Cow, or Über Cow?

A new genetic map shows that centuries of breeding better cows hasn’t emptied the bovine gene pool. At least not yet. By Anita Neal Harrison. Photos by Rob Hill

After six years of scientific heavy lifting, an international team involving hundreds of researchers announced last April that they had fully sequenced the genome of an 8-year-old Hereford cow from Montana, the first livestock mammal to have its genetic blueprint published.

View Animation - Narrated by Dr. Jerry TaylorJerry Taylor, MU’s Wurdack Endowed Chair of Animal Genomics, was one of the project leaders. His contribution involved leading the production of a bovine “HapMap,” a snapshot capturing the variation in DNA sequence patterns among the Montana Hereford and six other breeds. The map enabled Taylor and his colleagues to detail how today’s cattle, through years of drift and selective breeding, have diverged from a 29-million-year-old ruminant common ancestor.

That history shows that human intervention has had a profound effect on the bovine genome, particularly over the 10,000 or so years since cattle were first domesticated. The good news—a finding that came as something of a shock to Taylor and his colleagues—is that the gene pool of cattle today remains relatively diverse. The bad news, Taylor says, is that this situation may not last.

“Even though at this point in time we were surprised to find that there is as much nucleotide diversity in individual cattle breeds as there is within humans, the future is the important thing,” Taylor says. “Humans are going up; cows are going down. If we don’t do something about trying to preserve some of that diversity, we’re going to lose a lot of it as we go forward.”

Understanding how Taylor and his team crafted the Bovine HapMap involves grappling with the nature of haploid genotypes, usually abbreviated “haplotypes.”

Haplotypes, in the parlance of genetic sequencing researchers, refer to associated groupings of single nucleotide polymorphisms, or SNPs (pronounced “snips”). These SNPs, Taylor explains, represent “the points of fundamental variability that exist within the genome.”

Return with us now, for a moment, to Biology 101. You will recall that all living organisms contain DNA. The “NA” stands for “nucleic acid,” which is comprised of a long chain of subunits called “nucleotides.” There are four types of nucleotides, abbreviated T, C, A and G, depending on their base structure and composition. The sequence of nucleotides in DNA, like the dots and dashes of Morse code, spells out the genetic information needed to construct the organism’s proteins. Within a particular species, some of the nucleotides are not variable; that is, each member of that species will have exactly the same kind of nucleotide at a given location. Nucleotides that are variable are SNPs.

Cow standing in barn

Best of Breed: 3-year-old Guernsey #362, pictured above, is a descendant of department store magnate James Cash Penney’s beloved bull, Langwater Foremost. J.C. Penney donated the bull to MU, along with 495 acres of farmland, in 1952. The cows pictured below are also part of MU’s Foremost Herd.

Before the bovine genome was sequenced, researchers had identified fewer than 1,000 SNPs in cattle. By project’s end, they had found close to 2 million. This vast new data set allowed Taylor and the other HapMap researchers to use DNA differences to construct a bovine family tree.

William Barendse is a senior scientist with the Commonwealth Scientific and Industrial Research Organization of Australia and a HapMap Consortium group leader. Barendse says charting genetic variation in cattle is no esoteric exercise. Our understanding of positive and negative genetic traits in cattle and other “food” animals may be a crucial component in helping a hungry, hotter world deal with declining arable land and a rising population.

“We need to know how this genetic variation is spread over breeds, which breeds are low, which high, which breeds are essentially the same as some other breed, which breeds—particularly some relics in some backwater—have got unusual genes or genetic combinations,” he says. “In particular, we need to know what the snapshot of the cow genome is like now.”

Obtaining that “snapshot” wasn’t easy. The first step involved analyzing, or “interrogating,” as geneticists put it, SNPs from 497 cattle from 19 breeds. The researchers first built chemical “probes” capable of searching the 3 billion nucleotides in a cow’s genome for a particular SNP of interest. The probe then reported back whether the allele, or version of the SNP present, was a T, C, A or G.

Such probes work by exploiting the two-stranded structure of DNA’s nucleotides. Technicians first cause the two strands to melt apart, Taylor says. “Once you’ve got it melted, you send in your probe and say, ‘Go probe!’ And your probe runs in, and it goes looking for its piece of complementary DNA, and when it finds it, it sticks because it wants to be double-stranded.”

Scientists can then “extend” the DNA next to the probe by one nucleotide to reveal the allele of the targeted SNP in the subject’s DNA.

“It’s not trivial chemistry,” Taylor helpfully adds.

The probes can’t determine a long string; they can only report the next nucleotide in the sequence. However, a remarkable new device called a “SNP chip” allows scientists to run thousands of these probes on multiple animals in a chemical reaction called an assay. In one assay, a chip can score up to 200,000 SNPs on 12 different animals. The next generation of these assays, ready in 2010, will allow researchers to score close to 700,000 SNPs per animal.

Cow's from MU's Foremost Herd

Crunching these numbers is where the process delivers its real-world payoff. Researchers can combine these genotyped SNPs with an animal’s known qualities — its resistance to disease or its milk production, for example — and run statistical analyses to determine which SNPs are associated with which traits.

That SNP chip technology has cattle producers excited is hardly surprising. With one simple DNA test, the chips allow ranchers and dairy owners to weigh the genetic merit of an animal for several economically important traits. They can be more selective in breeding, producing cattle that are healthier, tastier, and more efficient eaters. The dairy industry has been particularly quick to embrace the technology, using it to determine which bulls and cows should be bred to maximize milk production.

Back in the lab, SNP chip technology has proven invaluable to the HapMap researchers, allowing them to compare and contrast cattle at tens of thousands of points on their genome in order to examine the extent of diversity within and between breeds.

The goal, Taylor says, was to use the SNPs to determine relationships among breeds and then to apply that information to “what we know about biogeography to figure out how humans domesticated cattle and how they then took them around the world with them.”

“The DNA of these animals actually contains signatures in it that reflect their origins, how they got into Italy and then into Spain and then into the Alps,” Taylor adds. “It’s really fascinating that you can essentially recreate the modern evolution of many breeds by looking at the differences and similarities that exist between their DNA.”

The process involves using modern DNA samples and population genetics theory to determine historical “effective population sizes.” Effective population size, Taylor says, is a measure of how much opportunity the cattle had to breed with genetically dissimilar mates.

Cows at feed trough

Genetic Marvels at MU’s Foremost Dairy Center west of Columbia. Scientists and students at the center study ways to maximize milk output and efficiency while maintaining the health of the 425-head herd.

The methods are highly technical but, as Taylor explains it, the key is knowing that the inheritance of one allele at a particular location on a chromosome can be tied to the inheritance of another allele at a different location.

When such a connection is found, genome investigators can measure the connection’s strength and estimate the population size of the ancestral herd at a specific point in history—a point determined by measuring the distance between the two alleles’ locations. This information, in turn, allows researchers to look at patterns of genetic inheritance in modern cattle, and use the data to determine how much genetic diversity existed within ancient populations.

Today’s cattle come in two types: taurine, which have no humps, and indicine, which do. Taurine cattle predominate in Europe, Africa and the Americas. Indicine cattle originated in South and East Asia, and were later introduced in the Americas. Both are species descended from aurochs, a species that became extinct during the early 1600s.

Indicine cattle, most of which now reside in India, still show a healthy level of genetic diversity. Their humpless cousins, however, have been less fortunate. Evidence points to three great “bottleneck” events that led to greater inbreeding and lesser taurine diversity. The first involved taurines’ initial domestication, when, some 11,000 years ago, humans captured and tamed a small sample of ancient bovines. The next involved migrations, as Middle Eastern people and their herds began to settle Europe. The last and greatest bottleneck began 200 years ago with the introduction of “special-purpose” breeds.

“What happened was when our forebears formed these breed societies, they set very stringent standards based upon the way the animal looked—the color of its coat, the shape of its horns, whether it had horns—so only a small fraction of the animals that formed the original populations got pulled into these individual breeds,” Taylor says.

The last 50 years have been especially hard on diversity as advances in technology, such as artificial insemination, have made selecting for certain traits even easier for breeders. “Nucleotide diversity is going down because we’re selecting these animals to be more and more alike in terms of their ability to make milk, produce beef, and so on,” Taylor says.

Branching of the Breeds

A portion of the bovine family tree showing the phylogenetic relationship among 48 contemporary breeds of cattle based upon genotypes as assigned by the IlluminaSNP50 assay (a.k.a., the cow “snip chip”). The chart and accompanying data were published this October in the Proceedings of the National Academy of Sciences. The dark triangles associated with each breed show the genetic variation within each breed. The depth of the branches represents the greatest subdivision between breeds. So, for example, the deepest branch partitions Indian indicine cattle from the remaining taurine breeds. Next comes the West African N’Dama which is a taurine breed like the rest, but has been separated for a very long time. Further up comes the East Asian taurine. These cattle were probably not separately domesticated in Asia, but migrated with humans from the fertile crescent. The rest of the figure shows how modern cattle got into Europe, first through Italy and the Balkans, then Central Europe, across the land bridge into Britain and finally pushing north into Scandanavia. It also shows an early division of Spanish cattle that were brought into the New World.

Chart showing bovine family tree

The lost diversity is troublesome, Taylor adds, because once diversity is lost in a breed, it’s lost for good. Imagine, if you will, a hypothetical situation 100 years from now. Selective breeding has led to all Angus cattle having a minimum yearling weight of 1,400 pounds. Many breeders begin to suspect, however, that these yearling weight levels are creating a host of health problems. Veterinarians confirm their fears, recommending that yearling weight should not exceed 1,200 pounds.

If the lower-weight-related alleles of the Angus weight genes have truly been eliminated from the population, there would be no simple way to hit the new weight target. The only course would involve either crossbreeding the large Angus with another breed — not an option most producers want to consider—or resurrecting sperm or embryos saved from earlier generations of Angus.

While he considers neither of these ideal options, Curt Van Tassell, another HapMap project leader and research geneticist with the USDA Agricultural Research Service, stresses that either one would almost certainly work.

“We have that fail-safe in place,” he says. “While there has been a loss of diversity, the diversity within cattle still exceeds humans. And that’s diversity within breeds. That said, I think there are concerns, and we need to pay attention to the impact of the selection decisions we make.”

Still, while danger presented by diversity diminution might be up for debate, most all scientists agree that preserving genetically diverse stock is a goal worth pursuing.

“The Bovine HapMap project quantified at a higher level of resolution what many livestock scientists already knew and were taking steps to remedy,” Barendse says. “For example, the Food and Agriculture Organization and groups such as the ECONOGENE consortium have had a decades-long set of studies to quantify genetic variability in livestock, partly to identify breeds worth conserving. The thing about the Bovine HapMap study and others of its kind is that it has generated tools to identify genes affecting traits. This will result in molecular genetic technologies that will be used in breeding programs—actually, are already being used.”

SNP chips are one of those tools. One might think that a technology touted for its ability to help ranchers and dairymen cherry-pick desirable qualities would only speed up diversity loss. But in fact, the scientists say, SNP chips will probably slow down the process.

Here’s why. Until now, breeders have relied on pedigree, or family, to decide which animals would be most profitably bred. “This results in a loss of diversity because of an accumulation of inbreeding,” says Taylor. “Using a SNP chip to determine the animals that have the best genes for any one trait will find those genes no matter in what animal they exist.”

As a result, he says, breeders will likely “start to sample animals from different families that are less related to each other than the current average, and this will slow down inbreeding and the loss of diversity.”

SNP chips will also allow producers to begin selecting for traits such as disease resistance and meat tenderness that in the past have been too difficult to measure. “The more traits that you include in the selection objective, the less pressure you apply to any one trait and, therefore, to the genes that underlie the trait,” says Taylor. More diversity will thus be preserved in the regions of the genome that are not being selected.

This preservation, he adds, is something producers should be encouraged to appreciate. Right now, it’s not always a priority.

“A lot of people have the attitude of, ‘If it’s not happening now, we’re not going to worry about it,’ ” he says. “There’s a disconnect between what we have to do now to be competitive and potentially where we have to be 200 years from now to have viable populations of cattle. The issue here is that if we lose all the diversity that currently exists between cattle, sometime in the very near future it will become a problem.”

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