OHSU Geneticist’s Analysis Figures in Key Discovery

07/20/09  Portland, Ore.

Cheryl Maslen confirmed the identity of a genetic mechanism that produces dachshunds and other short-legged dog breeds – which is suspected of playing a role in human growth development

An Oregon Health & Science University geneticist − Cheryl Maslen, Ph.D. − played a key role in identifying the biological mechanism, that appears to explain disproportional dwarfism, or chondrodysplasia, in a score of dog breeds such as dachshunds and that may play a role in human growth development. The research is described in the just published advance online edition of the journal Science.

Maslen is co-author of the study, which was conducted by a team of researchers led by Elaine A. Ostrander, Ph.D., a senior investigator at the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health.  Ostrander, senior author of the study, earned her Ph.D. at OHSU.

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, active in the DNA of very short-legged dog breeds during fetal development. Her analysis was a key underpinning for the study's conclusions.

"The reason this is important," said Maslen, "is because it can help us understand the mechanisms underlying dwarfism in humans and give us new insights into the basic biological mechanisms that limit growth and that are relevant to human disease." 

The report in Science concludes 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. The discovery provides new clues about how physical differences may arise within species.

Ostrander and her team of researchers reached this conclusion after examining DNA samples from 835 dogs, including 95 with short legs. Their survey of more than 40,000 markers of DNA variation uncovered a genetic signature exclusive to short-legged breeds. Through follow-up DNA sequencing and computational analyses, the researchers determined the dogs' disproportionately short limbs can be traced to one mutational event in the canine genome – a DNA insertion – that occurred early the evolution of domestic dogs.

"Every species, including canine and human, carries an amazing record of evolution scripted in its genome that can teach us about the mechanisms at work in biology, as well as about human health and disease," said NHGRI scientific director Eric Green, M.D., Ph.D. "This work provides surprising evidence of a new way in which genome evolution may serve to generate diversity within a species."

Maslen, professor of cardiovascular medicine, OHSU School of Medicine, has done extensive research into the genetics of skeletal development as part of her ongoing studies of Marfan syndrome, a genetic disorder of the connective tissue associated with a high risk of a weakening of the aorta and thoracic aortic aneurysms. Maslen identified and cloned the gene that causes the syndrome. People with Marfan's typically have the opposite characteristic from the condition in the current study: they have very long limbs.

The researchers in the current study found that in contrast to other dog breeds, all short-legged dog breeds have an extra copy of the gene that codes for FGF4. Although functional, the extra gene lacks certain parts of the DNA code, called introns, found in normal genes. These characteristics led researchers to conclude that the extra gene is a so-called retrogene that was inserted into the dog genome some time after the ancestor of modern dog breeds diverged from wolves.

To produce a protein, a gene's DNA code is transcribed into a molecule called messenger RNA, or mRNA.  Retrogenes are formed when the mRNA encounters something — often a type of virus called a retrovirus — that turns it back into DNA through a process called  reverse transcription. This new piece of DNA, which contains the same protein-coding information as the gene that produced the mRNA, may then be inserted back into the genome, usually at a much different place than the original gene. Depending on where it is inserted, this piece of DNA may or may not be capable of producing proteins. If it is functional, it is called a retrogene.

In the case of short-legged dogs, the inserted retrogene results in the overproduction of the FGF4 protein, which researchers hypothesize may turn on key growth receptors at the wrong times during fetal development. Veterinary researchers already know that in certain dog breeds the development of long bones is curtailed due to calcification of growth plates, resulting in short legs with a curved appearance. The trait, called disproportional dwarfism, or chondrodysplasia, is an American Kennel Club standard for more than a dozen domestic dog breeds, including the dachshund, corgi, Pekingese and basset hound.

Some people are affected by a similar appearing growth disorder, called hypochondroplasia, which belongs to a group of conditions commonly referred to as dwarfism. While about two-thirds of cases of human hypochondroplasia have been linked to a different gene, the cause of the other one-third remains a mystery. "This study points to a new gene that should be investigated for its possible role in human hypochondroplasia," said Ostrander.

In addition to Ostrander and her colleagues at NHGRI and Maslen at OHSU, the team included researchers from Cornell University in Ithaca, N.Y.; the University of California; the Waltham Center for Pet Nutrition in Leicestershire, England; and Affymetrix Corporation, Santa Clara, Calif.

To read the Science article, "An Expressed fgf4 Retrogene Is Associated with Breed-Defining Chondrodysplasia in Domestic Dogs," go to http://www.sciencemag.org/cgi/rapidpdf/1173275v1.pdf

For an image of a dachshund, go to http://www.genome.gov/pressDisplay.cfm?photoID=20173; for an image of a bassett hound, go to http://www.genome.gov/pressDisplay.cfm?photoID=20172.

About OHSU                          

Oregon Health & Science University is the state's only health and research university, and Oregon's only academic health center. OHSU is Portland's largest employer and the fourth largest in Oregon (excluding government). OHSU's size contributes to its ability to provide many services and community support activities not found anywhere else in the state. It serves patients from every corner of the state, and is a conduit for learning for more than 3,400 students and trainees. OHSU is the source of more than 200 community outreach programs that bring health and education services to every county in the state. As a leader in research, OHSU earned $299 million in research funding  in fiscal year 2008. OHSU serves as a catalyst for the region's bioscience industry and is an incubator of discovery, averaging one new breakthrough or innovation every three days, with more than 4,000 research projects current under way.

About NHGRI and NIH

NHGRI is one of the 27 institutes and centers at the NIH, an agency of the Department of Health and Human Services. The NHGRI Division of Intramural Research develops and implements technology to understand, diagnose and treat genomic and genetic diseases. Additional information about NHGRI can be found at its Web site, www.genome.gov.

The National Institutes of Health — "The Nation's Medical Research Agency" — includes 27 institutes and centers, and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments and cures for both common and rare diseases. For more, visit www.nih.gov.