Abstract
A diversity of clustered regularly interspaced short palindromic repeat (CRISPR)-Cas systems provide adaptive immunity to bacteria and archaea through recording "memories" of past viral infections. Recently, many novel CRISPR-associated proteins have been discovered via computational studies, but those studies relied on biased and incomplete databases of assembled genomes. We avoided these biases and applied a network theory approach to search for novel CRISPR-associated genes by leveraging subtle ecological cooccurrence patterns identified from environmental metagenomes. We validated our method using existing annotations and discovered 32 novel CRISPR-associated gene families. These genes span a range of putative functions, with many potentially regulating the response to infection.IMPORTANCE Every branch on the tree of life, including microbial life, faces the threat of viral pathogens. Over the course of billions of years of coevolution, prokaryotes have evolved a great diversity of strategies to defend against viral infections. One of these is the CRISPR adaptive immune system, which allows microbes to "remember" past infections in order to better fight them in the future. There has been much interest among molecular biologists in CRISPR immunity because this system can be repurposed as a tool for precise genome editing. Recently, a number of comparative genomics approaches have been used to detect novel CRISPR-associated genes in databases of genomes with great success, potentially leading to the development of new genome-editing tools. Here, we developed novel methods to search for these distinct classes of genes directly in environmental samples ("metagenomes"), thus capturing a more complete picture of the natural diversity of CRISPR-associated genes.
Highlights
A diversity of clustered regularly interspaced short palindromic repeat (CRISPR)-Cas systems provide adaptive immunity to bacteria and archaea through recording “memories” of past viral infections
The clustered regularly interspaced short palindromic repeat (CRISPR) immune system, widespread in both bacteria and archaea, enables us to designate specific sites that we would like to edit on a genome and either to corrupt or to add to the sequence in those locations [2]
This diversity has sparked something of a gold rush to characterize novel CRISPR proteins and other microbial defense systems
Summary
A diversity of clustered regularly interspaced short palindromic repeat (CRISPR)-Cas systems provide adaptive immunity to bacteria and archaea through recording “memories” of past viral infections. In order to paint a more complete picture of functional CRISPR diversity, we mined a large data set of ocean metagenomes [7] for novel cas genes. We predicted 32 novel putative CRISPR-associated gene families using a neural-network-based label propagation method specialized for annotation problems with a small number of positive annotations (Fig. 1b) [9].
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