In a study published in Current Biology on August 14, Prof. MIAO Wei's team at the Institute of Hydrobiology (IHB) of the Chinese Academy of Sciences, and Prof. ZHANG Jianzhi's team at the University of Michigan, estimated the somatic mutation rate in a ciliate, and discovered a linear correlation between germline and somatic mutation rates across ciliates and mammals. The findings challenge common opinions on why germline and somatic mutation rates differ. 

Because the DNA replication and repair machinery of the soma and germline are largely the same, their substantial disparity in mutation rate is hypothesized to be owing to their different cell division rates and/or differential mutagen exposures. However, this hypothesis has not been critically assessed because of the difficulty in experimentally manipulating the cell division rate and/or mutagen exposure across cell types in mammals.

Ciliates are unicellular and exhibit germline-soma nuclear differentiation. Their germline and somatic nuclei share the same cytoplasmic environment, and the genomes they contain replicate the same number of times during asexual growth. This configuration minimizes differences in DNA replication rate and mutagen exposure between the germline and somatic genomes, allowing the test of contributions of these factors to the disparity between germline and somatic mutation rate. 

In this study, researchers established 10 cell lines that underwent ~600 asexual generations through mutation accumulation experiments in model ciliate Tetrahymena thermophila (T. thermophila). As the somatic genome is about 90-ploid and exhibits substantial inter-copy variation, they conducted extremely high-coverage whole-genome sequencing and developed a dedicated mutation-calling pipeline. They validated candidate mutations and estimated that the somatic mutation rate in T. thermophila is 17.3 times that of the germline. 

Then, researchers analyzed the somatic mutation spectrum in T. thermophila, and found that its overall pattern closely resembles that of mammals. Interestingly, the mutation rate was significantly higher in genic than in intergenic regions. By examining nucleotide context, gene expression, and nucleosome occupancy, researchers suggested that enriched nucleosome distribution within gene bodies may contribute to the elevated genic mutation rate.

Moreover, researchers found a strong linear correlation between germline and somatic mutation rates across T. thermophila and six mammals.

This study offers the first somatic mutation rate estimate in unicellular eukaryotes, argues against common beliefs about the causes of the germline-soma mutation rate disparity, and unveils potentially universal linear coupling between germline and somatic mutation rates.