Evaluation of GRCh38 and de novo haploid genome assemblies demonstrates the enduring quality of the reference assembly
Evaluation of GRCh38 and de novo haploid genome assemblies demonstrates the enduring quality of the reference assembly
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DOI：
10.1101/gr.213611.116
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发表时间：
2017-05-01
期刊：
影响因子：
7
通讯作者：
Church, Deanna M.
中科院分区：
文献类型：
--
作者：
Schneider, Valerie A.;Graves-Lindsay, Tina;Church, Deanna M.
人类参考基因组组装在当今基础研究和临床研究的几乎所有方面都起着核心作用。GRCh38是自2009年以来首次坐标变更的组装更新；它解决了大约1000个问题，包含从数千个单碱基变化到百万碱基规模的路径重组、缺口填补以及先前孤立序列的定位等多种修改。我们开发了一种用于靶向碱基更新的新的序列生成方法，并利用来自新的基因组图谱技术和单倍型资源的数据来识别和解决更大的组装问题。参考组装首次包含了着丝粒的基于序列的呈现。我们还增加了替代位点的数量，以创建一个能更有力地呈现人类群体变异的参考。我们证明这些更新使参考成为一种改进的注释底物，改变了未改变区域的读段比对，并影响了临床相关位点的变异解读。我们还评估了一组新的从头长读段单倍体组装，得出的结论是，尽管新的组装在连续性、错误率和基因完整性方面与参考相比具有优势，但参考仍然为复杂的基因组区域和编码序列提供了最佳呈现。我们断言，GRCh38中收集的更新使新的组装成为一种更稳健的底物，可用于全面分析，这将促进我们对人类生物学的理解，并推动我们改善健康的努力。
The human reference genome assembly plays a central role in nearly all aspects of today's basic and clinical research. GRCh38 is the first coordinate-changing assembly update since 2009; it reflects the resolution of roughly 1000 issues and encompasses modifications ranging from thousands of single base changes to megabase-scale path reorganizations, gap closures, and localization of previously orphaned sequences. We developed a new approach to sequence generation for targeted base updates and used data from new genome mapping technologies and single haplotype resources to identify and resolve larger assembly issues. For the first time, the reference assembly contains sequence-based representations for the centromeres. We also expanded the number of alternate loci to create a reference that provides a more robust representation of human population variation. We demonstrate that the updates render the reference an improved annotation substrate, alter read alignments in unchanged regions, and impact variant interpretation at clinically relevant loci. We additionally evaluated a collection of new de novo long-read haploid assemblies and conclude that although the new assemblies compare favorably to the reference with respect to continuity, error rate, and gene completeness, the reference still provides the best representation for complex genomic regions and coding sequences. We assert that the collected updates in GRCh38 make the newer assembly a more robust substrate for comprehensive analyses that will promote our understanding of human biology and advance our efforts to improve health.