Studying breed-specific diseases could teach doctors new tricks

12:00 AM CST on Sunday, December 11, 2005

By DAVID BROWN The Washington Post

WASHINGTON – There probably isn't a tail-wagging gene or a face-licking gene. But there undoubtedly are groups of genes that explain why retrievers chase sticks, spaniels jump in the water at every opportunity, and border collies like to herd sheep and small children.

The biological basis of the astonishing variety of behaviors of man's best friend is a big step closer to comprehension with the publication this week of the dog's genome – its 2.41 billion nucleotides, or DNA "letters."

The dog – in the form of a female boxer named Tasha – joins the human being, the chimpanzee, the mouse and the rat on the list of mammals whose genetic instruction manual has been read and transcribed. The genomes of the fruit fly, a microscopic worm, yeast and several bacteria have also been decoded.

But the dog genome is far more than a curiosity. It is already providing insights into evolution and will probably make dogs the chief tool for understanding the genetic diseases of people.

Certain breeds are at much higher risk than others for specific ailments. Samoyeds have a tendency to become diabetic. Rottweilers get the bone cancer osteosarcoma. Springer spaniels are at risk for epilepsy, and Doberman pinschers suffer from narcolepsy. All these diseases have human counterparts.

"This offers a strategy for tracking down the location of genes involved in medical conditions that in the past we have just not been able to tackle," said Francis Collins, director of the federal government's National Human Genome Research Institute, which helped pay for the work.

The work is the product of nearly 250 scientists organized through the institute, in Cambridge, Mass. A much less detailed version of the dog genome by a different research group was published two years ago.

A genome is the total mass of genetic instruction an organism inherits. It consists of strings of DNA nucleotides, the biological equivalent of letters. The instructions on how to build a body – everything from permanent structures such as teeth and brain cells to short-lived substances such as blood and hormones – are contained in the order of the nucleotide "letters." Human beings have about 3 billion nucleotides in their genome.

Stretches of hundreds or thousands of nucleotides are copied inside cells and direct them to produce specific proteins, the building blocks of organisms. These stretches are called genes.

Human beings have about 22,000 genes. Dogs, according to the new research, have about 19,300. A given gene usually comes in slightly different variations, similar to pencils with different colored leads, or scissors of varying size.

In size, appearance, and behavior, the dog is the most diverse species on Earth. It was the first animal domesticated from the wild, at least 15,000 years ago. All dogs are descended from gray wolves, which were originally domesticated in East Asia. Some breeds, such as the Akita, are more than a thousand years old. Most, though, are the product of selective breeding in the last 400 years by dog owners who wanted animals with specific characteristics.

That breeding has, in effect, concentrated specific versions of specific genes in specific populations of dogs. The result is a breed with physical and behavioral traits that existed in ancestral dogs but are now greatly magnified.

This results in animals that can look and act very differently even though they scarcely differ from one another in their genetic identity. On a genetic level, breeds differ from one another only about as much as individual human beings do. Gray wolves have more in common with Mexican hairless Chihuahuas than with coyotes, which they more closely resemble.

As traits have coalesced in breeds, so have specific diseases. That happened because genes involved in the diseases are physical neighbors of the trait genes; they move together in long stretches of DNA called haplotype blocks.

The blocks are 50 times as long in dogs as in people. This is because most breeds are only 30 to 90 generations old, much younger than human populations.

By studying the genomes of individual dogs of the same breed that have the same disease – for example, a group of German shepherds with kidney cancer – scientists can home in the genes responsible. Because the blocks are so large, researchers can narrow the possible location of disease genes to just a few "neighborhoods" in the genome. They can then look intensively in those stretches of DNA for the culprit genes.

"Breed-creation gives us a genome structure that makes it very easy to find disease genes," said Kerstin Lindblad-Toh, the lead author of the paper, which appears in the journal Nature. "We now have the tools; we have actually started cancer studies."

Similarly, scientists may be able to figure out what genes contribute to complex behaviors such as retrieving and pointing. They will look for haplotype blocks shared by different breeds with the same trait – all retrievers or all pointers – but that aren't found in breeds lacking the trait.

That may provide new insights into behavioral genetics, which historically has been the murkiest and most controversial part of the field.