Systematic prediction of genes functionally linked to CRISPR-Cas systems by gene neighborhood analysis

Significance The CRISPR-Cas systems that mediate adaptive immunity in bacteria and archaea encompass a small set of core cas genes that are essential in diverse systems belonging to the same subtype, type, or class. However, a much greater number of genes only sporadically co-occur with CRISPR-Cas, and for most of these, involvement in CRISPR-Cas functions has not been demonstrated. We developed a computational strategy that provides for systematic identification of CRISPR-linked proteins and prediction of their functional association with CRISPR-Cas systems, and employed it to identify 79 previously undetected, putative CRISPR-accessory proteins. A large fraction of these proteins are predicted to be membrane-associated, revealing a potentially unknown side of CRISPR biology.