Abstract
The AID / APOBEC genes are a family of cytidine deaminases that have evolved in vertebrates, and particularly mammals, to mutate RNA and DNA at distinct preferred nucleotide contexts (or “hotspots”) on foreign genomes such as viruses and retrotransposons. These enzymes play a pivotal role in intrinsic immunity defense mechanisms, often deleteriously mutating invading retroviruses or retrotransposons and, in the case of AID, changing antibody sequences to drive affinity maturation. We investigate the strength of various hotspots on their known biological targets by evaluating the potential impact of mutations on the DNA coding sequences of these targets, and compare these results to hypothetical hotspots that did not evolve. We find that the existing AID / APOBEC hotspots have a large impact on retrotransposons and non-mammalian viruses while having a much smaller effect on vital mammalian genes, suggesting co-evolution with AID / APOBECs may have had an impact on the genomes of the viruses we analyzed. We determine that GC content appears to be a significant, but not sole, factor in resistance to deaminase activity. We discuss possible mechanisms AID and APOBEC viral targets have adopted to escape the impacts of deamination activity, including changing the GC content of the genome.
Highlights
The activation induced deaminase (AID)/APOBEC family of cytidine deaminases have important functions in both intrinsic and adaptive immunity
We examined the effects of mutation at each of the 16 different NNC hypothetical hotspots, referred throughout as NNC motifs (N = any nucleotide) to NNT, consistent with the AID/APOBEC deamination mechanism in the absence of further repair
Since we wanted to gain insight into why these particular hotspots evolved, we considered all motifs of the form NNC (N = any nucleotide), which includes 10 hotspots targeted by AID/APOBEC and 6 hypothetical hotspots such as GCC that have not evolved specificity within the AID/APOBEC family
Summary
The AID/APOBEC family of cytidine deaminases have important functions in both intrinsic and adaptive immunity. AID is expressed primarily in germinal center B cells as part of the adaptive immune response [1], whereas the APOBECs act primarily in the intrinsic immune response in various cell types (reviewed in [2]). These mutagenic enzymes act mostly upon single-stranded DNA [3] converting Cytosine in DNA or RNA to Uracil, or for AID, a methylated Cytosine to Thymine in vitro [4]. There appears to be a tradeoff between the benefits and the potential for self-damage of APOBEC-mediated mutations, yet the details on how this tradeoff is achieved both on a biochemical and evolutionary level are still not well understood
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