Repeat-induced point mutation in Neurospora crassa causes the highest known mutation rate and mutational burden of any cellular life

Background Repeat-induced point (RIP) mutation in Neurospora crassa degrades transposable elements by targeting repeats with C→T mutations. Whether RIP affects core genomic sequence in important ways is unknown. Results By parent-offspring whole genome sequencing, we estimate a mutation rate (3.38 × 10 −6 per bp per generation) that is two orders of magnitude higher than reported for any non-viral organism, with 93–98% of mutations being RIP-associated. RIP mutations are, however, relatively rare in coding sequence, in part because RIP preferentially attacks GC-poor long duplicates that interact in three dimensional space, while coding sequence duplicates are rare, GC-rich, short, and tend not to interact. Despite this, with over 5 coding sequence mutations per genome per generation, the mutational burden is an order of magnitude higher than the previously highest observed. Unexpectedly, the majority of these coding sequence mutations appear not to be the direct product of RIP being mostly in non-duplicate sequence and predominantly not C→T mutations. Nonetheless, RIP-deficient strains have over an order of magnitude fewer coding sequence mutations outside of duplicated domains than RIP-proficient strains. Conclusions Neurospora crassa has the highest mutation rate and mutational burden of any non-viral life. While the high rate is largely due to the action of RIP, the mutational burden appears to be RIP-associated but not directly caused by RIP.