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1. Nanorate sequencing reveals the Arabidopsis somatic mutation landscape

   https://doi.org/10.1073/pnas.2514194122  

   Meyer, Cullan A; Nelms, Brad; Schmitz, Robert J (December 2025, Proceedings of the National Academy of Sciences)

   The rate and spectrum of somatic mutations can diverge from that of germline mutations. This is because somatic tissues experience different mutagenic processes than germline tissues. Here, we use nanorate sequencing (NanoSeq) to identify somatic mutations inArabidopsisshoots with high sensitivity. We report a somatic mutation rate of 3.6 × 10⁻⁸mutations/bp, ~2 to 7× measured germline mutation rates. Somatic mutations displayed elevated signatures consistent with oxidative damage, UV damage, and transcription-coupled nucleotide excision repair. Both somatic and germline mutations were enriched in transposable elements and depleted in genes, but this depletion was greater in germline mutations. Somatic mutation rate correlated with proximity to the centromere, DNA methylation, chromatin accessibility, and gene/TE content, properties which were also largely true of germline mutations. We note that DNA methylation and chromatin accessibility have different predicted effects on mutation rate for genic and nongenic regions; DNA methylation associates with a greater increase in mutation rate when in nongenic regions, and accessible chromatin associates with a lower mutation rate in nongenic regions but a higher mutation rate in genic regions. Together, these results characterize key differences and similarities in the genomic distribution of somatic and germline mutations. 

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2. Associations between DNA methylation and gene regulation depend on chromatin accessibility during transgenerational plasticity

   https://doi.org/10.1186/s12915-023-01645-8  

   Bogan, Samuel N.; Strader, Marie E.; Hofmann, Gretchen E. (December 2023, BMC Biology)

   Abstract Background Epigenetic processes are proposed to be a mechanism regulating gene expression during phenotypic plasticity. However, environmentally induced changes in DNA methylation exhibit little-to-no association with differential gene expression in metazoans at a transcriptome-wide level. It remains unexplored whether associations between environmentally induced differential methylation and expression are contingent upon other epigenomic processes such as chromatin accessibility. We quantified methylation and gene expression in larvae of the purple sea urchin Strongylocentrotus purpuratus exposed to different ecologically relevant conditions during gametogenesis (maternal conditioning) and modeled changes in gene expression and splicing resulting from maternal conditioning as functions of differential methylation, incorporating covariates for genomic features and chromatin accessibility. We detected significant interactions between differential methylation, chromatin accessibility, and genic feature type associated with differential expression and splicing. Results Differential gene body methylation had significantly stronger effects on expression among genes with poorly accessible transcriptional start sites while baseline transcript abundance influenced the direction of this effect. Transcriptional responses to maternal conditioning were 4–13 × more likely when accounting for interactions between methylation and chromatin accessibility, demonstrating that the relationship between differential methylation and gene regulation is partially explained by chromatin state. Conclusions DNA methylation likely possesses multiple associations with gene regulation during transgenerational plasticity in S. purpuratus and potentially other metazoans , but its effects are dependent on chromatin accessibility and underlying genic features. 

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3. Genetic control of local mutation rates

   https://doi.org/10.1073/pnas.2625619123  

   Caballero, Madison; Koren, Amnon (September 2026, Proceedings of the National Academy of Sciences)

   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. 

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4. DNA methylation analysis reveals epimutation hotspots in patients with dilated cardiomyopathy-associated laminopathies

   https://doi.org/10.1186/s13148-021-01127-0  

   Morival, Julien L.; Widyastuti, Halida P.; Nguyen, Cecilia H.; Zaragoza, Michael V.; Downing, Timothy L. (December 2021, Clinical Epigenetics)

   Abstract Background Mutations in LMNA , encoding lamin A/C, lead to a variety of diseases known as laminopathies including dilated cardiomyopathy (DCM) and skeletal abnormalities. Though previous studies have investigated the dysregulation of gene expression in cells from patients with DCM, the role of epigenetic (gene regulatory) mechanisms, such as DNA methylation, has not been thoroughly investigated. Furthermore, the impact of family-specific LMNA mutations on DNA methylation is unknown. Here, we performed reduced representation bisulfite sequencing on ten pairs of fibroblasts and their induced pluripotent stem cell (iPSC) derivatives from two families with DCM due to distinct LMNA mutations, one of which also induces brachydactyly. Results Family-specific differentially methylated regions (DMRs) were identified by comparing the DNA methylation landscape of patient and control samples. Fibroblast DMRs were found to enrich for distal regulatory features and transcriptionally repressed chromatin and to associate with genes related to phenotypes found in tissues affected by laminopathies. These DMRs, in combination with transcriptome-wide expression data and lamina-associated domain (LAD) organization, revealed the presence of inter-family epimutation hotspots near differentially expressed genes, most of which were located outside LADs redistributed in LMNA -related DCM. Comparison of DMRs found in fibroblasts and iPSCs identified regions where epimutations were persistent across both cell types. Finally, a network of aberrantly methylated disease-associated genes revealed a potential molecular link between pathways involved in bone and heart development. Conclusions Our results identified both shared and mutation-specific laminopathy epimutation landscapes that were consistent with lamin A/C mutation-mediated epigenetic aberrancies that arose in somatic and early developmental cell stages. 

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5. Somatic selection shapes mutation accumulation in Citrus sinensis

   https://doi.org/10.1101/2025.09.24.678405  

   Beaulieu, Taylor R; Avila_de_Dios, Emmanuel; Seymour, Danelle K (September 2025, bioRxiv)

   An organism becomes genetically mosaic through the accumulation of somatic mutations. Genetic mosaicism is a commonality of multicellular life and has been studied extensively in humans due to its associations with aging and diseases. In humans, somatic selection shapes the accumulation of somatic mutations, with strong signatures of positive somatic selection in cancer cell lineages. So far, evidence for somatic selection in plants has been inconsistent. The evolutionary implications of genetic mosaicism in humans and other animals are limited by early specification of germline cells, preventing transmission of somatic mutations to progeny. In contrast, many plant lineages reproduce asexually with clonal progeny derived from vegetative tissues. We describe the patterns and processes shaping somatic mutation accumulation within a single, 149-year-old historic sweet orange (Citrus sinensis) tree and within a clonal lineage of sweet orange. More than 12,000 somatic mutations were identified in the historic tree and 28,000 somatic mutations were identified across 199 clonally related sweet orange accessions. Both the spatial and genomic distributions of somatic mutations are non-random. The spatial patterns of somatic mutations across the historic tree depend on tree growth and development and their accumulation across the tree canopy recapitulates branching topology. Analysis of the genomic distribution of somatic mutations revealed that the subtelomeres, which are large arrays of ~180 bp repeats, are mutation hotspots. Finally, there was genomic evidence that somatic selection shapes the accumulation of somatic mutations both within the historic tree and also during clonal propagation. 

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