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Structural variation and its potential impact on genome instability: Novel discoveries in the EGFR landscape by long-read sequencing.

结构变异及其对基因组不稳定性的潜在影响: 长读测序在EGFR景观中的新发现。

  • 影响因子:3.02
  • DOI:10.1371/journal.pone.0226340
  • 作者列表:"Cook GW","Benton MG","Akerley W","Mayhew GF","Moehlenkamp C","Raterman D","Burgess DL","Rowell WJ","Lambert C","Eng K","Gu J","Baybayan P","Fussell JT","Herbold HD","O'Shea JM","Varghese TK","Emerson LL
  • 发表时间:2020-01-15
Abstract

:Structural variation (SV) is typically defined as variation within the human genome that exceeds 50 base pairs (bp). SV may be copy number neutral or it may involve duplications, deletions, and complex rearrangements. Recent studies have shown SV to be associated with many human diseases. However, studies of SV have been challenging due to technological constraints. With the advent of third generation (long-read) sequencing technology, exploration of longer stretches of DNA not easily examined previously has been made possible. In the present study, we utilized third generation (long-read) sequencing techniques to examine SV in the EGFR landscape of four haplotypes derived from two human samples. We analyzed the EGFR gene and its landscape (+/- 500,000 base pairs) using this approach and were able to identify a region of non-coding DNA with over 90% similarity to the most common activating EGFR mutation in non-small cell lung cancer. Based on previously published Alu-element genome instability algorithms, we propose a molecular mechanism to explain how this non-coding region of DNA may be interacting with and impacting the stability of the EGFR gene and potentially generating this cancer-driver gene. By these techniques, we were also able to identify previously hidden structural variation in the four haplotypes and in the human reference genome (hg38). We applied previously published algorithms to compare the relative stabilities of these five different EGFR gene landscape haplotypes to estimate their relative potentials to generate the EGFR exon 19, 15 bp canonical deletion. To our knowledge, the present study is the first to use the differences in genomic architecture between targeted cancer-linked phased haplotypes to estimate their relative potentials to form a common cancer-linked driver mutation.

摘要

: 结构变异 (SV) 通常定义为人类基因组内超过 50 个碱基对 (bp) 的变异。SV可以是拷贝数中性的,或者它可以涉及重复、缺失和复杂的重排。最近的研究表明SV与许多人类疾病有关。然而,由于技术限制,SV的研究一直具有挑战性。随着第三代 (长读) 测序技术的出现,对以前不容易检查的较长DNA段的探索已经成为可能。在本研究中,我们利用第三代 (长读) 测序技术来检查来自两个人类样品的四个单倍型的EGFR景观中的SV。我们分析了EGFR基因及其景观 (+/- 500,000 碱基对) 使用这种方法,能够鉴定与非小细胞肺癌中最常见的激活EGFR突变具有超过 90% 相似性的非编码DNA区域。基于之前发表的Alu-元件基因组不稳定性算法,我们提出了一种分子机制来解释DNA的非编码区如何与EGFR基因相互作用并影响其稳定性,并可能产生这种癌症驱动基因。通过这些技术,我们还能够在四种单倍型和人类参考基因组 (hg38) 中识别出以前隐藏的结构变异。我们应用以前发表的算法来比较这五种不同EGFR基因景观单倍型的相对稳定性,以估计它们产生EGFR外显子 19,15 bp规范缺失的相对潜力。据我们所知,本研究首次利用靶向癌症相关的阶段性单倍型之间的基因组结构差异来估计其形成常见癌症相关驱动突变的相对潜力。

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影响因子:6.93
发表时间:2020-01-15
DOI:10.1002/ijc.32532
作者列表:["Hata A","Nakajima T","Matsusaka K","Fukuyo M","Morimoto J","Yamamoto T","Sakairi Y","Rahmutulla B","Ota S","Wada H","Suzuki H","Matsubara H","Yoshino I","Kaneda A"]

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影响因子:6.93
发表时间:2020-01-01
DOI:10.1002/ijc.32530
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