The Genomic Revolution. Seed provides an interactive timeline for perspective.
Billions of people across the world depend on the domesticated cow, be it for hide, milk, meat, or as a livelihood. Loveable and familiar, the humble farm staple is also something of a mystery: How have thousands of years of domestication affected an animal with bizarre metabolism that efficiently converts low-energy plant roughage into energy-rich fat, muscle, and milk that humans have exploited since “un-wilding” the beast somewhere in the Fertile Crescent about 6,000 BCE?
We now have an interesting new window into this mammal’s unique biology. Last month hundreds of researchers released the first genome-wide bovine analysis. The work performed by the Bovine Genome Sequencing and Analysis Consortium and the Bovine HapMap Consortium promises to revolutionize cattle breeding, lead to critical advances in biomedical research, and offer potential insight into the production of alternative fuel.
The cow genome, of course, follows in a series of known genomes. We now hold a growing number of keys to the complicated nucleotide patterns that make up life on Earth. Since the first bacteria was sequenced by Craig Venter in 1995, there’s been a steady flow of genetic code-breaking across a wide range of species: the fruit fly genome in 2000; our own in 2001; the mouse in 2004; our genetic near-twin, the chimpanzee, in 2005; and the honeybee in 2006. The modern-day cow belongs to the artiodactyl order, who split ways more than 95 million years ago with the mammals that eventually became rats, primates, and humans. From the artiodactyls emerged the ruminants—sheep, deer, llamas, and the beloved beast of a farm animal, the cow—known for their unique ability to break down biomass by regurgitating and re-chewing semi-digested plant matter. Perhaps counterintuitively, it’s this evolutionary distance of the cow—the first ruminant to be sequenced—from the other organisms sequenced thus far that makes its genome especially meaningful. “By having a more distant group from rodents, primates, and humans, we have a very important notch in the tree of life—particularly the mammalian branches—to begin exploring and learning how genomes have evolved,” says immunogenetics professor Harris Lewin. “We’re now able to fill in significant gaps and reconstruct many of the events that transpired in the evolution of life.”
“At times we need a more distant organism to study,” says Kim Worley from the Human Genome Sequencing Center at Baylor College of Medicine and an author of the bovine genome analysis. Worley was also involved with the sequencing of the genomes of the human, rat, honeybee, sea urchin, and macaque monkey. “What’s special about the bovine genome is that it maintains protein similarities to the human sequences that are greater than those found in mice and rats. So it provides a better window for human biology.” And because the cow diverged from the human branch so long ago, analysis of its genome makes it possible to identify which human traits are well-conserved: These are the portions of the genome that haven’t changed much over hundreds of millions of years of evolutionary constraint and are thereby most essential to fitness (i.e., not junk DNA).
Lewin is founding director of the W.M. Keck Center for Comparative and Functional Genomics and the Institute for Genomic Biology at the University of Illinois at Urbana-Champaign. He maintains that the oft-overlooked contributions of large domestic species to humanity throughout recent history are remarkable. Over the last 100 years, 17 Nobel Prizes have been won on the backs of farm animals such as cows, sheep, horses, and pigs. A rural English doctor, Edward Jenner, revolutionized immunology in 1796 when he discovered that injecting people with the crusts of lesions from cows infected with cowpox provided immunity to human smallpox. (The word vaccine in fact comes from the Latin root for cow, vaca.) “That’s how the smallpox epidemic plaguing Europe in the 18th century was stopped in its tracks,” says Lewin. Cryopreservation of sperm for artificial insemination was first performed in cattle in the 1940s before the technology was applied to humans in the 1950s. And since 1960, hundreds of thousands of pigs and cows have provided valves to pump the blood of human hearts.
Now, the cow genome shepherds a new era of animal sciences. “We’re in the midst of a radical transformation in the animal breeding industry brought about directly as a result of sequencing the cow genome,” says Lewin. The current system for statistically evaluating the genetic value of lineages in cattle breeding, called progeny testing, involves analyzing the phenotypic records of large numbers of individual cows to determine the breeding superiority of males and females: Each bull has thousands of offspring; the researchers then wait for the daughters to mature and test for quantitative traits, such as milk production; it takes five years for each bull to mature and costs about $100,000. This method of genotyping has already vastly improved cattle breeding efficiency: Over the past 50 years, the industry has managed to produce twice as much milk with half the number of cows through progeny testing. “Now with genetic markers from the genome,” Lewin says, “we have a way to make associations at every point in the genome for the position of a gene that affects a quantitative trait. It’s now possible to genotype a cow at birth and know exactly what its genetic value is.” Such a refined technique should make cattle breeding severalfold times more efficient. “I imagine that this will have a major impact on the dairy and meat industry in a relatively short period of time, ” says Worley.
Illustration by Tyler Lang
The potential value of this increased knowledge of ruminant biology spans beyond breeding efficiency and the cattle industry at large. A major hurdle in producing biofuel and other useful chemicals from biomass is understanding the role of cellulolytic enzymes in converting plant forage into energy. Ruminants hold many secrets on how to digest low-quality forage. And for the first time, we have the genomic tools to start unlocking some of these secrets. Being strictly herbivores, cows derive most of their protein from the bacteria residing on the grass they eat. These microbial populations live in the ruminant’s gut and are very efficient at breaking down complex cellular structures like cell walls in plants. Lewin predicts that mimicking this cellulytic process and understanding the cow’s microbial degradation process may prove vital in producing biofuels. “Knowing all the interesting bugs in the rumen and how they’re able to break down these complex carbohydrates is really going to go a long way to help solving the problems of biomass conversion.”
Just better understanding of the genetic basis behind the caloric efficiency of the rumen could potentially impact the environment. A byproduct of cud-chewing digestion is methane, the second most abundant greenhouse gas on Earth. With more sophisticated and robust genotyping, it may become possible to select for livestock with the most efficient digestion, resulting in minimum feed. The calculus is straightforward according to Lewin: “Feeding animals less creates fewer burps, which equals less methane.”
Despite the apparent value of investigating the biology of farm animals such as cows, there is a dearth of money supporting such research. “It’s pathetic,” says Lewin about the current state of funding for animal sciences. In a recent policy article appearing in Science, a professor from Michigan State University who studies new methods to regulate fertility in cattle, Jim Ireland, and colleagues reported that the “annual economic value of livestock and poultry sales in the United States currently exceeds $132 billion, yet only about 0.04 percent ($32.15 million) of the $88 billion Department of Agriculture budget in fiscal year 2007 was allocated to its competitive grants program for research that directly involves agriculturally important domestic animals.” For comparison, the Department of Health and Human Services gave 4.1 percent of its $716 billion budget in 2008 to the National Institutes of Health for applied and basic biomedical research. “People don’t think about food sources unless there’s a problem, and that can make it difficult to get funding,” says Worley.
If current funding trends can be reversed, and with the cow genome now in hand as well as other livestock species to come (another member of the artiodactyls, the pig, should be sequenced by the end of the year), there exists a real opportunity to improve the efficiency and sustainability of agricultural systems around the world.
In many ways, this is just the beginning of a new era of genome-enabled livestock models. As Lewin says, “The barnyard door is now wide open.” He maintains that there are all kinds of interesting questions out there, for which we finally have the tools to investigate. For instance, what are the consequences of having what is essentially a giant fermentation vat as a stomach? And what can we learn from its role in the evolution of a species we’ve become so crucially reliant upon?
Originally published June 8, 2009