Abstract
Mutation rates in different species have been extensively studied in eukaryotes. However, much less is known about variation in mutation rate across the genome. Chromatin modifications may be an important factor in determining mutation rate variation in eukaryotic genomes. We performed a mutation accumulation experiment in the filamentous fungus Neurospora crassa and detected mutations in the MA-lines by genome sequencing. We detected 1322 mutations, which happened during asexual propagation. Our results show a markedly different mutation rate and spectrum than previously reported during sexual reproduction. We observed that mutation rate was higher in regions of low GC, in domains of H3K9 methylation, in centromeric regions, and in domains of H3K27 methylation. Rate of single nucleotide mutations in euchromatin was 2.46 [2.19, 2.77] × 10−10. In contrast, this rate in H3K9me domains was tenfold higher: 2.43 [2.25, 2.62] × 10−9. We also observed that the spectrum of single nucleotide mutations was different in H3K9me and euchromatic domains. We validated our statistical model of mutation rate variation by comparing its predictions to natural genetic variation and observed that a moderate amount of extant genetic variation can be predicted by our model of mutation rate variation. Furthermore, we characterize mutation rates of structural variants and complex mutations in N. crassa. Our study highlights that chromatin modifications influence mutation rate and accurate evolutionary inferences should take variation in mutation rate across the genome into account.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Major revision of the manuscript: We have now estimated the number of mitoses that the mutation accumulation lines went through during the experiment and have now calculated mutation rates per mitosis. Reanalysis of of the mutation model data, now euchromatin is stricly those regions, where neither H3K9 nor H3K27 methylation occurs. For H3K27 we now calculate its effect in only those regions that lack H3K9. This changes the results slightly, and H3K27 now has a small effect on mutation rate. We also calculate mutation rates and mutation spectra separately for euchromating and H3K9 domains. Discussion and introduction have been rewritten. Numerous other smaller fixes Reanalysis of data from Wang et al. 2020 in the supplementary material, to be able to compare our results (mutation that happen during asexual reproduction) to those of Wang et al, (mutation that happen during sexual reproduction.
