Study into disease in sheep also benefited humans

Studying an inherited disease in sheep has provided valuable insight into a similar inherited disease in humans. The work demonstrates the power of comparative genomics, matching up and analysing the genomes from different species.

Senior lecturer and Science Foundation Ireland investigator Dr David MacHugh in University College Dublin's School of Agriculture, Food Science and Veterinary Medicine described the research, which involved a single-gene genetic disorder in sheep called arthrogryposis.

The research, published last week in the journal Mammalian Genome, was done in collaboration with colleagues in UCD including Prof Michael Doherty, professor of clinical veterinary medicine and research student Dr Angela Murphy. There were also collaborators in Trinity's Institute of Genetics and the Roslin Institute in Scotland.

Arthrogryposis is a congenital malformation affecting the limbs of newborn animals and human infants, explains Dr MacHugh. A flock of pedigree sheep in the Irish midlands was identified in 1997 as having a high incidence of the disease.

"More than half the lambs were being born with the disease. It is a physiological condition that occurs in the womb during foetal development," he says. "It prevents the animal moving around in the womb. Because this doesn't happen they are born with warped and twisted limbs."

Splints and exercise help to overcome these difficulties, but the risk of further inheritance of the disease remains high among these pedigree animals, adds Dr Mac Hugh. The inherited case load can also be added to by the animals eating toxic plants and also due to viral infections.

Early research confirmed that the disease passed on to the next generation when the lamb inherited two faulty copies of the target gene. "We realised we could do a more sophisticated study where we could map the genes involved," explains Dr MacHugh.

They used a small number of "founder" animals with the disorder to produce a large multigenerational genome mapping pedigree, allowing a "genome scan". This gave them three generations of sheep and they could use them to track where in the genome the causative gene might lie.

They used hundreds of "microsatellite" genetic markers to help identify the chromosome that contained the gene. "The marker data and the effect on the animal allows us to predict the chromosomal segment that contained the gene." They found the gene was located on chromosome five. They were also aware, however, that a similar disease occurred in humans, affecting about one child in 10,000 live births.

"This is where the power of comparative genomics comes in," he says. Work on the human condition in Israel had helped provide a location for the causative gene in humans. The UCD group was able to show that human arthrogryposis is located in exactly the same chromosomal region in both species.

"By studying the condition in sheep, if we can locate the ovine gene that will provide a target for the gene in humans," says Dr MacHugh. "This may help both diagnostics and therapeutics in humans."

It doesn't matter if the species are different because many genes are highly conserved between species. "The purpose of comparative genomics is to gain a better understanding of how species have evolved and to determine the function of genes and noncoding regions of the genome," he adds. "This field will become increasingly important as the database of complete genome sequences expands over the coming years."