Purple sea urchinThere’s a new paper just out on the sea urchin immune system, and since I’ve recently become a fan of sea urchin immune systems I’m not actually going to talk about that paper here. Instead, I’m going to rewrite a different blog post I made on the sea urchin immune system, pre-Mystery Rays. That way, when I do talk about the new one, I have my references set up in a row. Anyway, I think this is so cool it’s worth talking about twice.

Last fall the purple sea urchin (Strongylocentrotus purpuratus) genome sequence was published;1 it’s online at the Sea Urchin Genome Project. At the time one of the aspects of the urchin genome that was specially singled out was the immune system,2 but one of the most interesting things about the genome had already been published earlier that year:
An ancient evolutionary origin of the Rag1/2 gene locus.
Fugmann SD, Messier C, Novack LA, Cameron RA, Rast JP.
Proc Natl Acad Sci U S A. 2006 Mar 7;103(10):3728-33.

Sea urchins are the closest relatives of the chordates:

Based on similarities of embryonic organization, zoologists grouped echinoderms and Hemichordata (a phylum of marine worms) with chordates in the superclade Deuterostomia … Within the deuterostomes, the chordates (vertebrate and invertebrate) form one large assemblage, and the echinoderms and their sister group the hemichordates the other, all members of which are more closely related to one another than they are to any other animals.3

But echinoderms split off before the discovery of the adaptive immune system, which apparently appeared, full-fledged4, in sharks. Lampreys and hagfish, which of course have common ancestors with sharks, more or less lack adaptive responses, whereas sharks and all their descendants unto us do have adaptive responses.5

The key molecular development that makes this system work is the RAG1/RAG2 gene pair. The RAG genes rearrange DNA — given appropriate sequence cues, these genes (and their supporting cast) can grab and shuffle and splice DNA. That means you can get vastly more complexity out of your genome. (If you start with 10 upstream halves of a gene, and 10 downstream halves, you can get 100 possible genes by randomly rearranging the DNA. The adaptive immune molecules are more complicated than that, and in fact you can get something like 1013 different antibodies, and 1015 possible different T-cell receptors, by rearranging the DNA. It’s that huge number of possible sequences that allow the adaptive response to target variable regions of pathogens; it’s the fact that the DNA is permanently altered that allows persistent memory.)

Lampreys and hagfish don’t have RAG1/RAG2. However, some invertebrates do have things that look kind of RAG-ish.6 They’re transposable elements, which makes sense, since transposable elements would like to be able to cut and re-attach DNA so that they can transpose. But there’s nothing that looks like sharks’, and our, RAG1/RAG2. (Lampreys and hagfish haven’t had their genomes done yet, so it’s possible something has been missed in them, but it would have to be a fairly distant relative of RAG1/2.) The presumption has been that, around the time sharks split off from the lamprey ancestors, the transposable element entered their genome and mutated to become RAG1/RAG2, and the rest is history. And so echinoderms shouldn’t have RAGs. “The Rag1/2 gene cluster is predicted to be missing in this phylum by evolutionary scenarios in which the locus was assembled as a consequence of horizontal gene transfer close to the time of the emergence of jawed vertebrate adaptive immunity.” 7

You see where this is going, though. Sea urchins do have a RAG1/RAG2 gene cluster! Fugmann et al identified a set of genes that are pretty clearly RAG-ish:

We thus conclude that SpRag1L and SpRag2L represent homologs of vertebrate Rag1 and Rag2. In combination with the apparent absence of V(D)J recombination in echinoderms, this finding strongly suggests that linked Rag1– and Rag2-like genes were already present and functioning in a different capacity in the common ancestor of living deuterostomes, and that their specific role in the adaptive immune system was acquired much later in an early jawed vertebrate.

Fugmann et al Fig 3 In other words, instead of arising in sharks, the RAG1/RAG2 pair may have arisen well before that, in their common ancestor with sea urchins. In that case, lampreys may have lost the genes, rather than sharks gaining it. (The other possibility is that RAG1/RAG2 moved into sharks and urchins independently, perhaps from a common ancestor of the RAG-related transposon.) (The figure at right is Fugmann et al’s Figure 3, comparing SpRag1L and SpRag2L to various vertebrate RAGs.)

Sea urchins don’t appear to have an adaptive immune response, but this still simplifies the history of adaptive immunity. I’ve always been a little puzzled by the shark thing. It’s not just RAG1/2 that leads to an adaptive immune system: there are a host of other changes — molecular signals indicating where its safe to rearrange DNA, for example — that are essential for a functional adaptive response, and it seemed pretty remarkable that they’d all arise together, in a relatively short period. But this observation, along with other recent findings (lymphocyte-like cells in lampreys, for example) shows that many of the changes arose over a much, much longer period, and sharks were just the first to put together a set of unrelated changes to pull an adaptive immune system out of their molecular hats.

  1. The genome of the sea urchin Strongylocentrotus purpuratus. Sea Urchin Genome Sequencing Consortium. Science. 2006 Nov 10;314(5801):941-52. []
  2. Genomic insights into the immune system of the sea urchin. Rast JP, Smith LC, Loza-Coll M, Hibino T, Litman GW. Science. 2006 Nov 10;314(5801):952-6. []
  3. The Sea Urchin Genome Sequencing Consortium.[]
  4. Or at least, so I thought last year[]
  5. Though in the interest of complete disclosure, recently flies and other non-vertebrates, as well as lampreys, have been shown to have a completely different form of immune response which in some ways acts like an adaptive response.[]
  6. For example, see RAG1 core and V(D)J recombination signal sequences were derived from Transib transposons. Kapitonov VV, Jurka J., Jurka J. PLoS Biol. 2005 Jun;3(6):e181. []
  7. Fugmann et al., 2006[]