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Improved NGS variant calling tool for the PRSS1–PRSS2 locus
  1. Haiyi Lou1,
  2. Bo Xie2,
  3. Yimin Wang2,
  4. Yang Gao2,3,
  5. Shuhua Xu1,2,3,4,5,6,7,8
  1. 1 State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, Center for Evolutionary Biology, School of Life Sciences, Fudan University, Shanghai, China
  2. 2 Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
  3. 3 School of Life Science and Technology, ShanghaiTech University, Shanghai, China
  4. 4 Department of Liver Surgery and Transplantation Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
  5. 5 Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, China
  6. 6 Jiangsu Key Laboratory of Phylogenomics and Comparative Genomics, School of Life Sciences, Jiangsu Normal University, Xuzhou, China
  7. 7 Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
  8. 8 Human Phenome Institute, Zhangjiang Fudan International Innovation Center, and Ministry of Education Key Laboratory of Contemporary Anthropology, Fudan University, Shanghai, China
  1. Correspondence to Professor Shuhua Xu, School of Life Sciences, Fudan University, Shanghai, 200438, China; xushua{at}fudan.edu.cn; Dr Haiyi Lou, School of Life Sciences, Fudan University, Shanghai, 200438, China; louhaiyi{at}fudan.edu.cn

https://doi.org/10.1136/gutjnl-2022-327203

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    With interest, we read the two recent studies by Weiss et al and Genin et al, who reported the false positive calls of the missense variants with next-generation sequencing (NGS) on the PRSS1–PRSS2 locus which is associated with pancreatitis.1 2 The false positives were due to the homology between the pseudo-genes PRSS3P2, TRY7 and the protein-coding genes PRSS1, PRSS2, which caused misaligned short-reads and confounded genetic diagnosis of pancreas disease. Here, to provide a cost-effective solution, we offered a toolkit named NGS.PRSS1-2caller (https://github.com/Shuhua-Group/NGS.PRSS1-2caller) to improve variant-detecting on PRSS1–PRSS2 locus from the NGS data. NGS.PRSS1-2caller enables accurately detecting single nucleotide variants, small insertions and deletions and copy number variants with high sensitivity, which could be further applied in the genetic diagnosis at the PRSS1–PRSS2 locus.

    In the human reference genome GRCh38, the alternative contig of chromosome 7 is a 5-gene structure of 10.6 kb tandem duplication with trypsinogen genes PRSS1, PRSS3P1, PRSS3P2, TRY7 and PRSS2 (chr7_KI270803v1_alt:7 49 409-8 01 557),3 while a deletion form is included in the primary chromosome 7 with PRSS1, PRSS3P1 and PRSS2 (chr7:142746720–142778572)4 (online supplemental information). We assessed the NGS read-mapping with simulated short-reads from a typical 3-gene and a 5-gene genome assembly, respectively (online supplemental information). When short-reads from a 5-gene haplotype were aligned to a 3-gene haplotype, the misalignment occurred as reported.1 2 But in other cases, especially when the 5-gene haplotype was used as reference, such misalignment could …

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    Footnotes

    • HL, BX and YW contributed equally.

    • Contributors SX and HL conceived and designed the study. YW discovered the misaligned pattern and analysed the locus structure. HL discovered the link with pancreatitis. SX supervised the study. HL, BX and YW developed the toolkit. HL and BX performed the evaluation. HL, BX, YW and YG performed sequencing data processing and analysis. HL drafted the manuscript. SX revised the manuscript.

    • Funding This study was supported by the National Natural Science Foundation of China (NSFC) grant (32030020, 32041008, 31871256, 31771388 and 31961130380), the Strategic Priority Research Program (XDPB17, XDB38000000) of the Chinese Academy of Sciences (CAS), the UK Royal Society-Newton Advanced Fellowship (NAF\R1\191094) and the Shanghai Municipal Science and Technology Major Project (2017SHZDZX01). The funders had no role in study design, data collection, analysis, decision to publish or preparation of the manuscript.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.