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Sunday, July 19, 2009

The Origin of Dachshunds

A draft sequence of the dog (Canis lupus familiaris) genome has been available for several years. One of the reasons for working with dog genes and genomes is the fact that there are many different breeds. Since these breeds differ genetically and morphologically, there's a distinct possibility that the genes for various characteristics can be identified by comparing variants from different breeds.

One of the exciting possibilities is that some interesting behavioral genes could be identified since many breeds of dog are loyal, easy to train, and intelligent.1

In addition to possible behavioral genes, one can identify many genes affecting morphology. One of them is the gene affecting short legs in various breeds, including dachshunds. Parker et al. (2009) identified an extra gene in short-legged breeds. The extra gene is a retrogene of the normal gene encoding fibroblast growth factor 4 (fgf4).

What is a retrogene? It's a derivative of the mature mRNA of a normal gene. Recall that most mammalian genes have introns and the primary transcript contains extra sequences at the two ends, plus exons that encode the amino acid sequence of a protein, plus intron sequences that separate the exons.

This primary transcript is processed to produce the mature messenger RNA (mRNA) that is subsequently translated by the translation machinery in the cytoplasm. During processing, the intron sequences are spliced out, a 5′ cap is added to the beginning of the RNA, and a string of "A" residues is added to the terminus (= poly A tail).

On rare occasions the mature mRNA can be accidentally copied by an enzyme called reverse transcriptase that converts RNA into single-stranded DNA. (The reverse of transcription, which copies DNA into RNA.) The single-stranded DNA molecule can be duplicated by DNA polymerase to make a double-stranded copy of the original mRNA molecule.

This piece of DNA may get integrated back into the genome by recombination. This is an extremely rare event but over the course of millions of years the genome accumulates many copies of such DNA sequences. In the vast majority of cases the DNA sequence is not expressed because it has been separated from its normal promoter. (Sequences that regulate transcription are usually not present in the primary transcript.) These DNA segments are called pseudogenes because they are not functional. They accumulate mutations at random and the sequence diverges from the sequence of the normal gene from which they were derived.

Sometimes the DNA copy of the mRNA happens to insert near a functional promoter and the DNA is transcribed. In this case the gene may be expressed and additional protein is made. Note that the new retrogene doesn't have introns so the primary transcript doesn't require splicing in order to join the coding regions (exons). The fgf4 retrogene inserted into the middle of a LINE transposable elements and the LINE promoter probably drives transcription of the retrogene.

The short-legged phenotype is probably due to inappropriate expression of the retrogene in the embryo in tissues that generate the long bones of the legs. The inappropriate expression of fibroblast growth factor 4 causes early calcification of cells in the growth plates—these are the cells that regulate extension of the growing bones. The result is short bones that are often curved.

Breeders selected for this anomaly and this is part of what contributed to the origin of dachshunds and other short-legged dogs.

There's a reason why dogs are such good species for discovering the functions of many genes. It's because of the huge variety of different breeds. Is there a reason why the species has more morphological variation than other species of animals? Probably, but we don't know the reason. Here's how Parker et al. begin their paper.
The domestic dog is arguably the most morphologically diverse species of mammal and theories abound regarding the source of its extreme variation (1). Two such theories rely on the structure and instability of the canine genome, either in an excess of rapidly mutating microsatellites (2) or an abundance of overactive SINEs (3), to create increased variability from which to select for new traits. Another theory suggests that domestication has allowed for the buildup of mildly deleterious mutations that, when combined, create the variation observed in the domestic dog (4).
We still have a lot to learn about evolution.

[Photo Credit: Dog Gone Good]

1. You can see why working with the cat genome wouldn't be as productive.

Parker, H.G., Vonholdt, B.M., Quignon, P., Margulies, E.H., Shao, S., Mosher, D.S., Spady, T.C., Elkahloun, A., Cargill, M., Jones, P.G., Maslen, C.L., Acland, G.M., Sutter, N.B., Kuroki, K., Bustamante, C.D., Wayne, R.K., and Ostrander, E.A. (2009) An Expressed Fgf4 Retrogene Is Associated with Breed-Defining Chondrodysplasia in Domestic Dogs. Science. 2009 Jul 16. [Epub ahead of print] [PubMed] [doi: 10.1126/science.1173275]


  1. Very interesting note, I didn't know about this mechanism to originate new genes. Cool!

  2. To pick a small technical nit, you could just say the retrogenes are reincorporated into the genome. It probably doesn't happen by recombination but by direct ligation into coincidentally broken genomic loci. Bona fide recombination of exogenous DNA in mammalian genomes is notoriously (and inconveniently) rare, relative to generic cut and paste random ligation.

  3. 1. You can see why working with the cat genome wouldn't be as productive.

    Feline genome's useless anyway, it's just one big trinucleotide repeat.