title: The landscape of somatic mutations in protein coding genes in apparently benign human tissues carries signatures of relaxed purifying selection.
abstract: Mutations acquired during development and aging lead to inter- and intra-tissue genetic variations. Evidence linking such mutations to complex traits and diseases is rising. We detected somatic mutations in protein-coding regions in 140 benign tissue samples representing nine tissue-types (bladder, breast, liver, lung, prostate, stomach, thyroid, head and neck) and paired blood from 70 donors. A total of 80% of the samples had 2-39 mutations detectable at tissue-level resolution. Factors such as age and smoking were associated with increased burden of detectable mutations, and tissues carried signatures of distinct mutagenic processes such as oxidative DNA damage and transcription-coupled repair. Using mutational signatures, we predicted that majority of the mutations in blood originated in hematopoietic stem and early progenitor cells. Missense to silent mutations ratio and the persistence of potentially damaging mutations in expressed genes carried signatures of relaxed purifying selection. Our findings have relevance for etiology, diagnosis and treatment of diseases including cancer.
authors.affiliation: Department of Medicine, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors.forename: Vinod Kumar
authors.initials: VK
authors.lastname: Yadav
authors.affiliation: Department of Biochemistry and Molecular Genetics. University of Colorado School of Medicine, Aurora, CO 80045, USA Molecular Oncology Program, University of Colorado Cancer Center, Aurora, CO 80045, USA.
authors.forename: James
authors.initials: J
authors.lastname: DeGregori
authors.affiliation: Department of Medicine, University of Colorado School of Medicine, Aurora, CO 80045, USA Molecular Oncology Program, University of Colorado Cancer Center, Aurora, CO 80045, USA Department of Biostatistics and Informatics, Colorado School of Public Health, Aurora, CO 80045, USA subhajyoti.de@ucdenver.edu.
authors.forename: Subhajyoti
authors.initials: S
authors.lastname: De
mesh_terms: D000375:Aging / Q000235:genetics*; D059472:Exome; D005260:Female; D015894:Genome, Human; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008957:Models, Genetic; D059645:Mutation Rate; D020125:Mutation, Missense; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D016366:Open Reading Frames; D009928:Organ Specificity; D012641:Selection, Genetic; D059016:Tumor Microenvironment / Q000235:genetics*