Determinants of telomere length across human tissues.
Determinants of telomere length across human tissues.
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DOI：
10.1126/science.aaz6876
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发表时间：
2020-09-11
期刊：
影响因子：
--
通讯作者：
Pierce BL
中科院分区：
文献类型：
--
作者：
Demanelis K;Jasmine F;Chen LS;Chernoff M;Tong L;Delgado D;Zhang C;Shinkle J;Sabarinathan M;Lin H;Ramirez E;Oliva M;Kim-Hellmuth S;Stranger BE;Lai TP;Aviv A;Ardlie KG;Aguet F;Ahsan H;GTEx Consortium;Doherty JA;Kibriya MG;Pierce BL
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，这些样本代表了来自基因型-组织表达（GTEx）项目的>20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性，以及与年龄和血统的关联。我们发现，遗传变异影响TL在多种组织类型和TL可能介导的基因表达的年龄的影响。我们的研究结果提供了关于TL在健康组织中的基础知识，这是解释TL和人类健康的流行病学研究所需的。人体组织中的TL。使用基于Luminex的分析，在GTEx项目中，在来自952名已故供体的>25种不同人类组织类型的DNA样品中测量了TL。组织类型内的TL由许多因素决定，包括合子TL、年龄和暴露。TL在不同组织之间存在差异，并在组织类型之间存在相关性。大部分组织中的TL随年龄增长而下降。端粒是位于染色体末端的DNA-蛋白质复合物，其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。血细胞端粒长度作为人类衰老的生物标志物和与年龄相关疾病的危险因素已被广泛研究。全血中的TL在多大程度上反映了疾病相关组织类型中的TL尚不清楚，并且TL在人体组织中的变异性尚未得到很好的表征。由基因型-组织表达（GTEx）项目收集的死后组织样本提供了一个研究许多人类组织类型中TL的机会，并且关于遗传变异、基因表达和供体特征的伴随数据使我们能够检查组织类型内和组织类型间TL的人口统计学、遗传学和生物学决定因素和相关性。为了更好地了解TL的变化和决定因素，我们测量了952名GTEx供体（已故，年龄20至70岁）超过25种组织类型的相对TL（RTL，DNA样本中端粒重复序列相对于标准样本的丰度）。使用Luminex测定法测量了6391个独特组织样品的RTL，生成了最大的公开可用的多组织TL数据集。我们将我们的RTL测量与GTEx供体特征、遗传变异和组织特异性表达的数据相结合，并使用线性混合模型（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的变异来源，（ii）评估全血TL作为其他组织类型中TL的替代品，（iii）检查年龄和TL之间的关系，以及（iv）描述TL的生物学决定因素和相关因素。RTL的变异可归因于组织类型、供体和年龄，在较小程度上，还可归因于人种或种族、吸烟和已知影响白细胞TL的遗传变异。RTLs通常在组织间呈正相关，在大多数组织中，全血RTLs是RTL的代表。RTL因组织类型而异，全血中最短，睾丸中最长。在大多数组织中，RTL与年龄呈负相关，这种相关性在平均RTL较短的组织中最强。非洲血统与所有组织和特定组织类型内的RTL较长相关，表明TL中存在基于血统的差异，并传递给合子。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中的RTL相关，并且这些TL相关变异中的几种影响多种组织类型中附近基因的表达。TL维持基因中罕见的功能丧失变体的携带者具有较短的RTL（基于对多种组织类型的分析），这表明这些变体可能有助于来自一般人群的个体中较短的TL。端粒酶是一种TL维持酶，其组分在睾丸中的表达高于其他任何组织。我们发现的证据表明，RTL可能介导的影响，年龄对基因表达在人体组织。我们已经描述了TL在许多人体组织类型中的变异性，以及衰老、祖先、遗传变异和其他生物学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了宿主因素的存在，其对TL的影响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。
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. 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. 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. 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. 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. 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.
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影响因子：
4
作者：
Aston KI;Hunt SC;Susser E;Kimura M;Factor-Litvak P;Carrell D;Aviv A
通讯作者：
Aviv A
31种癌症类型的端粒长度和躯体改变的系统分析。
影响因子：
30.8
作者：
Barthel FP;Wei W;Tang M;Martinez-Ledesma E;Hu X;Amin SB;Akdemir KC;Seth S;Song X;Wang Q;Lichtenberg T;Hu J;Zhang J;Zheng S;Verhaak RG
通讯作者：
Verhaak RG
DOI：
10.1038/nrg3246
发表时间：
2012-10
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
通讯作者：
--
影响因子：
14.9
作者：
Ding Z;Mangino M;Aviv A;Spector T;Durbin R;UK10K Consortium
通讯作者：
UK10K Consortium
影响因子：
14.9
作者：
Cawthon, RM
通讯作者：
Cawthon, RM