Bacteria use CRISPR systems to store small pieces of DNA in their genome—called spacers—to guide an immune defense through the recognition, and ultimately destruction, of invading viruses.

New work proposes that foreign spacer acquisition is also a source of autoimmunity—an effect known as “heterologous autoimmunity.” This occurs when a foreign spacer and a segment of the host genome share similarity. The risk of autoimmunity plays a key role in shaping how CRISPR stores viral information, guiding how many spacers bacteria keep in their genes, and how long those spacers are. Balancing antiviral defense against autoimmunity, the authors of a new paper noted, predicts a scaling relation between spacer length and CRISPR repertoire size—a CRISPR repertoire scaling law.

This work is published in Current Biology in the paper, “A scaling law in CRISPR repertoire sizes arises from avoidance of autoimmunity.”

Ideally, spacers should only match DNA belonging to the virus, but there is a small statistical chance that the spacer matches another chunk of DNA in the bacteria itself. That could spell death for the bacteria from an autoimmune response.

“The adaptive immune system in vertebrates can produce autoimmune disorders. They’re very serious and dangerous, but people hadn’t really considered that carefully for bacteria,” said Vijay Balasubramanian, PhD, professor of physics at the University of Pennsylvania.

Balancing this risk can put the bacteria in an evolutionary bind. Having more spacers means they can store more information and fend off more types of viruses, but it also increases the likelihood that one of the spacers might match the DNA in the bacteria and trigger an autoimmune response.

Balasubramanian and colleagues realized that the bacteria could get around this by having longer spacers. This means that bacteria with longer spacers would be able to have more spacers overall without the risk of triggering an autoimmune response.

The researchers built a mathematical model to calculate the ratio between spacer length and the total number of spacers that the bacteria should be able to store without risking an autoimmune response.

Once they worked out the mathematical model, they checked to see if their prediction held true in bacteria by looking at the CRISPR DNA of thousands of species and comparing the spacer length to the number of spacers stored.

The researchers found a consistent, tight relationship between spacer length and number of spacers. In addition, the scaling is absent in strains with nonfunctional CRISPR loci.

“The surprise to me is that it matched so darn well just coming out of the box,” said Balasubramanian. “This is a very simple theoretical framework. There’s a risk of autoimmunity, but it’s nice to have more immune memory, and you must balance these two considerations. It’s just very, very rare that something so simple matches the data.”

Balasubramanian says that the success of the model shows that this framework of simple, mathematical trade-offs might apply to more complex systems, such as the immune systems of vertebrates, including humans.

“Just by doing that statistical kind of reasoning you can make a lot of progress,” he said. “So perhaps we can move back to vertebrate immunity and use the same techniques.”