Sometime, probably millions of years ago, the Atlantic cod swam down an evolutionary tributary that left it without a large chunk of the normal vertebrate immune system. The astonishing gap is revealed in the fish's genome, published today, which also exposes some of the alternative tricks cod appear to have evolved to successfully fight infections.
Atlantic cod is a commercially important catch in fisheries around the Northern Hemisphere, and Kjetill Jakobsen, an evolutionary geneticist at the University of Oslo, says his team set out to sequence the fish's genome primarily to provide a resource for managing cod fisheries. Now he thinks the genome has much broader implications. "Our findings affect fundamental assumptions about immune system evolution," he says.
When the researchers aligned the cod's DNA with that of the stickleback, the most closely related fish species whose genome has been sequenced, they found that cod are missing the genes that code for proteins called MHCII, CD4, and invariant chain. These proteins are integral components of the immune system of almost all vertebrate animals and are particularly important in fighting bacterial infections. When an animal cell is infected with bacteria, it attaches parts of the bacteria to MHCII molecules on its cell surface; when white blood cells called CD4+ T cells spot these flags, they send signals to B cells, which in turn start making antibodies. No MHCII means no CD4+ T cell activation and a weak antibody response.
"There are other examples of animals that have evolved slightly different immune systems," says Gary Litman, an immunologist at the University of South Florida in Tampa, who was not involved in the study, "but this stands out as an exceptional evolutionary event." Yet somehow, the omission isn't a death knell for cod, the team reports online today in Nature. They seem to deal with the bacteria in their normal environments just fine.
The authors say other parts of the genome hint at how this is possible. Cod have a broader range of Toll-like receptors, which are involved in innate immunity, a so-called rapid reaction immune response that is faster but less sophisticated than T and B cell responses. They also have a greater diversity of MHCI molecules. MHCI is the partner molecule of MHCII, but it usually activates CD8+ T cells, which specialize in fighting viruses. Jakobsen believes that cod rely more on their innate immune system and that the MHCI system has taken over some of the functions usually performed by MHCII—and that perhaps their CD8+ T cells can react to bacteria too.
The scientists are now trying to understand what led to this immune system shakeup. "This probably wasn't an evolutionary accident—suddenly losing MHCII would have been a huge disadvantage to any animal," says Martin Flajnik, an evolutionary immunologist at the University of Maryland School of Medicine in Baltimore, who was not involved in the study. One possibility, he says, is that the cod's immune strategy may be more effective at dealing with the fish's microbial enemies—the range of bacteria in cold water, for example. As the alternatives evolved, the MHCII system would have become less important, and perhaps eventually it could have been lost without severe consequences. Flajnik says it will be fascinating to look for similar immune adaptations in fish that share cod's environment.
The study might not be good news for the nascent cod aquaculture industry, which could help put an end to decades of overfishing. The fish's unique immune system may leave it particularly vulnerable to disease if they are farmed outside their natural environment, Jakobsen says. If so, "understanding their immune system might also help us design cod-appropriate vaccines," he says.