Somatic and germline mutational processes across the tree of life

Abstract The characterisation of mutational processes active in somatic and germline cells in vivo has predominantly focused on human cancers, normal tissues and model organisms. Beyond mammals, little is known about mutational processes across the tree of life. We developed an algorithm, himut, to identify somatic mutations from circular consensus long-read sequencing data, deploying it on 708 samples from 661 species from Britain and Ireland. The spectra of somatic mutations, categorised by mutation type and local sequence context, showed considerable between-species divergence but within-species similarity. From normalised spectra across the dataset, we extracted 95 distinct patterns, or ‘signatures’, of somatic mutations, together with 18 signatures of germline mutational processes. Only two of the somatic signatures resembled mutational signatures extracted from human cancers1,2. Of the somatic signatures, 22 had significant clustering within the taxonomic classification, with some distributed across an entire kingdom or phylum, while others were restricted to a single family or species. Three somatic signatures were found only in water-dwelling species, with one distributed across multiple clades that might suggest it derives from a water-borne mutagen. Of germline signatures, eight were found in multiple species, showed significant clustering by taxonomic classification and had counterpart somatic signatures with matching mutational spectrum and species distribution. Thus, there is considerably greater diversity of mutational processes across the tree of life than found in human tissues, likely reflecting either cell-intrinsic biological processes or environmental exposures (or both) operative within distinct clades.