An assessment of the amount of untapped fold level novelty in under-sampled areas of the tree of life

Previous studies of protein fold space suggest that fold coverage is plateauing. However, sequence sampling has been -and remains to a large extent- heavily biased, focusing on culturable phyla. Sustained technological developments have fuelled the advent of metagenomics and single-cell sequencing, which might correct the current sequencing bias. The extent to which these efforts affect structural diversity remains unclear, although preliminary results suggest that uncultured organisms could constitute a source of new folds. We investigate to what extent genomes from uncultured and under-sampled phyla accessed through single cell sequencing, metagenomics and high-throughput culturing efforts have the potential to increase protein fold space, and conclude that i) genomes from under-sampled phyla appear enriched in sequences not covered by current protein family and fold profile libraries, ii) this enrichment is linked to an excess of short (and possibly partly spurious) sequences in some of the datasets, iii) the discovery rate of novel folds among sequences uncovered by current fold and family profile libraries may be as high as 36%, but would ultimately translate into a marginal increase in global discovery of novel folds. Thus, genomes from under-sampled phyla should have a rather limited impact on increasing coarse grained tertiary structure level novelty.