"Draft Sequence" of Pig Genome Could Benefit Agriculture and Medicine

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"Draft Sequence" of Pig Genome Could Benefit Agriculture and Medicine

The detailed annotation of the pig genome will speed along efforts to help breed healthier and meatier pigs as well as create more faithful models of human disease

By Alison Abbott and Nature magazine

T. J. Tabasco is something of a porcine goddess at the University of Illinois, Urbana-Champaign, where her ruddy, taxidermied head looks down from the office wall of geneticist Lawrence Schook. Now she has been immortalized in this week’s Nature — not by name, but by the letters of her DNA.

Scientists are salivating. For the past couple of decades they have been slowly teasing information from the pig genome, applying it to breed healthier and meatier pigs, and to try to create more faithful models of human disease. This week’s draft sequence of T. J.’s genome (see page 393), with its detailed annotation — a ‘reference genome’ — will speed progress on both fronts, and perhaps even allow pigs to be engineered to provide organs for transplant into human patients. “Agriculture in particular will benefit fast,” says Alan Archibald of the Roslin Institute in Edinburgh, UK, one of the paper’s lead authors. “The pig industry has an excellent track record for rapid adoption of new technologies and knowledge.”

T. J., a domestic Duroc pig (Sus scrofa domesticus), was born in Illinois in 2001. The next year, Schook and his colleagues generated a fibroblast cell line from a small piece of skin from her ear and commissioned clones to be created from it, so that they could work on animals all with the same genome. One set of clones was created at the National Swine Resource and Research Center (NSRRC) in Columbia, Missouri, along with genetically engineered pigs with genes added or deleted to mimic human diseases.“Making such pigs has got increasingly easier as knowledge of the genome increases,” says physiologist Randall Prather, a co-director of the NSRRC, which is funded by the National Institutes of Health (NIH).

The NIH launched the NSRRC in 2003 to encourage research in pig disease models. Pigs are more expensive to keep than rodents, and they reproduce more slowly. But the similarities between pig and human anatomy and physiology can trump the drawbacks. For example, their eyes are a similar size, with photoreceptors similarly distributed in the retina. So the pig became the first model for retinitis pigmentosa, a cause of blindness. And four years ago, researchers created a pig model of cystic fibrosis that, unlike mouse models, developed symptoms resembling those in humans.

Geneticist and veterinarian Eckhard Wolf at the Ludwig-Maximilian University in Munich, Germany, has exploited the similarity between the human and pig gastrointestinal system and metabolism — like us, pigs will eat almost anything and then suffer for it — to develop models of diabetes. One pig model carries a mutant transgene that limits the effectiveness of incretin, a hormone required for normal insulin secretion. Mice with the transgene developed unexpectedly severe diabetes, but the pigs have a more subtle pre-diabetic condition that better models the human disease. “This shows the importance of using an animal with a relevant physiology,” says Wolf.

Pig models are now being developed for other common conditions, including Alzheimer’s disease, cancer and muscular dystrophy. This work will be enriched by the discovery, reported in the genome paper, of 112 gene variants that might be involved in human diseases. Knowledge of the genome is also allowing scientists to try to engineer pigs that could be the source of organs, including heart and liver, for human patients. Pig organs are roughly the right size, and researchers hope to create transgenic pigs carrying genes that deceive the immune system of recipients into not rejecting the transplants.

Genetically Engineered 'Mighty Mice' May Shed Light on Muscle-Wasting Diseases

By Sarah Graham – July 18, 2001

Four years ago, a group of Johns Hopkins researchers created a line of genetically engineered "mighty mice" by removing a growth-regulating gene. Now they have engineered another batch of overly muscular rodents. The first set of mice (see image) lacked the myostatin gene from their genetic codes. But in the new research, published in the July 17th issue of the Proceedings of the National Academy of Sciences, the pumped-up mice retained their myostatin. Instead the scientists altered the animals' physiques by tweaking three proteins capable of blocking myostatin's activity to varying degrees.

Myostatin acts as a negative regulator of skeletal muscle mass. If it is unable to function, muscles can grow uninhibited. Mice engineered to produce excess amounts of the protein follistatin had the most powerful muscles: one such mouse exhibited average muscle weights 261 percent greater than control animals. Mice with excess mutant activin II receptors and those with myostatin propeptide also showed increased muscle mass compared with their ordinary mousy counterparts.

"By expressing high levels of these proteins in mice, we have been able to increase muscle mass to levels comparable to those seen in mice completely lacking myostatin," Se-Jin Lee, the study¿s lead author, says. Because the function of myostatin appears to be conserved across species, the researchers are hopeful that the findings will be beneficial in shaping treatments for muscle-wasting diseases. Lee cautions, however, that more testing is necessary to determine whether administering the proteins directly, instead of altering the genome, can provide similar results. "The agricultural implications are probably more straight forward, since conceivably, one could try to find ways to block myostatin activity early during development," he says. "For human applications, this research is just the beginning."

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