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1. Mutation Rate Variability across Human Y-Chromosome Haplogroups

   https://doi.org/10.1093/molbev/msaa268  

   Ding, Qiliang; Hu, Ya; Koren, Amnon; Clark, Andrew G (October 2020, Molecular Biology and Evolution)

   Harris, Kelley (Ed.)

   Abstract A common assumption in dating patrilineal events using Y-chromosome sequencing data is that the Y-chromosome mutation rate is invariant across haplogroups. Previous studies revealed interhaplogroup heterogeneity in phylogenetic branch length. Whether this heterogeneity is caused by interhaplogroup mutation rate variation or nongenetic confounders remains unknown. Here, we analyzed whole-genome sequences from cultured cells derived from >1,700 males. We confirmed the presence of branch length heterogeneity. We demonstrate that sex-chromosome mutations that appear within cell lines, which likely occurred somatically or in vitro (and are thus not influenced by nongenetic confounders) are informative for germline mutational processes. Using within-cell-line mutations, we computed a relative Y-chromosome somatic mutation rate, and uncovered substantial variation (up to 83.3%) in this proxy for germline mutation rate among haplogroups. This rate positively correlates with phylogenetic branch length, indicating that interhaplogroup mutation rate variation is a likely cause of branch length heterogeneity. 

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2. 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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3. Nanorate sequencing reveals the Arabidopsis somatic mutation landscape

   https://doi.org/10.1101/2025.06.15.659769  

   Meyer, Cullan A; Nelms, Brad; Schmitz, Robert J (June 2025, bioRxiv)

   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 in Arabidopsis shoots with high sensitivity. We report a somatic mutation rate of 3.6x10^-8 mutations/bp, ~4-5x the germline mutation rate. 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 DNA methylation and chromatin accessibility have different predicted effects on mutation rate for genic and non-genic regions; DNA methylation associates with a greater increase in mutation rate when in non-genic regions, and accessible chromatin associates with a lower mutation rate in non-genic 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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4. The landscape of somatic mutations in lymphoblastoid cell lines

   https://doi.org/10.1016/j.xgen.2023.100305  

   Caballero, Madison; Koren, Amnon (June 2023, Cell Genomics)

   Somatic mutations have important biological ramifications while exerting substantial rate, type, and genomic location heterogeneity. Yet, their sporadic occurrence makes them difficult to study at scale and across individuals. Lymphoblastoid cell lines (LCLs), a model system for human population and functional genomics, harbor large numbers of somatic mutations and have been extensively genotyped. By comparing 1,662 LCLs, we report that the mutational landscape of the genome varies across individuals in terms of the number of mutations, their genomic locations, and their spectra; this variation may itself be modulated by somatic trans-acting mutations. Mutations attributed to the translesion DNA polymerase η follow two different modes of formation, with one mode accounting for the hypermutability of the inactive X chromosome. Nonetheless, the distribution of mutations along the inactive X chromosome appears to follow an epigenetic memory of the active form. 

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5. Genome-wide analysis of cadmium-induced, germline mutations in a long-term Daphnia pulex mutation-accumulation experiment over 1,123 generations.

   Glaholt, Stephen P; Young, Kimberly; Lynch, Michael; Shaw, Joseph R. (November 2022, Environmental health perspectives)

   Germline mutations provide the raw material for all evolutionary processes and contribute to the occurrence of spontaneous human diseases and disorders. Yet despite the daily interaction of humans and other organisms with an increasing number of chemicals that are potentially mutagenic, precise measurements of chemically induced changes to the genome-wide rate and spectrum of germline mutation are lacking. A large-scale mutation-accumulation experiment was propagated in the presence and absence of an environmentally relevant cadmium concentration to quantify the influence of cadmium on germline mutation rates and spectra. Cadmium exposure dramatically changed the genome-wide rates and regional spectra of germline mutations. In comparison with those in control conditions, exposed to cadmium had a higher overall mutation rates and a lower overall mutation rate. exposed to cadmium had a higher intergenic mutation rate and a lower exonic mutation rate. The higher intergenic mutation rate under cadmium exposure was the result of an elevated intergenic rate, whereas the lower exon mutation rate in cadmium was the result of a complete loss of exonic mutations-mutations that are known to be enriched at 5-hydroxymethylcytosine. We experimentally show that cadmium exposure significantly reduced 5-hydroxymethylcytosine levels. These results provide evidence that cadmium changes regional mutation rates and can influence regional rates by interfering with an epigenetic process in the germline. We further suggest these observed cadmium-induced changes to the germline mutation rate may be explained by cadmium's inhibition of zinc-containing domains. The cadmium-induced changes to germline mutation rates and spectra we report provide a comprehensive view of the mutagenic perils of cadmium and give insight into its potential impact on human population health. https://doi.org/10.1289/EHP8932. 

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