Comparing the predictors of mutability among healthy human tissues inferred from mutations in single cell genome data

Author:

Oman MadeleineORCID,Ness Rob W.ORCID

Abstract

AbstractStudying mutation in healthy somatic tissues is key for understanding the genesis of cancer and other genetic diseases. Mutation rate varies from site to site in the human genome by up to 100-fold and is influenced by numerous epigenetic and genetic factors including GC content, trinucleotide sequence context, DNAse accessibility, and histone modifications. These factors influence mutation at both local and regional scales and are often interrelated with one another, meaning that predicting mutability or uncovering its drivers requires modelling multiple factors and scales simultaneously. Historically, most investigations have focused either on analyzing the local sequence scale through triplet signatures or on examining the impact of epigenetic processes at larger scales, but not both concurrently. Additionally, sequencing technology limitations have restricted analyses to mutations only in coding regions (RNA-seq) or to those that have been influenced by selection (bulk tissue). Here we present a comprehensive analysis of epigenetic and genetic factors at multiple scales in the germline and three somatic tissues. We leverage publicly available data for 21 genomic predictors, and somatic mutations from single cell whole genome sequencing. We create models that accurately predict mutability in each tissue, and compare how the genomic predictors of mutability vary across the human body. Our analysis reveals that triplets emerge as robust predictors of mutability in comparison to epigenetic factors. Importantly, we observe both universal and tissue-specific mutagenic processes in healthy tissues, with implications for understanding the maintenance of germline versus soma and the mechanisms underlying early tumorigenesis.

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