Gene Found for Short Legs Trait of Dachshunds

To learn more RNA-based gene duplication (retrotransposition of processed mRNAs), researchers studied the gene that codes for chondrodysplasia (short-limbed or disproportional dwarfism). There are 19 breeds, including the Dachshund, who display this phenotype, which stops growth by calcifying growth plates in early development.

      To define chondrodysplastic breeds, the researchers used descriptions on breed standards (short legs, etc). In the case (chondrodysplasia) group, there were 95 dogs from 8 breeds. The control group had dogs that lacked these descriptions and contained 702 dogs from 64 breeds.

      They found a single nucleotide polymorphism (SNP- a mutation of DNA where one nucleotide base is switched for another) on chromosome 18 at base position 23,298,242. A second was found at base position 23,729,786. Various tests such as the Mann-Whitney U-tests on the distribution of allele frequencies within chondrodysplastic and control breeds that verified this. The gene was named fibroblast growth factor 4 (FGF4).

       Authors hypothesized that this breed-defining trait would be under strong selective pressure (because it is required in the breed standard). To prove this, they found that the cases displayed much lower levels of heterozygosity than the controls (1.9% compared to 19.6%, p=6x10^-6). This means the dogs with chondrodysplasia had two alleles coding for this trait ,but in the control dogs there was a greater chance of finding either one or zero. Therefore, while the chances for the case dogs for having chondrodysplasia was almost 100%, it was much lower in the control dogs.

       To find the cause of the mutations, the researchers sequenced amplicons – repeatedly reproduced sequence of DNA or RNA- in 44 dogs from 20 breeds (9 case and 11 control breeds). An insert starting at position 23,431,136 was found present in all dogs from the original 8 breeds, and was not found in all 204 dogs that do not display the trait. To address whether the position of the insert or its specific content was causative, genes of two unrelated chondrodysplastic dogs (dachshund and Scottish terrier) were sequenced. They were then aligned and compared. The authors found that FGF4 was on both at the same location in their DNA. In other words, both the position and the specific content on the gene probably caused chondrodysplasia.

       In addition, while chondrodysplatic dogs come from many regions of the world, the FGF4 gene remains uniform between them. Researchers suggest that it is likely the phenotype arose only once before the division of dogs into early breeds.  There are wolves from Europe and the Middle East with the genes that would make this possible, but the wolves that the authors studied did not have these genes.

       Also of note: FGF4 was expressed in the tissues of fetal and neonatal dogs. However it was not expressed in adult dogs, suggesting that the gene is time-sensitive.

       In all, the gene that codes for shortness of legs for Dachshunds is unique. Called a “retrogene”, it was made in an unusual way (using reverse transcription from RNA). This is one of the only known functional genes that was made in this manner, and it has greatly influenced the dog population. FGF4 could give insight into speciation on the molecular level, specifically a new kind of mutation of DNA.

 

Heidi G. Parker, Bridgett M. VonHoldt, Pascale Quignon, Elliott H. Margulies, Stephanie Shao, Dana S. Mosher, Tyrone C. Spady, Abdel Elkahloun, Michele Cargill, Paul G. Jones, Cheryl L. Maslen, Gregory M. Acland, Nathan B. Sutter, Keiichi Kuroki, Carlos D. Bustamante, Robert K. Wayne, and Elaine A. Ostrander, 2009. "An expressed Fgf4 gene Is Associated with Breed-Defining Chondrodysplasia in Domestic Dogs". Science. Vol. 325, Issue 5943, pp. 995-998

http://science.sciencemag.org/content/325/5943/995.full

 
Reviewed by: Anna Day