In 2012, entrepreneur Craig Venter was going to save the world with synthetic microbes. In his view life is simply "DNA software" with a "cell there to read it" .
He set about creating a cell with the smallest number of genes, "a cell so simple that we can determine the molecular and biological function of every gene". His plan was to identify a core set of genes and synthesise a minimal genome able to produce an independent, replicating cell. The ultimate goal was the construction of a designer cell with whatever properties human beings desired.
By the time he published a paper on his project four years later, Venter had realised the whole life thing is more complex than he'd envisaged: the genes not critical for simply staying alive in a perfect, stress-free environment are nevertheless needed for "robust growth".
Meanwhile, scientists less obsessed with creating artificial life have noticed that physical and physiological traits are rarely directly related to specific genes. Their understanding has moved from single gene effects as famously described by Mendel in his pea inheritance experiments, to hubs of genes contributing to the same trait, and on to huge numbers of genes within a genome-wide regulatory network all contributing tiny amounts to the outcome, and finally to a whole-cell genetic network in which genes work in concert, interact with each other and connect coherently within and between protein complexes and pathways. This last picture came from a "magisterial", "monumental" (some said "insane") set of experiments involving 52 scientists and 17 years of work.
Using yeast, a very well characterised and easily-grown laboratory life-form, and yeast colony-size as a proxy for fitness, the team systematically disabled individual pairs of genes in twenty-three million yeast strains.
Their conclusion was not that the genome is full of redundant historical dross which for some reason has never gone away, but that evolution has built many overlapping systems into the cell so that if one part goes, the whole thing doesn't fall apart.
When the experiment was extended for another couple of years by a reduced team of 32 scientists who disabled triplets of genes in the yeast, the conclusion became inescapable: living cells need all their genes. The minimal genome is a fantasy, incompatible with healthy life.
This explains why it's possible to add bits, remove bits and edit bits of the genome without killing the resulting genetically modified organism: successful novel organisms have other genes which adapt to compensate for the disturbance. It also explains why GMOs are inherently unpredictable, why they may be exquisitely vulnerable to stress, and why they're never going to be 'substantially equivalent'  to their non-GM counterpart unless you widen the 'equivalence' goal-posts to the ends of the world.
 CRAIG VENTNER'S WEIRD WORLD - July 2012
 META-ANALYSIS SHOWS HOW DIFFERENT GM REALLY IS - August 2018
- Clyde A. Hutchison, et al., March 2016, Design and synthesis of a minimal bacterial genome, Science Magazine
- Michael Costanzo, et al., September 2016, A global genetic interaction network maps a wiring diagram of cellular function, Science Magazine
- Veronique Greenwood, Giant Genetic Map Shows Life's Hidden Links, Quanta Magazine 26.10.16
- Evan A. Boyle, et al., June 2017, An Expanded View of Complex Traits: From Polygenic to Omnigenic, Cell 169
- Elena Kuzmin, et al., April 2018, Systematic analysis of complex genetic interactions, Science Magazine
- Veronique Greenwood, Theory Suggests That All Genes Affect Every Complex Trait, Quanta Magazine, 20.06.18
- Veronique Greenwood, How Many Genes Do Cells Need? Maybe Almost All of Them, Quanta Magazine 19.04.18Photo Creative Commons