By Dean A. Haycock

Special to BioWorld Today

Determining self from nonself on the microscopic level is as important as determining if someone is for you or against you in human society. It can mean survival or annihilation. On the cellular level, this determination depends on the recognition of specific proteins.

The proteins that allow an organism to distinguish self from nonself are encoded by a group of genes in the major histocompatibility complex (MHC). This is known as the H-2 complex in mice and the human lymphocyte antigen (HLA) complex in humans. MHC genes encode cell-surface proteins called histocompatibility antigens. They are key determinants of tissue type and transplant compatibility and more than 50 different versions of them have been described.

Naturally, scientists want to know what processes favor the evolution of such extraordinary specificity in MHC tissue recognition in vertebrates. This specificity was discovered following tissue transplantation experiments begun more than 50 years ago. But, as Richard Grosberg at University of California in Davis put it, "What could drive the evolution of that specificity, because tissue transplantation outside of the context of human pregnancy is not a normal state of affairs for vertebrates? They don't have intimate, sustained tissue contact."

Numerous hypotheses were put forward to answer this question. Some suggested the MHC variations are of no functional biological significance. Others suggested the variation was instrumental in defending against pathogens.

"This became, of course, a much more plausible hypothesis when scientists began to understand how nonself antigens of things such as viruses, which are intracellular parasites, were presented to the immune system in the context of self-MHC," Grosberg told BioWorld Today. According to this explanation, evolution would favor pathogens that have MHC determinants that mimic their host's MHC type. Under this cloak, they could evade detection.

"Now, the host's immune system counters that by building defenses against those MHC types. So a rare MHC type in the host population will have an advantage over common MHC types in the host population because there are fewer pathogens that can mimic them," Grosberg explained. "You get a constant selection favoring new host MHC types and then the new pathogen [produced] 'mimics' of those MHC types."

A third hypothesis emerged from the finding made in the late 1970s that female mice could select prospective mates based on their MHC genes. Some research even suggested that women look favorably on men with different MHC genes.

This "mate recognition" hypothesis implies that if females prefer to mate with males that differ from them with regard to their MHC gene variety, then males who have rare MHC genes will have better mating success than males who have common MHC genes.

Kin Recognition Promotes Genetic Diversity

Yet another explanation relies on the reasoning that it is advantageous for an organism to help its close relatives if it can distinguish them from more distant relatives. This is because kin have more genes in common. According to this theory, Grosberg explained, "selection should favor the evolution of kin recognition." Furthermore, selection should favor the accumulation of genetic diversity because it reduces the chances of making an error in recognizing a close relative.

Like mice and humans, marine invertebrate sea squirts are chordates. Sea squirts are invertebrate chordates and mice and humans are vertebrate chordates. They have been evolving independently as chordates for half a billion years. Yet, like mice and humans, sea squirts and other marine invertebrates can distinguish self from nonself. There appears to be a genetic basis for this in both invertebrates and vertebrates. Because they attach themselves to a surface, marine invertebrates experience more close contact and close competitive interactions with each other than do most vertebrates. They can fight each other or cooperate even to the extent of fusing their tissues if they are compatible.

Some scientists suggested that sea squirts, like mice and humans, had a mate recognition system that ensured they would not fuse with too-distant kin.

"Although the logic was flawless," Grosberg said, "there was simply no empirical foundation because the data weren't there. It was just an idea. And then a few people said 'Aha, sea squirts are chordates; vertebrates are chordates; we are all just one big happy family. Sea squirts are really just primitive chordates. The whole vertebrate immune system could have been derived from a sea squirt and it all starts to make beautiful sense.'"

The problem, as Grosberg pointed out, is that there is no sign that the genetic basis of self-nonself recognition in sea squirts bears any closer resemblance to the vertebrate immune system. "They aren't the same thing . . . you would hardly expect there to be much retention of an ancestral character state - especially of that kind. That is where we came in."

The "we" is Grosberg and his colleague Michael Hart, of Dalhousie University in Halifax, Nova Scotia. In an article titled "Mate Selection and the Evolution of Highly Polymorphic Self/Nonself Recognition Genes," in the Sept. 22, 2000, issue of Science, they explain how they applied breeding and fusion techniques to two species of colonial marine invertebrates. Their results show that mate selection is not a factor in maintaining a healthy variation in genes that influence self-nonself discrimination. Instead, they conclude, "The regulation of intraspecific competitive interactions appears to promote the evolution of polymorphisms in these species."

Other species - even other marine invertebrates - might be capable of mate selection, but the important point, according to Grosberg, is that "you can get extraordinary polymorphism in tissue specificity or tissue recognition without there being any sort of push or assistance given by mate recognition, mating preferences or mate selection."

Grosberg warns that "there is simply no evidence at this point that there are genes that are involved in invertebrate self-nonself recognition that were the direct precursors to the genes of the vertebrate immune system."

In their paper, he and Hart help clarify "the bigger role that mate recognition, and that social recognition, plays in the evolution of specificity of self-nonself recognition. Without that specificity, social interactions and societies in multicellular organisms are simply not stable."

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