Smell genes must wander

Choosing which 1 of 1,300 odorant receptor genes to express depends on a random interchromosomal encounter, acccording to Stavros Lomvardas, Richard Axel, and colleagues (Columbia University, New York, NY). The receptor gene that nestles nearest the single enhancer available in the genome is the single gene that gets expressed in a given cell.

Various other models for odorant receptor choice had already been deemed unlikely or incorrect. A unique set of transcription factors for each receptor sounded too complicated. And irreversible DNA recombination to place a single receptor gene at a single expression site was clearly not happening, as mice cloned from the nucleus of a mature olfactory neuron expressed the full repertoire of odorant receptors.

The Columbia group started with the H enhancer, which was known to be necessary for the expression of at least some nearby receptor genes. They cut and ligated DNA so that DNA regions that were close to each other would now be covalently linked. They found that the H sequence was now linked to one of 22 different odorant receptor genes. In cells expressing a particular receptor, the H region colocalized with the gene for that receptor in ∼29% of cells, and with nascent RNA for that receptor in 85% of cells.

Additional safeguards ensure that only one receptor is expressed. The H enhancer is probably restricted to a single functional copy by the CpA methylation that the group discovered at one of the H alleles. There would still be a risk of olfactory receptor genes latching onto the H enhancer one after another, except that any productively expressed receptor protein represses the production of any other receptor protein. If a pseudogene is the first gene that latches onto H, this previously characterized feedback mechanism will not kick in, and a productive receptor can still be produced.

This model is consistent with the group's findings: introducing an extra H element allowed two receptors genes to be expressed, but only if one was a pseudogene. Deleting the H element will tell the group whether this element rules the production of all 1,300 receptor genes, or just a subset. Clues about what proteins bridge the H element and individual genes may come from flies, which use a process called transvection to bridge enhancers and genes that lie on different homologous chromosomes.

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