Unlocking the potential of agricultural biotechnology

Dr Dieter Adam is group general manager for innovation with New Zealand's Livestock Improvement Corporation (LIC) and will describe how his country has applied genomic research to drive systematic improvement in the national dairy herd.

The Hamilton-based LIC, founded as a farmers' cooperative, has built a massive database containing information on 30 million dairy cattle, extending back two decades.

For the past 20 years, LIC has been accumulating a huge library of DNA samples from dairy bulls in the form of frozen semen, stored in liquid nitrogen. Every bull represented in the database is been progeny tested, and the database records the performance of his daughters over several generations.

"We just associate the performance of the daughters of each bull with his DNA - that's been one of the major assets driving herd improvements," Adam says. The approach has already helped identify elite alleles of two genes with a major influence on milk yield, and total milk solids, dubbed Quantum and Optimum respectively.

LIC and giant New Zealand dairy cooperative Fonterra have patented the genes and are commercialising them through a joint venture, biotechnology company Vialactia Biosciences.

Adam says Optimum is a particularly important gene. "It produces a favourable level of total solids to the water content of milk.

"Unlike Australia, New Zealand's domestic market consumes only about five per cent of our milk production. I suspect if Fonterra could do so, it would get milk powder straight from the udder - water content is the major factor in transport costs."

The partners all share research facilities in New Zealand, he says. "We don't do any research on genes for milk composition ourselves - Vialactia has a lot of interest in bioactive components in milk, whilst our focus is on all aspects of milk production on farm. That is the basis of our collaboration with Fonterra.

"We look for associations between genetic markers and performance traits. We can look over our three-generation pedigrees and track performance, and we have millions of data points, which makes gene discovery a lot easier."

Much of the data comes from a special herd of 800 Holstein-Jersey crossbreds, developed since 1997 in collaboration with Fonterra. The herd is maintained on a dedicated research farm in Hawera, situated in the Taranaki area on NZ's North Island. "We made our own Friesian-Jersey cross for scientific reasons," Adam says. "You get the best information from a specific cross by studying multiple traits segregating in the F2 generation."

Holstein-Jersey crosses

NZ farmers began making Holstein-Jersey crosses decades ago, seeking to combine the Holstein-Friesian's exceptional productivity with the Jersey's superior milk quality. In the northern hemisphere, bigger is regarded as better, but Adam says New Zealand farmers use cross-breeding to keep their cows to a more tractable size.

Holstein-Jersey crossbreds account for about 30 per of the national herd, and the proportion is rising, he says. The rest are purebred Holsteins (47 per cent) and Jerseys (15 per cent).

"It's absolutely clear that crossbreeding is here to stay. Farmers originally crossed Holsteins and Jerseys for pragmatic reasons, and if you drive through the countryside today, the great majority of dairy herds have brown cows mixed in with black and whites. It's quite rare to see a purebred Holstein or Jersey herd.

"In the absence of any systematic cross-breeding programs, farmers have done what they could. LIC has now put crossbreeding on a systematic track with KiwiCross bulls."

Adam says researchers are measuring 181 traits in the animals in their experimental herd - obvious traits like yield and milk quality and resistance to diseases like mastitis, but also more subtle physiological traits like food conversion efficiency.

In one test, researchers injected glucose into the bloodstream of animals and took blood samples at 10-minute intervals to identify rapid metabolisers - the ability to digest grass rapidly is fundamental to high milk productivity. "We take a large number of blood and tissue samples and keep them in the freezer, because there will always be something you want to know next year," he says.

"It's a very comprehensive trial - in fact, a trial of this size is unlikely to be repeated anywhere in the world. If you were to do it in the northern hemisphere, it would have to be done indoors, and keeping 800 animals indoors for many years would be prohibitively expensive.

"We're still only taking the cream off the data. We've finished most of the measurements, but our biggest problem is finding people with the specialist bioinformatics skills to analyse it.

"They're in short supply and we've had to look beyond our own R&D group to publicly funded research providers. The actual DNA analysis has become easier - most of it is now done by robots - but to make sense of the data, in terms of relating it to performance, you need skilled geneticists and bioinformaticians.

"We have a long-standing relationship with Professor Michel Georges at the University of Lieges, in Belgium, who is a world expert in the field."

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Systematic breeding

The program has two outputs: the genetic markers identified are used to advance the LIC breeding program, while farmers' own breeding efforts benefit from commercial DNA tests for genes to improve productivity or quality, like Optimum and Quantum. LIC operates a commercial DNA testing unit.

Adam says the gene tests provide a simple way for farmers to identify elite animals and undertake more systematic breeding.

But farmers typically need only a simple yes or no answer; few are interested in detailed explanations of how Gene X contributes to productivity or quality. "This has implications for patents, but gene discovery and IP is quite a difficult field," he says.

"Our approach is to regard the function of our genes as a trade secret - our farmers are primarily interested in increased performance rather than the detail of which individual gene contributes what to that performance.

"A gene test will cost them a certain amount, and we tell them what benefit they are likely to get from a test to tell them whether their animals have that gene." The cost-benefit equation becomes tricky when the gene test relates to improving traits of low heritability, where the proportion of the phenotype determined by the genetics is quite low.

There tends to be an expectation that any commercial gene test will deliver significant benefits, when in fact the elite alleles being tested for may already be present at high frequency in the national herd. For example, many bulls in farmer's herds are already homozygous for the Optimum and Quantum genes. Farmers are unlikely to pay a premium for a test for a gene that already occurs at high frequency in their own herds.

Adam says it is unsurprising that some promising loci identified in a first pass subsequently disappear. The statistical correlation between a particular trait and a marker-defined locus turns out to be non-robust, because of complex interactions between the allele and anonymous genes at other loci - either in cis phase (on the same chromosome) or trans phase (between chromosomes).

"And some traits are more complex at a physiological level: fertility is a good example. There are many nutritional aspects that influence fertility. We know that if we don't feed our cows adequately in spring, they'll have more difficulty to get in calf. Fertility is of increasing importance on the farm - it's currently one of our prime targets."

When heritability is low, it becomes harder to find the genes, so large-scale experiments have to be conducted to provide the requisite statistical power to identify prospective loci, he says.

"There is a view in the biotechnology industry that if a breeding company has bred a bull using genetic markers, it will automatically be able to charge more for its semen.

"New Zealand farmers have made some progress in improving fertility through conventional breeding, and our fertility is a lot better than in many overseas herds, and farmers can now buy semen from bulls that will demonstrably improve fertility. In this instance, you might charge a premium.

"But we're unlikely to find an allele that occurs at a frequency of only one in a million in the 800 animals in our research herd. We can only look for very rare outliers in the national herd, using our database, and we've done that.

"We need to be realistic in our expectations, because we're really making improvements at the margins of what has been achieved through decades of conventional breeding.

"We're adding about one per cent improvement per year to what we call 'breeding worth' - a compound measure of extra genetic worth in relation to what could have been achieved through conventional breeding."