Enhancing Variant Calling in Whole-exome Sequencing Data Using Population-matched Reference Genomes  

作　　者：Shuming Guo Zhuo Huang Yanming Zhang Yukun He Xiangju Chen Wenjuan Wang Lansheng Li Yu Kang Zhancheng Gao Jun Yu Zhenglin Du Yanan Chu 

机构地区：[1]Linfen Clinical Medicine Research Center,LinFen Central Hospital,LinFen 041000,China [2]China National Center for Bioinformation,Beijing 100101,China [3]Beijing Institute of Genomics,Chinese Academy of Sciences,Beijing 100101,China [4]University of Chinese Academy of Sciences,Beijing 100049,China [5]Department of Respiratory and Critical Care Medicine,Peking University People's Hospital,Beijing 100044,China [6]Institute of PSI Genomics,Wenzhou 325024,China

出　　处：《Genomics, Proteomics & Bioinformatics》2024年第5期99-107,共9页基因组蛋白质组与生物信息学报(英文版)

基　　金：supported by grants from the National Key R&DäProgram of China(Grant No.2021YFC 2301000);the National Science Foundation of China(Grant No.32371537);the Linfen Soft Science Research Project(Grant No.2126);the National and Provincial Key Clinical Specialty Capacity Building Project 2020(Department of the Respiratory Medicine);the Peking University People's Hospital Scientific Research Development Funds(Grant No.RDGS2022-11),China.

摘　　要：Whole-exome sequencing(WES)data are frequently used for cancer diagnosis and genome-wide association studies(GWAS),based on high-coverage read mapping,informative variant calling,and high-quality reference genomes.The center position of the currently used genome assembly,GRCh38,is now challenged by two newly published telomere-to-telomere(T2T)genomes,T2T-CHM13 and T2T-YAO,and it becomes urgent to have a comparative study to test population specificity using the three reference genomes based on real case WES data.Here,we report our analysis along this line for 19 tumor samples collected from Chinese patients.The primary comparison of the exon regions among the three references reveals that the sequences in up to∼1%of target regions in T2T-YAO are widely diversified from GRCh38 and may lead to off-target in sequence capture.However,T2T-YAO still outperforms GRCh38 by obtaining 7.41%of more mapped reads.Due to more reliable read-mapping and closer phylogenetic relationship with the samples than GRCh38,T2T-YAO reduces half of variant calls of clinical significance which are mostly benign,while maintaining sensitivity in identifying pathogenic variants.T2T-YAO also outperforms T2T-CHM13 in reducing calls of Chinese-specific variants.Our findings highlight the critical need for employing population-specific reference genomes in genomic analysis to ensure accurate variant analysis and the significant benefits of tailoring these approaches to the unique genetic background of each ethnic group.

关 键 词：Population-specific reference genome T2T-YAO TUMOR Variant calling Whole-exome sequencing 

分 类 号：Q34[生物学—遗传学]