Cross-species analysis identifies APOBEC3-associated spliceosomal snRNA hypermutability
Spliceosomal small nuclear RNA (snRNA) genes show unusually high germline mutation rates, with R-loop formation previously implicated in this mutability. Our cross-species rare-variant and de novo mutation analyses show that hypermutability is concentrated in RNA polymerase II-transcribed spliceosomal snRNA genes, with strong enrichment in primates but a much weaker excess in rodents and chicken,…
Spliceosomal small nuclear RNA (snRNA) genes exhibit higher mutation rates in germline cells, with R-loop formation previously thought to contribute to this hypermutability. By examining rare-variant and de novo mutations across species, researchers found that this hypermutability is primarily concentrated in RNA polymerase II-transcribed spliceosomal snRNA genes.
Notably, this pattern shows a strong enrichment in primates, while rodents and chicken display a much weaker excess, suggesting lineage-specific differences in APOBEC3 repertoires. Human Pol II-transcribed spliceosomal snRNA genes exhibit a strand asymmetry in mutations, as well as APOBEC3-associated mutational signatures and strong signals for APOBEC3B binding.
Additionally, R-loops are frequently observed at these loci, even in mouse genes with considerably less hypermutability, implying that R-loop formation alone is not enough to account for the hypermutability observed in these genes. Overall, comparing data across species supports the idea that lineage-specific APOBEC3 activity plays a significant role in spliceosomal snRNA gene hypermutability, rather than R-loop formation being the sole cause.
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