Tasha, the boxer with the sequenced genome. Credit: National Institute of Health
This week marks the dog days of science, when the publication of a new book, The Dog and Its Genome, coincides with a series of dog genome articles in Genome Research and a high-quality draft sequence of the dog genome in Nature.
“It’s an exciting time to be working on the dog genome,” said Ewen Kirkness, of The Institute for Genomic Research, via e-mail.
“Canine genetics has entered a period of unprecedented growth and discovery,” as Elaine Ostrander and Francis Galibert wrote in their foreword to The Dog and Its Genome. “The dog is now set to take its rightful place as a valued system for genetic studies along with the mouse, rat, and several insect species.”
Gordon Lark’s research uncovers the power of a single region of a chromosome to change several aspects of skeletal shape; Ewen Kirkness and Wei Wang found a type of variation that may be responsible for differences between breeds; and Chris Ponting and Caleb Webber identified genetic “hot spots” where chromosomes are likely to break. All of these were observed in dogs, but discoveries in our canine friends may have crucial implications for understanding the human genome.
Lark, of the University of Utah, was bribed into researching dog genetics. He had previously studied quantitative genetics in soy beans and only briefly thought about extending his results to the animal kingdom. Then, a Portuguese Water Dog breeder gave him a free dog, and dug up genealogical information on another 5,000, with the hope that he’d study dog genetics. It worked.
The principal investigator in two studies published in Genome Research, Lark exclusively studies Portuguese Water Dogs. He said they make for good subjects because the entire breed descends from a mere 30 ancestors.
In both of his studies, Lark compared DNA and skeletal structure to determine correspondences between regions of the genome and aspects of the skeleton. He then observed how changes in these regions alter a dog’s shape and size.
The first paper concerns why female dogs are smaller than males. Through his comparison of genes and phenotype, Lark concluded that all dogs tend to get larger, but in females this process is inhibited. In males, the inhibition is, itself, inhibited, so males grow more than females.
In the second paper, Lark details 40 markers that are responsible for determining skeletal size. From this work, he concluded that single markers control multiple, related skeletal traits.
“It turns out that the shape of the head and the shape of the limb bones are connected by a single region of the chromosome, and this makes sort of functional sense,” Lark said, noting that a fast dog, such as a greyhound, will want to have a small head, pointy nose and long legs, whereas a strong dog, such as a pit bull, will want to have a massive jaw and short, thick legs.
Lark said the greatest benefit of his technique lies in its medical applications. Dogs suffer from many diseases common to humans, including diabetes, hemophilia and autoimmune diseases. If we can take quantitative measurements that correspond to these diseases and compare those to genetic markers, we can find the genetic roots of the disorders.
“Initially, dog diseases were studied by waiting until the genetic cause of a human disease was discovered and seeing how that applied to dogs,” he said. “But now, with the dog genome sequenced, it’s really highly probable that we can discover the cause of a disease in a dogs and apply it to a human.”
Ewen Kirkness and Wei Wang of The Institute for Genomic Research used a similar technique to compare the genome of a boxer to that of a poodle. The genome of Shadow, the poodle, was sequenced in 2003. Tasha, the boxer, had her genome sequenced in 2004 (she’s the main subject of this week’s Nature paper on the dog genome).
The researchers aligned the two genomes and noted variations between the nearly identical sequences. Past studies comparing dog genomes have focused on either single base differences or numbers of repeated bases. Kirkness said his study used a newly identified type of genomic variation that is rare in humans but common in dogs. SINE elements, which consist of about 200 base pairs, can be found at any of 20,000 locations on the dog genome. Their presence or absence at these spots accounts for many of the differences between dogs, Kirkness said.
“The results of our SINE study indicate a major source of genomic variation in the canine genome, that differs from what we currently know of other mammalian genomes,” he said via e-mail. “We can speculate that this type of variation may contribute to the plasticity of the dog genome that has permitted the breeding of a species with such an unusually large range of shapes, sizes and behaviors.”
Chris Ponting and Caleb Webber of Oxford University have an article in Genome Research detailing their comparison of the dog genome with the human genome. Dogs have 78 chromosomes, whereas humans only have 46. Ponting said the dog’s recent ancestors had a mere 42 chromosomes. He and Webber set out to find how these chromosomes break.
“The dog genome sequence presented us with an exciting opportunity to study
how, over aeons of time, chromosomes have broken apart and then been stuck
back together in different arrangements,” Ponting said via email. “We know that much rearrangement of its chromosomes has occurred in the past 60 million years.”
By comparing the canine and human genomes with complex computer programs, the researchers found particular types of DNA sequences, which they call “hot spots,” tend to break more frequently. Ponting said these hot spots contain many more G and C base pairs than they do A and T base pairs. They also found that hot spots are prone to mutations that change these letters.
“The discovery of these hot spots means that we can now predict how
chromosomes break and what the consequences of breakage might be,” he said. “This is important because breakage of human chromosomes is known to cause leukemia and other cancers.”
Gordon Lark, of Portuguese Water Dog fame, said dog genetics will not only bring medical advances for canines, the actual process of studying dogs will help researchers develop ethical standards for human genetic study.
“In almost every respect they mimic human genetics,” he said. “You don’t own the dogs, they’re out there with their owners. Dogs are considered by most people very much like you consider your children. So you can’t hurt them; you can’t do bad things ethically. You have to practice pretty much the ethical and moral constraints that are applied to humans.”
Originally published December 12, 2005
