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Stubby Dog Legs Linked To Retrotransposition Event

NEW YORK (GenomeWeb News) – A single retrotransposition event in the dog genome led to the development of a retrogene behind the characteristically squat legs found in more than a dozen dog breeds, according to new research by National Human Genome Research Institute-led team.

In a paper appearing online today in Science, the researchers did a multi-breed analysis assessing more than 40,000 DNA markers to find genes associated with leg length in domestic dogs. Their search, along with subsequent sequencing experiments, turned up a retrogene called fgf4 that was strongly associated with the short-legged phenotype seen in dachshunds, basset hounds, and 17 other breeds. The team speculated that fgf4, which codes for a fibroblast growth factor, might alter growth factor receptor function during development.

"Our findings suggest that retrogenes may play a larger role in evolution than has been previously thought, especially as a source of diversity within species," lead author Heidi Parker, a post-doctoral researcher in senior author Elaine Ostrander's lab in NHGRI's Cancer Genetics Branch, said in a statement. "We were surprised to find that just one retrogene inserted at one point during the evolution of a species could yield such a dramatic physical trait that has been conserved over time."

Functional retrogenes arise when processed mRNAs are reverse transcribed to DNA and deposited back into the genome. In contrast to typical retrogenes, which quickly take on damaging mutations, functional retrogenes can stick around and code for proteins.

Researchers detected the functional fgf4 retrogene while doing a multi-breed study of dog traits. First, they genotyped 35 individual dogs from 76 breeds using the Affymetrix version 2.0 SNP array. Among them: 95 dogs from eight short-legged phenotype breeds.

Using single marker analysis, the researchers detected strong associations between short-leggedness and two SNPs on chromosomes 18. Their subsequent SNP and amplicon sequencing experiments revealed 50 SNPs that formed a homozygous haplotype in short-legged dogs.

Within this region, the researchers detected a roughly 5,000 base insert that was also associated with the short dog legs. When they sequenced the insert using an Illumina Genome Analyzer, the team discovered that the insert was actually an intronless FGF4 gene whose coding sequence differed from the original by just one base.

The team detected fgf4 transcripts in cDNA generated from dogs belonging to short-legged breeds, supporting the notion that the retrogene is expressed. But the retrogene's expression did not depend on that of its neighboring genes, they noted. Instead, fgf4 appears to have a time-sensitive role in dog development.

Based on their findings, the team speculated that fgf4 alters the activity of a fibroblast growth factor receptor called FGFR3 — a gene that has also been implicated in at least two forms of human dwarfism — leading to FGFR3 over-expression.

That, in turn, suggests the dog study could eventually shed light on a type of human dwarfism called hypochondroplasia, the researchers asserted. Previous studies have shown that nearly two-thirds of hypochondroplasia cases are due to an activating mutation in FGFR3. But so far researchers haven't come up with a genetic explanation for the remaining cases.

"Our findings may prove valuable to scientists studying other aspects of human growth and development," Ostrander said in a statement. "The work also underscores the value of canine studies for uncovering new biological mechanisms that are likely relevant to human disease."

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