Digital telomere measurement by long-read sequencing distinguishes healthy aging from disease.
Digital telomere measurement by long-read sequencing distinguishes healthy aging from disease.
复制标题
通过长读长测序进行数字端粒测量可以区分健康衰老和疾病。
DOI：
10.1101/2023.11.29.569263
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Artandi,StevenE
中科院分区：
文献类型：
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作者：
Sanchez,SantiagoE;Gu,Jessica;Golla,Anudeep;Martin,Annika;Shomali,William;Hockemeyer,Dirk;Savage,SharonA;Artandi,StevenE
端粒长度是生物体衰老和细胞复制潜能的重要生物标志物，但现有的测量方法在分辨率和准确性方面存在局限性。在这里，我们采用纳米孔测序的数字端粒测量(DTM)来了解人类端粒长度的分布如何随着年龄和疾病的变化而变化。我们在基因定义的人类细胞群体、健康捐赠者的血细胞和有端粒维持遗传缺陷的患者的血细胞中，以高达30 BP的分辨率测量端粒磨损和从头延伸。我们发现，人类的衰老伴随着长端粒的逐渐丧失和较短端粒的积累。在端粒维持缺陷的患者中，短端粒的积累更为明显，并与表型严重程度相关。我们应用机器学习来训练一个二进制分类模型，该模型区分健康的个人和那些患有端粒生物疾病的人。这条测序和生物信息学管道将促进我们对端粒维持机制的理解，并将端粒长度用作衰老和疾病的临床生物标记物。
Telomere length is an important biomarker of organismal aging and cellular replicative potential, but existing measurement methods are limited in resolution and accuracy. Here, we deploy digital telomere measurement (DTM) by nanopore sequencing to understand how distributions of human telomere length change with age and disease. We measure telomere attrition and de novo elongation with up to 30 bp resolution in genetically defined populations of human cells, in blood cells from healthy donors and in blood cells from patients with genetic defects in telomere maintenance. We find that human aging is accompanied by a progressive loss of long telomeres and an accumulation of shorter telomeres. In patients with defects in telomere maintenance, the accumulation of short telomeres is more pronounced and correlates with phenotypic severity. We apply machine learning to train a binary classification model that distinguishes healthy individuals from those with telomere biology disorders. This sequencing and bioinformatic pipeline will advance our understanding of telomere maintenance mechanisms and the use of telomere length as a clinical biomarker of aging and disease.