Metagenomic ventures into outer sequence space

Dutilh, Bas E

Metagenomics is the untargeted sequencing of genetic material isolated from communities of micro-organisms and viruses. These communities may be derived from bioreactors, environmental, clinical, or industrial samples; in short, from anywhere in our unsterile biosphere. The classical questions in metagenomics that are asked about the sampled microbial community are "Who is there?" and "What are they doing?." 1 Originally an approach to answer these classical questions, metagenomics as a field has made great progress in the past decade. Applications include the use of metagenomics for the discovery of novel genetic functionality, 2 for describing microbial ecosystems and tracking their variation, 3 in untargeted medical diagnostics and forensics, 4 and as a powerful tool to determine the genome sequences of rare, uncultivable microbes. 5 Powered by advances in next-generation sequencing technology, metagenomics has the potential to venture beyond the limits of currently explored sequence space by sampling environmental microbes and viruses at an unprecedented scale and resolution. Quite literally, sequence space is defined as the multi-dimensional space of all possible nucleotide (or protein) sequences. 6 Sequence space contains n dimensions; one dimension per residue that can take one of 4 (or 20, for proteins) states, with a total volume of S4 n sequences when summed over all possible sequence lengths n. Evolution may have largely explored this space, 7 but it remains an open question how large the current biological sequence space is, i.e. the fraction occupied by extant life. Figuratively, and within the context of this paper, "outer sequence space" is the remainder of this biological sequence space waiting to be explored by science.