Unified somatic calling and machine learning-based classification enhance the discovery of clonal hematopoiesis of indeterminate potential

Author:

Tian Shulan,Jenkinson Garrett,Ferrer Alejandro,Yan Huihuang,Morales-Rosado Joel A.,Wang Kevin L.,Lasho Terra L.,Yan Benjamin B.,Baheti Saurabh,Olson Janet E.,Baughn Linda B.,Ding Wei,Slager Susan L.,Patnaik Mrinal S.,Lazaridis Konstantinos N.,Klee Eric W.

Abstract

ABSTRACTClonal hematopoiesis (CH) of indeterminate potential (CHIP), driven by somatic mutations in leukemia-associated genes, confers increased risk of hematologic malignancies, cardiovascular disease and all-cause mortality. In blood of healthy individuals, small CH clones can expand over time to reach 2% variant allele frequency (VAF), the current threshold for CHIP. Nevertheless, reliable detection of low-VAF CHIP mutations is challenging, often relying on deep targeted sequencing. Here, we present UNISOM, a streamlined workflow for CHIP detection from whole-genome and whole-exome sequencing data that are underpowered, especially for low VAFs. UNISOM utilizes a meta-caller for variant detection, in couple with machine learning models which classify variants into CHIP, germline and artifact. In whole-exome data, UNISOM recovered nearly 80% of the CHIP mutations identified via deep targeted sequencing in the same cohort. Applied to whole-genome data from Mayo Clinic Biobank, it recapitulated the patterns previously established in much larger cohorts, including the most frequently mutated CHIP genes, predominant mutation types and signatures, as well as strong associations of CHIP with age and smoking status. Notably, 30% of the identified CHIP mutations had <5% VAFs, demonstrating its high sensitivity toward small mutant clones. This workflow is applicable to CHIP screening in population genomic studies.

Publisher

Cold Spring Harbor Laboratory

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3