4.4 Synthetic pan-genomes
Large-scale sequencing studies have unravelled the fundamentals of
genetic diversity leading to the concept of a pan-genome (Peter et al.,
2018). Similar to minimal genomes, pan-genomes seek industrial workhorse
applications by stretching the bounds of what genetic substrates can
encode within a functional organism. The laboratory strain S288C, and
future minimal genome derivatives, are ultimately restricted in their
application and lack many of the genotypic features found in industrial
strains that define their utility in niche environments (Warringer et
al., 2011). In this context, encoding pan-genomic functionality onto a
defined neochromosome will complement the objectives of a minimal
genome. For example, additional phenotypic plasticity was added to the
Sc2.0 substrate through the pan-genomic bolt-on of a
17th neochromosome (Kutyna et al., 2022). In this
example, not only does a potential minimal genome gain from the
rationalisation of the Sc2.0 chassis as an engineering platform, but the
neo-chromosome provides a mechanism to selectively reintroduce naturally
occurring wild-type genomic diversity in an abstracted manner. This
approach can be used to drive differential carbon source use but would
also be amenable to modifying or modulating many of the minimal genomic
attributes of the Sc2.0 platform.
The pan-genomic approach to biodesign has also been shown to integrate
well with the SCRaMbLE methodology. This provides the researcher with
two techniques, one probabilistically random and one based on active
human choices. When both techniques are integrated, they provide a way
to combinatorially build large phenotypic diversity from a singular
starter platform. SCRaMbLE introduces the large opportunity space to
work in concert with the genetic diversity of a defined neo-chromosome,
thus directing phenotypic diversity towards user-defined evolutionary
outcomes and attributes.
Finally, although these concepts represent good examples of ‘top-down’
and ‘bottom-up’ approaches to engineering yeast for industrial
biotechnology, exploring these methods in concert with microbial
community dynamics represents a largely untouched and exciting research
opportunity.