1371/journal.pgen.0020035
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发表时间：
2006-03
期刊：
影响因子：
4.5
通讯作者：
Bedalov A
中科院分区：
文献类型：
--
作者：
Gatbonton T;Imbesi M;Nelson M;Akey JM;Ruderfer DM;Kruglyak L;Simon JA;Bedalov A
利用酿酒酵母缺失菌株的端粒长度变异来鉴定调节端粒长度的基因和途径。我们发现72个基因，当删除赋予短端粒，和80个基因，赋予长端粒相对于野生型酵母。在已确定的基因中，有88个以前没有涉及端粒长度控制。调节端粒长度的基因跨越多种功能，这些功能可以大致分为端粒酶依赖性途径和端粒酶非依赖性途径。我们还发现了39个基因，有一个重要的作用，在端粒的维护或细胞增殖的情况下，端粒酶，包括基因参与脱氧核糖核苷酸的生物合成，姐妹染色单体凝聚力，和空泡蛋白分选。鉴于大量的基因座确定，我们调查了端粒长度在13个野生酵母菌株，发现大量的端粒长度的菌株之间的自然变异。此外，我们将野生菌株与实验室菌株杂交，并分析了122个后代的端粒长度。全基因组连锁分析表明，这两个基因座占端粒长度变异的30%-35%。这些发现支持了远交群体中端粒长度变异的一般模型，该模型是由大量基因座的多态性引起的。此外，我们的研究结果为研究端粒长度变异的遗传决定因素及其在人类疾病中的作用奠定了基础。端粒的维持对于确保线性基因组生物的基因组稳定性具有重要意义。在人类中，端粒作为年龄的函数缩短，并作为细胞复制历史的标志。了解端粒长度维持的遗传差异可能有助于了解个体之间不同衰老速率的基础以及个体对衰老相关疾病（如癌症）的倾向差异。在酵母和其他模式生物中的研究已经确定了几种确保染色体末端稳定性的途径。为了捕获参与酵母酿酒酵母中端粒维持的基因的完整互补，作者对影响端粒长度的基因进行了全面筛选。在152个已鉴定的基因中，作者发现了39个基因，它们的功能在没有端粒酶的情况下对端粒的维持至关重要。作者将他们的研究从实验室酵母菌株扩展到远交酵母群体，并发现分离株之间端粒长度的显着表型变异。野生酵母分离株和实验室菌株之间的杂交的端粒长度分析支持远交群体中端粒长度变异的一般模型，该模型由大量基因座的多态性引起。这一发现为人类群体中端粒维持的遗传学研究提供了基础。
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.
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