Friday, October 19, 2007

What do Harry Potter, Sherlock Holmes, Martha's Vineyard & Science Magazine have in common?

As the Harry Potter series went on, more and more of the characters' names telegraphed a key component of their properties. One of the most blatant of these is Sirius Black, (spoiler alert), who turns out to be capable of transforming into a black dog (Sirius being the dog star). Black dogs show up elsewhere in literature: the hound of the Baskervilles is reported to be a huge black hound. On the Vineyard, there is a restaurant/bar whose apparel has spread around the globe with it's black Labrador log, The Black Dog. Now, joining the parade is Science (currently available in full in the Science Express prepublication section to subscribers only), with the identification of the gene responsible for black coat color, a locus previously known as K.

The new gene turns out to be a beta defensin, a member of a family known previously for its role in immunity. Dogs are unusual in having black driven by a gene other than Mc1R and agouti. Mc1R is a G-protein coupled receptor (GPCRs) and agouti encodes a ligand. Strikingly, beta defensins turn out to be ligands for Mc1R, closing the circle.

GPCRs constitute one of the biggest classes of targets for existing drugs, so one of the first tasks of anyone during the genome gold rush was to identify every GPCR they could. However, it is very difficult to advance a GPCR if it lacks a known ligand ("orphan receptor"), so drug discovery groups spent a lot of effort attempting to 'de-orphan' the GPCRs flowing from the genome project -- and very few had much luck. I haven't kept close tabs on the field for a few years, but it would seem there are still a lot of orphans left. Plus, from a physiological standpoint you don't just want to know 'a' ligand for a receptor but the full complement. This work is a reminder that new GPCR discoveries can come from a largely unanticipated angle.

It's been a huge year for dog genetics, and I've touched on a few items in this space. I suspect that someone really in tune to the field could easily fill a blog with it; I just catch the things in the front-line journals and the occasional stray from a literature or Google search. Much of the work this year has been on morphology, and there's still plenty to do. Many dog breeds have common abnormalities and those are beginning to be unraveled as well -- and many will likely have relevance to human traits. One I stumbled on recently is the identification of a deletion responsible for a common eye defect in collies.

The really big fireworks will come when behavior genetics studies really fire up in dog. Some traits have been deliberately bred into particular breeds (think herding & hunting dogs) and others inadvertently (such as anxiety syndromes). Temperament varies by breed, and of course just about any dog is more docile than their wild lupine relatives. There will be lots of interesting science -- and probably more than a few findings that will be badly reported and misinterpreted in the popular press. Let's hope, for his sake, that James Watson keeps his mouth shut about any of it.

BTW, Lupine? -- another telegraph character name. Fluffy, on the other hand, not quite the name you'd expect on a gigantic three-headed dog. Alas, there's only one Fluffy mentioned, so it might not be possible to map the genes responsible for that!

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