Telomere length within an individual varies in a correlated manner across most tissues. Telomere length within individuals Telomeres are DNA-protein complexes that protect chromosome ends. Their length is of great interest because short telomeres are associated with specific diseases and with aging. Demanelis et al. measured telomere length from 952 Genotype-Tissue Expression (GTEx) project donors across tissues, of which 24 tissue types have measurements for more than 25 samples. This dataset shows that telomere length is not constant but is correlated across tissues. Most tissue telomeres shorten with age, but some, such as those in the testis and cerebellum, do not. In African Americans, telomeres are longer on average than those from individuals of primarily European descent across many tissue types. This observation is consistent with variability being passed from germ cells to zygote to differentiated cells during development. Science, this issue p. eaaz6876 INTRODUCTION Telomeres are DNA-protein complexes located at the end of chromosomes that protect chromosome ends from degradation and fusion. The DNA component of telomeres shortens with each cell division, eventually triggering cellular senescence. Telomere length (TL) in blood cells has been studied extensively as a biomarker of human aging and risk factor for age-related diseases. The extent to which TL in whole blood reflects TL in disease-relevant tissue types is unknown, and the variability in TL across human tissues has not been well characterized. The postmortem tissue samples collected by the Genotype-Tissue Expression (GTEx) project provide an opportunity to study TL in many human tissue types, and accompanying data on inherited genetic variation, gene expression, and donor characteristics enable us to examine demographic, genetic, and biologic determinants and correlates of TL within and across tissue types. RATIONALE To better understand variation in and determinants of TL, we measured relative TL (RTL, telomere repeat abundance in a DNA sample relative to a standard sample) in more than 25 tissue types from 952 GTEx donors (deceased, aged 20 to 70 years old). RTL was measured for 6391 unique tissue samples using a Luminex assay, generating the largest publicly available multitissue TL dataset. We integrated our RTL measurements with data on GTEx donor characteristics, inherited genetic variation, and tissue-specific expression and analyzed relationships between RTL and covariates using linear mixed models (across all tissues and within tissues). Through this analysis, we sought to accomplish four goals: (i) characterize sources of variation in TL, (ii) evaluate whole-blood TL as a proxy for TL in other tissue types, (iii) examine the relationship between age and TL across tissue types, and (iv) describe biological determinants and correlates of TL. RESULTS Variation in RTL was attributable to tissue type, donor, and age and, to a lesser extent, race or ethnicity, smoking, and inherited variants known to affect leukocyte TL. RTLs were generally positively correlated among tissues, and whole-blood RTL was a proxy for RTL in most tissues. RTL varied across tissue types and was shortest in whole blood and longest in testis. RTL was inversely associated with age in most tissues, and this association was strongest for tissues with shorter average RTL. African ancestry was associated with longer RTL across all tissues and within specific tissue types, suggesting that ancestry-based differences in TL exist in germ cells and are transmitted to the zygote. A polygenic score consisting of inherited variants known to affect leukocyte TL was associated with RTL across all tissues, and several of these TL-associated variants affected expression of nearby genes in multiple tissue types. Carriers of rare, loss-of-function variants in TL-maintenance genes had shorter RTL (based on analysis of multiple tissue types), suggesting that these variants may contribute to shorter TL in individuals from the general population. Components of telomerase, a TL maintenance enzyme, were more highly expressed in testis than in any other tissue. We found evidence that RTL may mediate the effect of age on gene expression in human tissues. CONCLUSION We have characterized the variability in TL across many human tissue types and the contributions of aging, ancestry, genetic variation, and other biologic processes to this variability. The correlation observed among TL measures from different tissues highlights the existence of host factors with effects on TL that are shared across tissue types (e.g., TL in the zygote). These results have important implications for the interpretation of epidemiologic studies of leukocyte TL and disease. TL in human tissues. Using a Luminex-based assay, TL was measured in DNA samples from >25 different human tissue types from 952 deceased donors in the GTEx project. TL within tissue types is determined by numerous factors, including zygotic TL, age, and exposures. TL differs across tissues and correlates among tissue types. TL in most tissues declines with age. Telomere shortening is a hallmark of aging. Telomere length (TL) in blood cells has been studied extensively as a biomarker of human aging and disease; however, little is known regarding variability in TL in nonblood, disease-relevant tissue types. Here, we characterize variability in TLs from 6391 tissue samples, representing >20 tissue types and 952 individuals from the Genotype-Tissue Expression (GTEx) project. We describe differences across tissue types, positive correlation among tissue types, and associations with age and ancestry. We show that genetic variation affects TL in multiple tissue types and that TL may mediate the effect of age on gene expression. Our results provide the foundational knowledge regarding TL in healthy tissues that is needed to interpret epidemiological studies of TL and human health.

中文翻译：

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人体组织端粒长度的决定因素

个体内的端粒长度在大多数组织中以相关方式变化。个体内的端粒长度 端粒是保护染色体末端的 DNA-蛋白质复合物。它们的长度很受关注，因为短端粒与特定疾病和衰老有关。德马内利斯等人。测量了来自 952 位基因型组织表达 (GTEx) 项目捐赠者的端粒长度，其中 24 种组织类型对超过 25 个样本进行了测量。该数据集显示端粒长度不是恒定的，而是跨组织相关的。大多数组织端粒会随着年龄的增长而缩短，但有些则不会，例如睾丸和小脑中的端粒。在非裔美国人中，在许多组织类型中，端粒平均比主要欧洲血统的人的端粒更长。这一观察结果与发育过程中从生殖细胞到受精卵再到分化细胞的变异性一致。科学，这个问题 p。eaaz6876 简介 端粒是位于染色体末端的 DNA-蛋白质复合物，可保护染色体末端免于降解和融合。端粒的 DNA 成分随着每次细胞分裂而缩短，最终引发细胞衰老。血细胞中的端粒长度 (TL) 作为人类衰老的生物标志物和年龄相关疾病的危险因素已被广泛研究。全血中 TL 反映疾病相关组织类型中 TL 的程度尚不清楚，并且人类组织中 TL 的变异性尚未得到很好的表征。基因型-组织表达 (GTEx) 项目收集的死后组织样本为研究许多人类组织类型的 TL 提供了机会，并且附带的关于遗传变异、基因表达和供体特征的数据使我们能够检查人口统计、遗传和组织类型内和组织间 TL 的生物决定因素和相关性。基本原理 为了更好地了解 TL 的变异和决定因素，我们测量了来自 952 名 GTEx 供体（已故、20 至 70 ）。使用 Luminex 测定法测量了 6391 个独特组织样本的 RTL，生成了最大的公开可用多组织 TL 数据集。我们将 RTL 测量与 GTEx 供体特征数据相结合，遗传变异、组织特异性表达以及使用线性混合模型（跨所有组织和组织内）分析 RTL 和协变量之间的关系。通过这种分析，我们试图实现四个目标：（i）表征 TL 变异的来源，（ii）评估全血 TL 作为其他组织类型中 TL 的代表，（iii）检查年龄与 TL 之间的关系组织类型，以及 (iv) 描述 TL 的生物决定因素和相关性。结果 RTL 的变化可归因于组织类型、供体和年龄，在较小程度上，种族或民族、吸烟和已知影响白细胞 TL 的遗传变异可归因于。RTL 在组织之间通常呈正相关，全血 RTL 是大多数组织中 RTL 的代表。RTL 因组织类型而异，在全血中最短，在睾丸中最长。在大多数组织中，RTL 与年龄呈负相关，并且这种关联对于具有较短平均 RTL 的组织最强。非洲血统与所有组织和特定组织类型内更长的 RTL 相关，这表明基于血统的 TL 差异存在于生殖细胞中并传递给受精卵。由已知影响白细胞 TL 的遗传变异组成的多基因评分与所有组织的 RTL 相关，并且这些 TL 相关变异中的一些影响了多种组织类型中附近基因的表达。TL 维持基因中罕见功能丧失变异的携带者具有较短的 RTL（基于对多种组织类型的分析），表明这些变异可能导致来自一般人群的个体的 TL 更短。端粒酶的成分，一种 TL 维持酶，在睾丸中的表达比在任何其他组织中都要高。我们发现了 RTL 可能介导年龄对人体组织基因表达影响的证据。结论 我们已经描述了许多人类组织类型中 TL 的变异性，以及衰老、血统、遗传变异和其他生物过程对这种变异性的贡献。在来自不同组织的 TL 测量值之间观察到的相关性突出表明存在对 TL 有影响的宿主因素，这些因素在组织类型之间共享（例如，受精卵中的 TL）。这些结果对解释白细胞 TL 和疾病的流行病学研究具有重要意义。人体组织中的 TL。使用基于 Luminex 的分析，在来自 GTEx 项目中 952 位已故捐赠者的超过 25 种不同人类组织类型的 DNA 样本中测量了 TL。组织类型内的 TL 由多种因素决定，包括合子 TL、年龄和暴露。TL 因组织而异，且与组织类型相关。大多数组织中的 TL 随着年龄的增长而下降。端粒缩短是衰老的标志。血细胞中的端粒长度 (TL) 作为人类衰老和疾病的生物标志物已被广泛研究。然而，关于非血液、疾病相关组织类型中 TL 的变异性知之甚少。在这里，我们表征了来自 6391 个组织样本的 TL 的变异性，代表来自基因型组织表达 (GTEx) 项目的 20 多种组织类型和 952 个个体。我们描述了组织类型之间的差异，组织类型之间的正相关，以及与年龄和血统的关联。我们表明遗传变异影响多种组织类型的 TL，并且 TL 可能介导年龄对基因表达的影响。我们的结果提供了有关健康组织中 TL 的基础知识，这些知识是解释 TL 和人类健康的流行病学研究所需的。