High-resolution characterization of sequence signatures due to non-random cleavage of cell-free DNA.
High-resolution characterization of sequence signatures due to non-random cleavage of cell-free DNA.
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DOI：
10.1186/s12920-015-0107-z
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发表时间：
2015-06-17
影响因子：
2.7
通讯作者：
Bahlo M
中科院分区：
文献类型：
--
作者：
Chandrananda D;Thorne NP;Bahlo M
人血浆中游离DNA片段的高通量测序已被用于非侵入性检测胎儿非整倍体，监测器官移植和研究肿瘤DNA。然而，这种细胞外遗传物质的许多生物学特性仍然未知。进一步表征循环DNA的研究可以通过允许应用更复杂的生物信息学工具来大幅提高其诊断价值，从而改善测序数据中的信噪比。在这项研究中，我们使用来自两名孕妇（> 70 X，> 50 X）的深度测序数据研究血浆中游离DNA的各种特征，并将其与匹配的细胞DNA进行比较。我们利用一个描述性的方法来研究如何生物裂解的游离DNA影响不同的序列签名，如片段长度，在片段末端的序列基序和裂解位点的分布沿着基因组。我们表明，这些游离DNA分子的大小分布取决于其常染色体和线粒体的起源，以及染色体内的基因组位置。DNA映射到特定的微卫星和阿尔法重复元件显示独特的大小签名。我们展示了无细胞片段如何沿着基因组沿着成簇出现，定位于核小体阵列，并通过将这些片段的映射位置与染色质组织的ENCODE注释相关联，优先在接头区域切割。我们的工作进一步证明了无细胞常染色体DNA切割是序列依赖性的。跨越DNA切割位点两侧多达10个位置的区域显示出对特定核苷酸的一致偏好模式。该序列基序存在于定位于核小体核心和接头区域的切割位点中，但在无核小体的线粒体DNA中不存在。无细胞DNA测序数据中的这些背景信号源于这些片段的非随机生物切割。这种序列结构可以用于改进生物信息学算法，特别是用于CNV和结构变异检测。这里开发的无细胞DNA特征的描述性测量也可以用于生物标志物分析，以监测在不同病理条件下发生的变化。本文的在线版本（doi：10.1186/s12920-015-0107-z）包含补充材料，可供授权用户使用。
High-throughput sequencing of cell-free DNA fragments found in human plasma has been used to non-invasively detect fetal aneuploidy, monitor organ transplants and investigate tumor DNA. However, many biological properties of this extracellular genetic material remain unknown. Research that further characterizes circulating DNA could substantially increase its diagnostic value by allowing the application of more sophisticated bioinformatics tools that lead to an improved signal to noise ratio in the sequencing data. In this study, we investigate various features of cell-free DNA in plasma using deep-sequencing data from two pregnant women (>70X, >50X) and compare them with matched cellular DNA. We utilize a descriptive approach to examine how the biological cleavage of cell-free DNA affects different sequence signatures such as fragment lengths, sequence motifs at fragment ends and the distribution of cleavage sites along the genome. We show that the size distributions of these cell-free DNA molecules are dependent on their autosomal and mitochondrial origin as well as the genomic location within chromosomes. DNA mapping to particular microsatellites and alpha repeat elements display unique size signatures. We show how cell-free fragments occur in clusters along the genome, localizing to nucleosomal arrays and are preferentially cleaved at linker regions by correlating the mapping locations of these fragments with ENCODE annotation of chromatin organization. Our work further demonstrates that cell-free autosomal DNA cleavage is sequence dependent. The region spanning up to 10 positions on either side of the DNA cleavage site show a consistent pattern of preference for specific nucleotides. This sequence motif is present in cleavage sites localized to nucleosomal cores and linker regions but is absent in nucleosome-free mitochondrial DNA. These background signals in cell-free DNA sequencing data stem from the non-random biological cleavage of these fragments. This sequence structure can be harnessed to improve bioinformatics algorithms, in particular for CNV and structural variant detection. Descriptive measures for cell-free DNA features developed here could also be used in biomarker analysis to monitor the changes that occur during different pathological conditions. The online version of this article (doi:10.1186/s12920-015-0107-z) contains supplementary material, which is available to authorized users.
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影响因子：
1.7
作者：
Jurka, J;Kapitonov, VV;Walichiewicz, J
通讯作者：
Walichiewicz, J
影响因子：
3.7
作者：
Jiang P;Sun K;Lun FM;Guo AM;Wang H;Chan KC;Chiu RW;Lo YM;Sun H
通讯作者：
Sun H
影响因子：
17.1
作者：
De Vlaminck I;Valantine HA;Snyder TM;Strehl C;Cohen G;Luikart H;Neff NF;Okamoto J;Bernstein D;Weisshaar D;Quake SR;Khush KK
通讯作者：
Khush KK
DOI：
10.1196/annals.1448.046
发表时间：
2008-01-01
期刊：
CIRCULATING NUCLEIC ACIDS IN PLASMA AND SERUM V
影响因子：
--
作者：
Gahan, Peter B.;Anker, Philippe;Stroun, Maurice
通讯作者：
Stroun, Maurice
影响因子：
7.1
作者：
Ashoor, G.;Syngelaki, A.;Nicolaides, K. H.
通讯作者：
Nicolaides, K. H.