The leading region of many conjugative plasmids is depleted in restriction-modification targets

The leading region of conjugative plasmids is the first to enter recipient cells during conjugation. This region is enriched in anti-defence genes, suggesting that defence system evasion shapes plasmid organization. Might this selective pressure also variably impact sequence composition? Here we hypothesize that the leading region is subject to stronger selection to avoid triggering defence systems. We investigate this for Type II restriction-modification (RM) systems, using a dataset of thousands of conjugative plasmids belonging to different plasmid taxonomic units (PTUs). Consistent with our hypothesis, we find evidence of RM target depletion in leading regions, despite higher average GC-content in the leading region which should increase palindrome density. We find evidence of strand-specific nucleotide skews that could cause this depletion, which we suggest could have drivers beyond RM evasion. Our work opens up intriguing questions about how the sequence composition of the leading region has been shaped by different selective pressures.