Transcription may be mutagenic in germline but not somatic tissues
When a mutation arises in an egg or sperm cell, it could be evolutionarily important. But if a mutation occurs in somatic tissue instead, the result could be cancer. Mutations in the germline and soma not only have contrasting consequences, they also arise at different rates that may reflect the balance of DNA damage and repair pathways in different tissue types. In the September issue of GENETICS, Chen et al. predict gene mutation rates in different tissues and find that high expression increases mutation rates in the germline, but not in somatic tissue.
The first step was to obtain a reliable estimate of the mutation rate in both germ cells and somatic tissues. The researchers relied on a set of germline mutations, previously identified using exome data from thousands of sets of parents and children. Any variation that was unique to the children must be caused by germline mutation in either the father or mother. To identify somatic mutations, the researchers analyzed three different cancer samples that included whole exome sequence of both normal and malignant cells. Variation unique to either tissue type predates the tumor and should be due to somatic mutations.
A statistical model that evaluated how well various factors predict the mutation rate revealed a key difference. In germ cells, a high gene expression level was linked to a higher mutation rate, but the opposite was observed in somatic tissues. Though the magnitude of the effect varied in the three different cancer types, there was always a negative correlation with expression. Other factors also contributed differently to mutation in the germline and somatic tissues, including GC content for the germline and replication timing in the soma.
Gene expression level probably affects mutation rate because the DNA double helix unzips to accommodate transcription machinery, making the individual strands more vulnerable to mutagens, and because there is a dedicated repair mechanism to fix DNA damage that occurs in transcribed regions. The opposite effects of expression level on mutation rates suggests germline and somatic tissues have marked differences in the balance between damage and repair. For example, expression may be more mutagenic in the germline, or repair mechanisms may be more efficient in the soma. There could even be unidentified DNA damage repair processes that are unique to certain tissues. Though somatic mutations can’t be passed down to the next generation like germline mutations, they are the root cause of most cancers. Quickly and correctly repairing this DNA damage is vital for an organism’s survival.
Contrasting Determinants of Mutation Rates in Germline and Soma
Chen Chen, Hongjian Qi, Yufeng Shen, Joseph Pickrell, and Molly Przeworski
GENETICS September 1, 2017. 207 (1): 255-267