Ancient eukaryotic immunity through genome editing of viral sequences

Mutations provide the raw material for evolution, but mutation rates are not uniform across genomes. Using a mutation accumulation experiment in the marine phytoplankton Bigelowiella natans, we discovered extreme local variation in mutation rate: over 1000-fold differences across its nuclear genome. While the baseline single-nucleotide mutation rate is approximately 3.5x10-10 per site per generation, a common value for unicellular species, two genomic regions derived from ancient integrated viruses exhibit strikingly elevated rates of about 6x10-7. These regions show a distinctive mutational signature with almost exclusively T/A[->]C/G transitions, a pattern also found in other virus-derived sequences, contrary to the usual GC to AT mutation bias. Notably, hypermutation occurs only on TA dinucleotides, and only in a subset of experimental lines, suggesting a regulated process rather than random genomic instability. We propose that B. natans targets invading DNA through localized hypermutation, reminiscent of ADAR and APOBEC antiviral defense systems in animals. Our results suggest that genome-editing-based immunity may have deep evolutionary roots, predating the divergence of major eukaryotic lineages. This is in line with the idea of ancestral immunity, a concept that argues a common and very ancient origin of immune systems, in particular against viruses, which probably exist since the first cell. SIGNIFICANCE STATEMENTDe novo mutations provide the raw material for adaptation, but at exceptionally high frequencies they can compromise genome integrity. Here, we describe a hypermutable process targeting an integrated viral genome in a chlorarachniophyte alga, reminiscent hypermutation-based antiviral defenses described in humans against HIV and influenza; whereby host-mediated deamination of the viral genome increases its mutation rate such that the virus loses its infectivity. The idea of genome-editing-based defenses shared in very divergent branches of eukaryotes supports the ancestral immunity hypothesis, which suggests a deeply conserved origin of immune mechanisms in the tree of life.