A central undertaking in synthetic biology (SB) is the quest for the 'minimal 
genome'. However, 'minimal sets' of essential genes are strongly 
context-dependent and, in all prokaryotic genomes sequenced to date, not a 
single protein-coding gene is entirely conserved. Furthermore, a lack of 
consensus in the field as to what attributes make a gene truly essential adds 
another aspect of variation. Thus, a universal minimal genome remains elusive. 
Here, as an alternative to defining a minimal genome, we propose that the 
concept of gene persistence can be used to classify genes needed for robust 
long-term survival. Persistent genes, although not ubiquitous, are conserved in 
a majority of genomes, tend to be expressed at high levels, and are frequently 
located on the leading DNA strand. These criteria impose constraints on genome 
organization, and these are important considerations for engineering cells and 
for creating cellular life-like forms in SB.