Some Evolutionary Thoughts

Chemosensory evolution presents various challenges. For example, there is a potential conflict of interest between mechanisms that preserve specificity and those that generate diversity. The immune system provides interesting contrasts and similarities.

Chemosensory receptor clusters have a history of frequent gene duplication, with the subsequent accumulation of diversity between OR genes. That is typical of tandemly repeated clusters of related genes, including the immunoglobulin and MHC clusters. Indeed, the pressure for olfactory diversity is shown by the fact that the OR family is even larger. The similarity between OR and immune allelic exclusion provides a kind of perceptive specificity, within diversity, sequestered in specific cells to keep things orderly and coherent. This tempts the speculation that ORs are also rearranged somatically during development of the olfactory epithelium (e.g., Mombaerts 1999). However, if this is going on it has not yet been demonstrated.

A partial similarity between immune and chemodetection is that both systems bind their target molecules combinatorially. Many antibody molecules may bind the same or different haptens of a circulating antigen, and a given odorant will typically be a ligand for several different ORs. Unlike the vertebrate somatic recombination-generated diversity, however, the strategy for detection of an odorant appears to involve a combinatorial process. The brain senses a signal from a particular set of simultaneous signals from multiple, presumably replicable and inherited, ORs. Once an antibody molecule has been generated, the combinatorial aspect of somatic rearrangement is over for that particular cell; combinatorial immune attacks involve multiple cells each with rearranged genomes, but there needs to be no centralized accounting of which cells are at work. By contrast, such accounting is vital for organismal response to chemosensation.

Another difference is that in mammalian immunity a response gradually becomes "focused" by selecting for the preferential amplification of cells producing the best among the diversity of antibodies that recognize an intruding molecule. Immune focusing can continually occur, so as to track mutational changes in the pathogen. To some extent, each generation of vertebrates faces a different diversity of pathogenic organisms. The olfactory environment may change from moment to moment just as the immune environment can, but changes occur much less rapidly and unpredictably across generations. Although immune recognition sharpens, olfactory perception becomes dulled with prolonged exposure; the evidence to date doesn't seem to suggest that there is olfactory focusing. A far as we know, however, our immune system does not require any form of cognitive integration—so what ensures that different individuals, who smell the same thing in combinatorally different ways, will react appropriately?

We should remember that somatic recombination is not a requisite for effective immune resistance, and in fact even long-lived plants do perfectly well with their olfaction-like R-gene system (which uses genomic combinatorial rather than somat-ically recombinatorially generated diversity). The large number of OR genes and their intergenic diversity has typically been viewed (as in the R-gene system in plants) as having been selected to generate high amounts of odorant binding diversity. The general lack of pseudogenes has reinforced this idea of stringent natural selection for odorant-specific OR genes. Plants do appear to have pathogen-specific R genes. There seems to be a consistent pattern of a large number of ORs, with few pseudogenes, in species with high reliance on olfaction. The many OR genes in dogs and few if any in dolphins are good examples, but our own olfactory epithelium is more patchy than continuous, and we have only around 350 functional OR genes, with the rest of our OR genes being pseudogenes.

There is a high degree of polymorphism within human OR genes (see Mombaerts 2001), which might seem consistent with this evolutionary story, for example, if there has been relaxed selection in our ancestry, which is the usual inference. One upshot of this level of variation is that an OR may be "pseudo" in some people and functional in others. Among other changes, many human OR pseudogenes have had stop codons created by mutations in the coding region; these are either not fixed in our species or mutation may have recreated open reading frames by converting such stops back into amino acid codons. With a high degree of heterozygosity, each person may bear two different alleles at their roughly 350 functional OR genes, which effectively doubles the available repertoire of diversity, even if no two people have the same set of alleles or even the same set of functional genes.

Rather than viewing human olfaction as degenerate, one might make an alternative darwinian interpretation that, as in immunology and MHC specification, selection has favored olfactory diversity even in humans. This may sound fine in principle, but, unlike the immune system, we have to react cognitively to an odorant. If there is too much variation, we might not be able to detect any given odorant, and indeed odorant-specific anosmias are common and the perfume industry is kept busy because we more. Yet, with the amount and chaotic organization of variation, we should be than we are different vary in what we perceive or how we react.

The pattern of variation in the major OR gene cluster on human chromosome 17 is interesting in this regard (Gilad et al. 2000). As seen in 20 sequenced individuals, the functional OR genes in this cluster vary less than the pseudogenes, and there is evidence from comparison with orthologs in chimps that there has been weak positive selection at the genes (but not the pseudogenes), which may maintain OR diversity. This may be too weak to be attributed to odorant specificity, although for some odorants most people do react in a similar positive or negative way, as if there is some form of specificity. These facts need to be reconciled with the observation that at least many human OR genes are not pseudo in everyone.

At the same time, a comparison between humans and other primates found that humans have accumulated pseudogene-producing mutations (that is, that disrupt coding relative to functional orthologs) at a rate roughly four times that in other primates (Gilad et al. 2003; Rouquier, Blancher et al. 2000).This suggests excess loss of genes in the human lineage, though the other primates also have considerably higher fractions of pseudogenes than does the mouse. Whether what has been favored is a kind of variable pseudogene pattern remains to be shown.

Important information will come from the analysis of variation in the OR genes in animals that have few pseudogenes, which is assumed to be due to selection for function. Interestingly, based on the early indications, mice do have OR polymorphisms (P. Mombaerts, personal communication). What is preventing pseudogenes in these species? The question is cogent because even in mice the evidence suggests that odorant detection is combinatorial and open-ended rather than prescriptively specifying one set of receptors for each possible odorant.Why wouldn't mice benefit from a high mutational repertoire, even at the expense of making some genes pseudogenes in some individuals? Possibly, the determination of olfactory genetics from inbred mice (in most cases, probably from studies of a single strain) could obscure some of these questions until wild mice, or mice from multiple independently-derived strains, are examined.

A cautionary note in any such functional evolutionary speculation is that ORs are expressed in nonolfactory tissues like testis and heart and thus may have pleiotropic functions. One possibility is that there have been various types of balancing selection, but a simpler explanation may be that this just reflects "leaky" nonspecific gene expression; the testis expresses many genes that have no obvious germline function (Mombaerts 1999). Alternatively, it has been rather loosely speculated that distributed expression of highly variable OR genes can be used in development as a kind of "area code" to identify tissue-specific codes during development (Dryer 2000).

The answers to these many questions will be interesting. We need to remember also that it is after the fact that we evaluate the nature or importance of chemosen-sation to a given species. Chemosensation is a generic need of cellular life, but a given species uses what it has and has what it uses. Why, for example shouldn't birds or humans have a better sense of smell? There is no one chemosensory "need" for an organism or a chemosensory problem to "solve."

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