Linear covariation between germline and somatic mutation rates across ciliates and mammals

Somatic mutations have received increased attention due to their roles in disease (e.g., cancer) and possibly aging.¹ In mammals, the somatic mutation rate per site per year (μ_S) is at least 10 times higher than the corresponding germline rate (μ_G).^2,3,4,5,6 Because the DNA replication and repair machinery is largely shared between the germline and soma, their substantial disparity in mutation rate is commonly hypothesized to be owing to their different cell division rates and/or differential mutagen exposures.^6,7,8 To test the above hypothesis, we take advantage of ciliates-unicellular eukaryotes that contain in the same cell 2 nuclei dividing at the same rate but respectively harboring the germline and somatic genome.⁹ Performing mutation accumulation experiments in the model ciliate Tetrahymena thermophila, we estimate that its base-substitution somatic mutation rate is 1.32 × 10^-10 per site per generation, 17.3 times the germline rate.¹⁰ Strikingly, we find μ_S and μ_G to covary linearly across T. thermophila and 6 mammals, despite the independent origins of the germ-soma separation in ciliates and animals. The overall pattern of somatic mutations in T. thermophila also resembles that in mammals. These observations call for the investigation of a possible linear coupling between μ_S and μ_G across diverse organisms and argue against a primary role of different cell division rates or differential mutagen exposures in determining the relationship between μ_S and μ_G. They also suggest that whatever the evolutionary forces shaping μ_S and μ_G, these 2 traits are simultaneously impacted, likely because mutations influencing one of them also influence the other.