�鶹��ýӳ��

Gene Insertion Underlies Origin of Dogs With Short Legs

Tyrone Spady, NHGRI

A single evolutionary event is responsible for the short, curved legs that characterize certain dog breeds, according to a new study. The unexpected discovery provides clues about how physical differences may arise within species and suggests new approaches to understanding a form of human dwarfism.

Dogs today have a wide range of body types and behaviors because of their unique history of selective breeding by humans. This diversity makes them ideal for studying genes that affect body size and shape.

Disproportional dwarfism, or chondrodysplasia, affects more than a dozen domestic dog breeds, including the dachshund, corgi, Pekingese and basset hound. It’s caused by calcification of growth plates, which curtails long bone development and results in short legs with a curved appearance. The trait is distinct from the uniformly miniature size of toy breeds, such as the toy poodle.

To understand what causes chondrodysplasia, a team of researchers led by Dr. Elaine Ostrander of NIH’s National Human Genome Research Institute (NHGRI) examined DNA samples from 835 dogs from 76 distinct breeds, including 95 dogs from 8 breeds with short legs. The scientists surveyed more than 40,000 markers of DNA variation.

In the advance online edition of the journal Science on July 16, 2009, the researchers reported finding a genetic signature exclusive to short-legged breeds. Through follow-up DNA sequencing and computational analyses, they found that the dogs’ short limbs can be traced to one mutational event in the canine genome—a DNA insertion—that occurred early in the evolution of domestic dogs, some time after the ancestor of modern dog breeds diverged from wolves.

The dogs have an extra copy of the gene that codes for a growth-promoting protein called fibroblast growth factor 4 (FGF4). This results in overproduction of the FGF4 protein, which the researchers hypothesize may turn on key growth receptors at the wrong times during fetal development. The scientists noted that, although functional, the extra gene lacks certain parts of the DNA code, called introns, found in normal genes. That led them to conclude that the extra gene is a so-called retrogene.

Retrogenes arise from molecules called messenger RNA (mRNA), which are copies of a gene’s DNA code that the cell needs in order to make proteins. Retrogenes are formed when an mRNA encounters something—often a type of virus called a retrovirus—that copies it back into DNA. The new DNA can be inserted into the genome, usually at a different place than the original gene.

These findings suggest that retrogenes may play a larger role in creating diversity within species than previously thought. They may also have implications for understanding human biology and disease. Some people are affected by a similar growth disorder called hypochondroplasia. While about two-thirds of cases of human hypochondroplasia have been linked to a different gene, the cause of the other third remains a mystery.

“This study points to a new gene that should be investigated for its possible role in human hypochondroplasia,” Ostrander says. “The work also underscores the value of canine studies for uncovering new biological mechanisms that are likely relevant to human disease.”