Cheryl Maslen and Elaine Ostrander were close friends as graduate studies students working toward their PhDs on Marquam Hill a couple of decades ago. They speak on the phone or exchange emails almost weekly to compare notes, discuss projects, and enlist a second set of eyes for one another’s scientific papers. But they hadn’t found an opportunity to formally collaborate on a project until recently when they linked up as co-authors of a path-breaking new study published this past summer in Science.
Dr. Ostrander – chief of the Cancer Genetics Branch at the National Human Genome Research Institute (NHGRI), a part of the National Institutes of Health – led a team of researchers who reported in the Science article that a single evolutionary event appears to explain the short, curved legs that characterize dachshunds, corgis, basset hounds and at least 16 other breeds of dogs. Dr. Maslen played a key role in confirming the identity of the biological mechanism that appears to explain this disproportional dwarfism, or chondrodysplasia.
Dr. Maslen, PhD, Professor, Medicine and Cardiovascular Medicine, was invited to collaborate on the study because of the extensive research she has done into the genetics of skeletal development as part of her ongoing studies of Marfan syndrome. People with Marfan have exactly the opposite condition from the one in the Ostrander study: they have very long limbs.
"I had the expertise, the resources and the tools to do a piece of the project, and that, after all, is what collaboration is about,” said Dr. Maslen.
Dr. Ostrander’s study uncovered a genetic signature exclusive to short-legged dog breeds in a survey of more than 40,000 markers of DNA variation in samples from 835 dogs, including 95 with short legs. Through follow-up DNA sequencing and computational analyses, the researchers traced the dwarfism of the short-legged breeds to one mutational event in the canine genome – a DNA insertion – that occurred early in the evolution of domestic dogs.
Dr. Maslen's analysis confirmed that an extra copy of a gene that codes for a growth-promoting protein called fibroblast growth factor 4 (FGF4) is, in fact, a region of genetic activity during fetal development. The extra gene – or retrogene – lacks certain parts of the DNA code, called introns, found in normal genes and it was inserted into the dog genome, the study concluded, that some time after the ancestor of modern dog breeds diverged from wolves. The inserted retrogene results in the overproduction of FGF4, which researchers hypothesized may turn on key growth receptors at the wrong times during fetal development. This finding, the researchers suggested, may offer clues to the causes of hypochondroplasia, or dwarfism, in humans.
Dr. Ostrander has been chasing down clues like that since the mid 1990s as she has gone about mapping the dog genome. “What we find is that by and large the same genes and families of genes are responsible for diseases in dogs and humans. And it’s becoming much easier to map using canines than humans. The reason is a statistical one. It’s hard to map diseases in humans because families usually are small and after people have one or two children affected by a given disease they often don’t have more. You can only sample a couple of generations and maybe the older generation is deceased and the younger generation hasn’t lived long enough to get the disease. And any one family doesn’t have a lot of statistical power.
“Then there are dogs. They’re divided into 150 breeds and each one is an isolated pure breeding population that have gone for generation after generation with strong selection for the same exact traits. There may be a 100 genes out there, for example, that cause epilepsy in humans and probably just as many in dogs. But in dogs we can say, ‘I’m just going to look at the Doberman breed, or the German shepherd breed and within any one breed, it’s not going to be 100 genes, it’s only going to be maybe one or two genes. So we have a way of simplifying the problem statistically that is hard to come by in humans because there are very few isolated human populations. Each dog breed is a mini Finland or Iceland.”