---
title: "Genetic determinants of local mutation rates and identification of mutQTLs"
id: "pubmed-42658760"
canonical_url: "https://medichelpline.com/clinical-feed/pubmed-42658760"
content_type: "clinical_feed_article"
specialty: "Oncology"
source_name: "PubMed / NCBI"
source_url: "https://pubmed.ncbi.nlm.nih.gov/42658760/"
doi: "10.1073/pnas.2625619123"
published_at: "2026-08-27T12:00:00.000Z"
evidence_level: "Journal Article"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Genetic determinants of local mutation rates and identification of mutQTLs
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/pubmed-42658760
- **Specialty:** [Oncology](https://medichelpline.com/clinical-feed/oncology.md)
- **Primary Source:** PubMed / NCBI
- **Source URL:** [Original Journal Publication](https://pubmed.ncbi.nlm.nih.gov/42658760/)
- **DOI:** [10.1073/pnas.2625619123](https://doi.org/10.1073%2Fpnas.2625619123)
- **Published At:** 2026-08-27T12:00:00.000Z
- **Evidence Rating:** Journal Article
## Executive GIST (TL;DR)
- The study investigated whether **local mutation rates** vary among individuals and whether such variation is genetically determined. - Researchers analyzed the chromosomal distribution of somatic mutations in cell lines from 1,662 individuals. - Analyses controlled for confounders including DNA replication timing and trans-acting factors that alter global mutation rates. - The authors report substantial interindividual variation in mutation rates across the human genome after accounting for those confounders. - By comparing mutation-rate variation to germline genotypes, the study identified 35 genomic loci where polymorphic alleles associate with increased or decreased somatic mutation rates in nearby regions. These loci are termed **mutation quantitative trait loci (mutQTLs)**. - Some mutQTLs associated with mutation patterns observed in lymphoblastoid cell lines and in chronic lymphocytic leukemia, and they overlapped with germline variation. - Four mutQTLs were inferred to be associated with germline mutation-rate variation; two of those four localized within large clusters of **zinc-finger genes** and transposable elements and acted as **cis-mutators**, increasing local mutation rate. - The findings indicate that genetic variation can shape heterogeneity in mutation rates across the genome and among individuals, offering a window into the evolution of mutation-rate landscapes. - The study frames mutQTLs as tools to understand how mutation-rate heterogeneity arises and may impact both somatic disease (including cancer) and germline mutation processes.
## Clinical Analysis & Structured Key Points
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Epub 2026 Aug 27. # Genetic control of local mutation rates [Madison Caballero](https://pubmed.ncbi.nlm.nih.gov/?term=Caballero+M&cauthor_id=42658760)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42658760/#full-view-affiliation-1 "Department of Molecular and Cellular Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263."), [Amnon Koren](https://pubmed.ncbi.nlm.nih.gov/?term=Koren+A&cauthor_id=42658760)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42658760/#full-view-affiliation-1 "Department of Molecular and Cellular Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263.") Affiliations Expand ### Affiliation * 1 Department of Molecular and Cellular Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263. * PMID: **42658760** * DOI: [ 10.1073/pnas.2625619123 ](https://doi.org/10.1073/pnas.2625619123) Item in Clipboard # Genetic control of local mutation rates Madison Caballero et al. Proc Natl Acad Sci U S A. 2026 Sep. Show details Display options Display options Format Abstract PubMed PMID Proc Natl Acad Sci U S A Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Proc+Natl+Acad+Sci+U+S+A%22%5Bjour%5D&sort=date&sort_order=desc) * [ Search in NLM Catalog ](https://www.ncbi.nlm.nih.gov/nlmcatalog?term=%22Proc+Natl+Acad+Sci+U+S+A%22%5BTitle+Abbreviation%5D) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42658760/) . 2026 Sep;123(35):e2625619123. doi: 10.1073/pnas.2625619123. Epub 2026 Aug 27. ### Authors [Madison Caballero](https://pubmed.ncbi.nlm.nih.gov/?term=Caballero+M&cauthor_id=42658760)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42658760/#short-view-affiliation-1 "Department of Molecular and Cellular Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263."), [Amnon Koren](https://pubmed.ncbi.nlm.nih.gov/?term=Koren+A&cauthor_id=42658760)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42658760/#short-view-affiliation-1 "Department of Molecular and Cellular Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263.") ### Affiliation * 1 Department of Molecular and Cellular Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263. * PMID: **42658760** * DOI: [ 10.1073/pnas.2625619123 ](https://doi.org/10.1073/pnas.2625619123) Item in Clipboard Cite Display options Display options Format Abstract PubMed PMID ## Abstract Mutations are the source of evolutionary novelty but also the cause of genetic diseases and cancer. Mutation rates are known to be heterogeneous along the genome, however the extent to which local mutation rates vary among individuals in a population and are genetically determined is unknown. To test this, we analyzed the chromosomal distribution of somatic mutations in cell lines from 1,662 individuals, controlling for the confounding effects of DNA replication timing on local mutation rates and of _trans_ -acting modulators on global mutation rates. We describe substantial interindividual variation in mutation rates across the human genome. By comparing mutation-rate variation to individuals' genotypes, we identified 35 instances in which polymorphic alleles in the population associate with somatic mutation rates in their vicinity. We call these mutation quantitative trait loci (mutQTLs). mutQTLs associated with somatic mutations in lymphoblastoid cell lines and in chronic lymphocytic leukemia, and with germline genetic variants. Two of the four mutQTLs inferred to be associated with germline mutation-rate variation were located within large clusters of zinc-finger genes and transposable elements, where they functioned as _cis_ -mutators conferring an increased rate of mutation in their vicinity. mutQTLs provide a portal into the evolution of mutation rate heterogeneity across the genome and across individuals. **Keywords:** QTL; genetics; mutation. 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