小柯机器人

2022年2月7日，美国贝勒医学院Fritz J. Sedlazeck、美国国家标准与技术研究院Justin M. Zook和美国DNAnexus, Inc Chen-Shan Chin团队合作在《自然-生物技术》杂志发表论文，宣布他们的最新研究提出了用于挑战医学相关常染色体基因的准确变异基准。

在本研究中，研究人员使用单倍型解析全基因组组装来表征了395个具有挑战性常染色体基因中的273个。这个精准的基准报告了HG002人类基因组参考集GRCh37和GRCh38中超过17,000个单核苷酸变异、3,600个插入和缺失以及200个结构变异。该研究结果表明，GRCh37或GRCh38中的错误重复会导致医学相关基因（包括CBS、CRYAA和KCNE1）中短读长和长读长技术的参考特异性缺失变体。当掩盖这些错误重复时，变异召回率可以从 8%提高到100%。从单倍型解析全基因组组装形成的基准可能成为未来涵盖全基因组的基准提供原型。

研究人员表示，一些医学相关基因的重复性和复杂性使得在临床环境中对其进行准确分析具有挑战性。Bottle基因组联盟提供了变异基准集，但由于它们的重复性或多态性复杂，这些基因组排除了近400个医学相关基因。

附：英文原文

Title: Curated variation benchmarks for challenging medically relevant autosomal genes

Author: Wagner, Justin, Olson, Nathan D., Harris, Lindsay, McDaniel, Jennifer, Cheng, Haoyu, Fungtammasan, Arkarachai, Hwang, Yih-Chii, Gupta, Richa, Wenger, Aaron M., Rowell, William J., Khan, Ziad M., Farek, Jesse, Zhu, Yiming, Pisupati, Aishwarya, Mahmoud, Medhat, Xiao, Chunlin, Yoo, Byunggil, Sahraeian, Sayed Mohammad Ebrahim, Miller, Danny E., Jspez, David, Lorenzo-Salazar, Jos M., Muoz-Barrera, Adrin, Rubio-Rodrguez, Luis A., Flores, Carlos, Narzisi, Giuseppe, Evani, Uday Shanker, Clarke, Wayne E., Lee, Joyce, Mason, Christopher E., Lincoln, Stephen E., Miga, Karen H., Ebbert, Mark T. W., Shumate, Alaina, Li, Heng, Chin, Chen-Shan, Zook, Justin M., Sedlazeck, Fritz J.

Issue&Volume: 2022-02-07

Abstract: The repetitive nature and complexity of some medically relevant genes poses a challenge for their accurate analysis in a clinical setting. The Genome in a Bottle Consortium has provided variant benchmark sets, but these exclude nearly 400 medically relevant genes due to their repetitiveness or polymorphic complexity. Here, we characterize 273 of these 395 challenging autosomal genes using a haplotype-resolved whole-genome assembly. This curated benchmark reports over 17,000 single-nucleotide variations, 3,600 insertions and deletions and 200 structural variations each for human genome reference GRCh37 and GRCh38 across HG002. We show that false duplications in either GRCh37 or GRCh38 result in reference-specific, missed variants for short- and long-read technologies in medically relevant genes, including CBS, CRYAA and KCNE1. When masking these false duplications, variant recall can improve from 8% to 100%. Forming benchmarks from a haplotype-resolved whole-genome assembly may become a prototype for future benchmarks covering the whole genome. Variant detection in problematic genes is facilitated with a curated benchmark.

DOI: 10.1038/s41587-021-01158-1

Source: https://www.nature.com/articles/s41587-021-01158-1

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