Georgetown University

Washington, D.C. – In an article published today by the journal Science, an international research consortium presents the genome sequence of taurine cattle, the first livestock mammal to have its genetic blueprint sequenced and analyzed. The landmark research, supported in part by Christine Elsik, assistant professor in Georgetown University’s biology department, provides new information about mammalian evolution as well as cattle-specific biology. It also points the way to research that could result in more sustainable food production in a world challenged by global population growth.

Researchers from the Bovine Genome Sequencing and Analysis Consortium estimate that the genome of the cow (Bos taurus) contains approximately 22,000 genes and shares about 80 percent of its genes with humans. The analyses, which involved comparing the cow genome sequence to those of the human, dog, mouse, rat, opossum and platypus, provide critical insights into the structure and function of the human genome.

“Human genes are more similar to cow genes than to genes of mice, commonly used in biomedical research, so the cow genome is likely to fill gaps in our understanding of human biology and disease,” said Elsik.

The findings will also assist researchers working to improve the quality and safety of beef and dairy products. Genomic information can be used to develop better strategies for treating and preventing diseases that affect cattle. Some of those diseases, including bovine spongiform encephalopathy, commonly known as mad cow disease, also can be transmitted to humans.

“The future challenge will be to explore the bovine genome sequence in greater depth to fully understand the genetic basis of the evolutionary success of ruminants as this will provide opportunities to address some of the crucial issues of the present time – efficient and sustainable food production for a rapidly increasing human population,” said Dr. Richard Gibbs, director of the Baylor College of Medicine Human Genome Sequencing Center and principal investigator on the project.”

The Bovine (Cow) Genome Sequencing Project sequenced the genome of a female Hereford cow, a breed used in beef production. The cattle sequence took six years to complete, annotate and analyze and involved over 300 scientists from 25 countries. Most of more than 25 companion reports describing detailed analyses associated with this project and with a related project by another international group, the Bovine Hapmap Consortium, appear online at www.biomedcentral.com in a special electronic issue of the BioMed Central journal group.

“The mammals we have looked at previously have been laboratory animals and humans,” said Kim Worley, associate professor in the sequencing center and a corresponding author. ”This is the first mammalian livestock animal we have studied.”

Elsik, who specializes in bioinformatics, led the group of scientists who ran computational analyses to identify the genes that encode proteins, which make up about one percent of the 2,870 million nucleotides in the cow genome. Her colleagues Roderic Guigó from Universitat Pompeu Fabra in Spain and Alexandre Reymond from University of Lausanne in Switzerland did laboratory experiments to validate the computational gene predictions.

Elsik also led the group of scientists who manually annotated the genome, and is in charge of the Bovine Genome Database (http://BovineGenome.org), which hosts gene model data submitted by 150 of the co-authors. The database is publicly available, and allows both scientists and the general public to query and download the genome and gene data.

Several Georgetown science students and post doctoral researchers helped to update the database and are listed among the paper’s authors.

“During evolution, domesticated cattle and other ruminants diverged from a common ancestor that gave rise to humans about 95 million years ago, yet cattle and humans still share a high degree of conservation in the organization of their chromosome architectures, far more so than humans and mice do,” said Harris Lewin, one of the lead analysts from the University of Illinois at Urbana-Champaign. “We were surprised to find that, like humans, duplicated segments appear to have played a major role in the rearrangements of chromosomes in the cattle lineage.”

Some of these rearrangements appear important to cattle biology because they affect genes involved in immunity, lactation, metabolism and digestion. These changes could help explain the amazing ability of cattle to convert low-quality forage efficiently into energy-dense meat and milk, a fact that benefits humans.

One particular genetic rearrangement involves the histatherin gene in mammary tissue, which undergoes special regulation during lactation to produce a novel protein in milk that has anti-microbial activity. Other gene changes aid in the transfer of immunoglobulin G to milk and the subsequent transference of innate immunity to suckling calves from their dams.

The researchers said, “Observation suggests that species-specific changes in genome organization and gene regulation may help tailor the functional components of milk to the specific needs of newborn mammals. They also add to the mounting evidence that milk contains ‘innate immune’ proteins that may be important for gut protection and gut development in the suckling young as well as the health of the mammary gland.”

“More generally, it appears that the cow has significant rearrangements in many of its immune genes and enhanced innate immune defense capacity. This may be in response to increased risk of opportunistic infections at mucosal surfaces caused by the large number of microorganisms carried in the rumen (the largest of the four compartments that make up the bovine stomach),” said Ross Tellam of the Commonwealth Scientific and Industrial Research Organization of Australia.

The knowledge gleaned from this sequencing could lead to more efficient beef and milk production, the researchers noted.

“Genetic tools are already being developed and proving useful to the dairy industry and we predict they will be applied to improve the beef industry. We hope the information will also be used to come up with innovative ways to reduce the environmental impact of cattle, such as greenhouse gases released by herds,” said Richard Gibbs.

An example of the use of the genome sequence to develop new genetic research tools is published in related paper that appears in the same issue of Science, but did not include authors from Georgetown. In that paper, the Bovine HapMap Consortium unveils a map that charts key DNA differences, called haplotypes, among the diverse branches of the bovine tree. The scientists compared the Hereford genome sequence with those of six other breeds (the Holstein, Angus, Jersey, Limousin, Norwegian Red and Brahman) to look for changes called single nucleotide polymorphisms or SNPs in 497 cattle from 17 geographically and biologically diverse breeds and two related species (Anoa and Water Buffalo).

These polymorphisms provide a means of selection of more energy-efficient animals with a smaller environmental footprint, particularly animals with less greenhouse gas emissions.

The implications of the genome project for the beef and dairy industries loom large.

Gordon Doak, president of National Association of Animal Breeders, an industry trade group of organizations that market semen for breeding dairy and beef cattle, said, “The availability of very large numbers of single nucleotide polymorphisms (single letter changes in the genetic blueprint) has allowed the development of gene chips that measure genetic variation in cattle populations and will allow the rapid selective breeding of animals with higher value commercial traits,” he said. “This technology is quickly transforming the dairy genetics industry and has the potential to dramatically alter beef cattle industries as well.”

The sequencing project was led by Richard Gibbs and George Weinstock, co-directors of the BCM-HGSC, Steven Kappes of the United States Department of Agriculture, Christine Elsik of Georgetown University and Ross Tellam of CSIRO Australia. The HapMap project was led by Gibbs, Curt Van Tassell of the United States Department of Agriculture and Jeremy Taylor of the University of Missouri. A full listing of participants can be found in the articles at www.sciencemag.org.

Funding for sequencing the cow genome was provided by an international group including the National Human Genome Research Institute, which funded more than half of the project; the U.S. Department of Agriculture's Agricultural Research Service and Cooperative State Research, Education, and Extension Service National Research Initiative; the state of Texas; Genome Canada through Genome British Columbia; The Alberta Science and Research Authority; The Commonwealth Scientific and Industrial Research Organization of Australia (CSIRO); Agritech Investments Ltd., Dairy Insight, Inc. and AgResearch Ltd., all of New Zealand; the Research Council of Norway; the Kleberg Foundation; and the National, Texas and South Dakota Beef Check-off Funds.

When the embargo lifts, the full report is available at www.sciencemag.org.

A high-resolution photo of the Hereford cow, named L1 Dominette 01449, whose DNA was sequenced is available at: http://www.genome.gov/12512900.

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