Comparative whole-genome analyses of articular chondrocytes and skin fibroblasts reveal distinct genome instability landscapes in mesenchymal cell types

Abstract

DNA damage lesions can result in mutations and genome rearrangements that are associated with cellular aging and diseases. The landscape of somatic mutations in individual tissue and cell types are dictated by their unique physiological states, cellular functions, mutagenic exposures, and efficiency of DNA repair. Articular chondrocytes and skin fibroblasts are two cell types of mesodermal origin with distinct exposure to internal and external sources of DNA damage. While somatic genome instability features of skin fibroblasts have been well detailed, knowledge about mechanisms underlying genome changes in chondrocytes is scarce. Here, we took a whole-genome sequencing approach to evaluate the load, sources, and patterns of genome changes in 18 primary human chondrocyte clones from donors with and without osteoarthritis (OA). Findings in chondrocyte clones largely agreed with a recent study of 100 single-cell sequenced chondrocytes. We compared genome changes in chondrocytes with clonally-expanded human skin fibroblasts sequenced in our previous studies. We demonstrated that skin fibroblasts show a higher burden of somatic mutations, with an increased rate of mutation accumulation per cell division. Motif-centered analyses of mutation catalogues identified only endogenous sources of mutations in chondrocytes, as opposed to skin fibroblasts which also showed a heavy burden of UV-induced mutations. Spontaneous deamination of meCpG and mutagenesis by exposure to small epoxides and SN2 electrophiles showed higher mutagenic activities in chondrocytes compared to skin fibroblasts. Chondrocytes showed ubiquitous prevalence of indels in homonucleotide runs of ≥5 bases, while skin fibroblasts showed high contributions of UV-associated deletions of ≥5 bp not in repeats. Structural variants in rearrangement hotspots colocalized with human common fragile sites in skin fibroblasts, but not in chondrocytes. Together, our study comprehensively recorded genome instability features in chondrocytes and highlighted the unique mutagenesis landscapes of two mesenchymal cell types. Author summary: Genomes of all human cells accumulate somatic mutations over a lifetime due to exposure to various DNA damaging agents, as well as errors in DNA replication and repair. The source, load, and rate of accumulation of these mutations are variable between individual cell types. High burden of somatic mutations can result in genome instability and contribute to chronic diseases. Hence, it is imperative to identify the modulators of somatic mutagenesis during aging and understand the cell-specific stressors. In this work, we sequence and analyze clonally expanded chondrocyte genomes from donors with and without OA, the most common form of joint disease. We report the baseline levels of somatic SNVs, indels, and large rearrangements in chondrocyte clones and analyze single chondrocyte genomes from a recent paper to corroborate the biological findings. We compare the somatic instability features in chondrocytes with previously sequenced skin fibroblasts. We find higher overall mutagenesis burden in skin fibroblasts compared to chondrocytes, with environmentally induced mutagenic lesions only in skin fibroblasts, and higher levels of endogenous mutagenic activities in chondrocytes. Comparison of these two mesenchymal cell types reveal the roles of anatomic locations and physiological functions in determining the genome instability landscapes of individual cell types.

Original publication: PLOS Genetics (2026-05-20). Source. Source DOI: 10.1371/journal.pgen.1012156.