Venter’s group published a new paper on minimal genome.
A goal in biology is to understand the molecular and biological function of every gene in a cell. One way to approach this is to build a minimal genome that includes only the genes essential for life. In 2010, a 1079-kb genome based on the genome of Mycoplasma mycoides (JCV-syn1.0) was chemically synthesized and supported cell growth when transplanted into cytoplasm. Hutchison III et al. used a design, build, and test cycle to reduce this genome to 531 kb (473 genes). The resulting JCV-syn3.0 retains genes involved in key processes such as transcription and translation, but also contains 149 genes of unknown function.
What do those 149 genes do? The authors suggest existence of undiscovered functions essential for life.
Conclusion: The minimal cell concept appears simple at first glance but becomes more complex upon close inspection. In addition to essential and nonessential genes, there are many quasi-essential genes, which are not absolutely critical for viability but are nevertheless required for robust growth. Consequently, during the process of genome minimization, there is a trade-off between genome size and growth rate. JCVI-syn3.0 is a working approximation of a minimal cellular genome, a compromise between small genome size and a workable growth rate for an experimental organism. It retains almost all the genes that are involved in the synthesis and processing of macromolecules. Unexpectedly, it also contains 149 genes with unknown biological functions, suggesting the presence of undiscovered functions that are essential for life. JCVI-syn3.0 is a versatile platform for investigating the core functions of life and for exploring whole-genome design.
Readers may also enjoy the discussions on the paper in ‘In the Pipeline’ blog
Think about that for a minute. One third of this stripped-down minimialist genome is still made of of genes that we dont understand. There are some kinases and hydrolases, etc., whose substrates, products, and functions are unknown, but there are some that are just big question marks. Clearly we have some work to do if there are so many fundamental processes that arent even annotated. Even the annotated ones can be mysterious, though to pick one example, the organism still has six different efflux pathways, and the paper notes that It is somewhat disconcerting to imagine that all of these exclude or remove toxic substances. And some of the genes even in this organism may still be overlapping, because theyve noted a number of synthetic lethal pairs redundant genes that look like they can be eliminated if you take one of them out, but are fatal if both are removed. The biggest design challenges for this organism, the paper says, was working through these and figuring out what had gone wrong in each case. Theyre still not sure how many redundant genes are present.
Interestingly, they also tried defragmenting a large stretch of this genome, placing similar functions next to each other in an orderly arrangement. This rationalized organism was viable, and grew at basically the same rate as the other one, showing that at least at this level, a good deal of genetic rearrangement can take place without having that much effect. (This makes me wonder, a little bit, about the huge-stretches-of-noncoding-DNA-are-vital- because-theyre-scaffolding argument).