Plasmid biology is compressed in host chromosomal architecture

Plasmids drive horizontal gene transfer and the spread of antibiotic resistance, yet their distribution across microbial genomes is highly uneven and often viewed as environmentally driven, leaving unresolved whether host chromosomal architecture imposes predictable constraints. Here, using machine learning on 52,393 complete prokaryotic genomes, we show that chromosomal gene content encodes predictive information for multiple dimensions of plasmid biology: carriage status, quantitative load, and mobility potential. Remarkably, highly compressed chromosomal signatures— as few as 15 genes or the coarse-grained composition of seven major enzyme classes—suffice for robust prediction. Moreover, different functional cargoes carried by plasmids, including antibiotic resistance classes, can also be predicted from host chromosomal signatures. These findings establish that plasmid–host compatibility is systematically encoded in host chromosomes, reframing plasmid ecology from environment-driven to host-constrained—a shift with direct implications for combating resistance and engineering stable microbial chassis.