Assessing reproducibility of inherited variants detected with short-read whole genome sequencing.
Assessing reproducibility of inherited variants detected with short-read whole genome sequencing.
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DOI：
10.1186/s13059-021-02569-8
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发表时间：
2022-01-03
期刊：
影响因子：
12.3
通讯作者：
Hong H
中科院分区：
文献类型：
--
作者：
Pan B;Ren L;Onuchic V;Guan M;Kusko R;Bruinsma S;Trigg L;Scherer A;Ning B;Zhang C;Glidewell-Kenney C;Xiao C;Donaldson E;Sedlazeck FJ;Schroth G;Yavas G;Grunenwald H;Chen H;Meinholz H;Meehan J;Wang J;Yang J;Foox J;Shang J;Miclaus K;Dong L;Shi L;Mohiyuddin M;Pirooznia M;Gong P;Golshani R;Wolfinger R;Lababidi S;Sahraeian SME;Sherry S;Han T;Chen T;Shi T;Hou W;Ge W;Zou W;Guo W;Bao W;Xiao W;Fan X;Gondo Y;Yu Y;Zhao Y;Su Z;Liu Z;Tong W;Xiao W;Zook JM;Zheng Y;Hong H
通过全基因组测序 (WGS) 重复检测遗传变异对于精准医学的实施至关重要，并且是一个复杂的过程，其中每个步骤都会影响变异检测质量。为了理解和提高 WGS 遗传变异的质量，需要通过 WGS 系统地评估遗传变异的重现性以及过程中每个步骤的影响。为了剖析 WGS 检测遗传变异所涉及的因素的影响，我们在三个短读长测序平台上使用六个实验室的三个文库试剂盒对代表两个群体的八个 DNA 样本进行了三次重复测序，并使用 56 种比对器和识别器组合来识别变异体。我们发现生物信息学管道（识别器和比对器）对变异重现性的影响比 WGS 平台或文库制备更大。单核苷酸变异 (SNV)，特别是在难以定位的区域之外，比小的插入和缺失 (indel) 具有更高的可重复性，而当 > 5 bp 时，小插入和缺失 (indel) 的可重复性最差。增加测序覆盖度可提高插入缺失的重现性，但对 30× 以上的 SNV 影响有限。我们的研究结果强调了变异检测的变异来源以及在全基因组测序精准医疗时代改进生物信息学流程的必要性。在线版本包含可在 10.1186/s13059-021-02569-8 获取的补充材料。
Reproducible detection of inherited variants with whole genome sequencing (WGS) is vital for the implementation of precision medicine and is a complicated process in which each step affects variant call quality. Systematically assessing reproducibility of inherited variants with WGS and impact of each step in the process is needed for understanding and improving quality of inherited variants from WGS. To dissect the impact of factors involved in detection of inherited variants with WGS, we sequence triplicates of eight DNA samples representing two populations on three short-read sequencing platforms using three library kits in six labs and call variants with 56 combinations of aligners and callers. We find that bioinformatics pipelines (callers and aligners) have a larger impact on variant reproducibility than WGS platform or library preparation. Single-nucleotide variants (SNVs), particularly outside difficult-to-map regions, are more reproducible than small insertions and deletions (indels), which are least reproducible when > 5 bp. Increasing sequencing coverage improves indel reproducibility but has limited impact on SNVs above 30×. Our findings highlight sources of variability in variant detection and the need for improvement of bioinformatics pipelines in the era of precision medicine with WGS. The online version contains supplementary material available at 10.1186/s13059-021-02569-8.
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