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HCD: How to identify and overcome cholesterol deficiency

David Wilson for Progressive Dairyman Published on 24 February 2016

Chronic diarrhea. Weakness. Low bodyweight. Loss of appetite. Death.

For decades, Holstein calves not responding to treatment left animal health professionals perplexed while costing dairy farmers worldwide countless dollars in veterinary care and losses.

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However, with the advent of bovine genomics, the mystery of cholesterol deficiency started to unravel.

What is HCD?

Cholesterol deficiency is a genetic mutation known as haplotype cholesterol deficiency (HCD). It affects Holstein calves, peaking in frequency in 2001 and affecting Holstein herds until very recently.

Symptoms show up soon after birth, and research has indicated that up to 5 percent of a given Holstein cow population can be carriers. If both parents are carriers of the mutation, 25 percent – that is, one out of every four calves born of those parents – is suffering from this fatal genetic disorder.

It is not only distressful for the animal as it suffers, but as expected, caring for these animals for any length of time adds operational, financial and emotional burdens to the farmer.

Calves born with the genetic defect lack cholesterol in their cells. Without the required fat-producing cholesterol in its system, it is impossible for the animal to convert energy to fat – fat needed to carry out basic physiological functions that allow the calf to thrive. Most often, the calf dies within one to six months, but in some cases, it may survive up to two years.

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Most concerning to farmers is that the mutation affects live births, creating a greater financial burden to the farmer than simply absorbing an expected level of overhead cost associated with embryonic loss.

In order for a calf to be a defective carrier, the HCD mutation must occur on both chromosomes (i.e., homozygous) inherited from its parents. If a carrier is mated with another carrier, a 1-in-4 chance exists of that offspring inheriting the disease.

Additionally, heterozygous animals (e.g., animals having the mutation on only one chromosome) have reduced levels of cholesterol, making it a challenge to become a viable member of the herd and jeopardizing a pedigree if it is mated and produces calves.

Defect discovered in Maughlin Storm bloodline

A haplotype (sometimes referred to as a genetic marker) is a distinct group of DNA markers an animal inherits from one parent. As in the case of cholesterol deficiency, the haplotype does not define the disease but rather simply represents a section of a chromosome that seems to be associated with the disease.

The first step in identifying disease genes and mutations like HCD comes by analyzing DNA markers of samples of both carrier and non-carrier bloodline or pedigree members. As a result, the haplotype associated with the disease can be determined.

In July of 2015, German research company VIT, an animal production IT solutions company (with the help of USDA-AGIL and the Canadian Dairy Network), announced it had identified the HCD haplotype, tracing it to a Holstein bull in Canada, Maughlin Storm, a great-grandson of Fairlea Royal Mark.

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As a result of discovering the bloodline and the sire responsible for the defect as well as identifying the haplotype (or section) of chromosome on which the defect can form, VIT developed a test that could determine if a calf was HCD homozygous (definite carrier), HCD heterozygous (suspect or possible carrier) or a non-carrier.

However, because the locus (the exact location of where the mutation occurred within the haplotype) remained hidden, heterozygous animals that were HCD carriers could only predict with up to 80 percent accuracy (including room for false positives) the basis of a heterozygous calf’s carrier status, leaving farmers doubtful about what to do with heterozygous calves that carried the defect on only one of their chromosomes.

Then, on Dec. 10, 2015, just six months after Maughlin Storm was determined to be the carrier of the HCD haplotype, researchers at the University in Liège – Belgium announced they identified the gene and causal mutation for HCD. A test that is 100 percent accurate in determining the carrier status of an animal was underway.

Realizing a genetic breakthrough

To assure accuracy in discovering and identifying the haplotype within the gene, the Unit of Animal Genomics (UAG) at the University in Liège – Belgium required numerous DNA samples consisting of both carrier and non-carrier animals.

The greater the number and diversity of samples, the easier it would be to uncover the exact location of where the cholesterol-deficient mutation occurred. Upon discovering the locus, a test would be developed that would leave no doubt about a calf’s carrier status – even if it was HCD heterozygous.

Molecular biologist Michael Georges, head of UAG’s research team, reached out to longstanding partner CRV. Having collaborated with the university for more than 20 years, the DNA samples from the company’s globally established daughter groups already in the university’s sample library would be included in the university’s HCD research.

Now with the expansive, well-defined DNA sample library at hand, and the carrier status of each sample known, combined with what was already known about the haplotype, the university’s research team was able to compare and determine the precise order of nucleotides (adenine, guanine, thymine and cytosine) on each DNA sample.

By process of elimination, this data would lead them directly to the location of where the HCD mutation occurred within the chromosome’s haplotype.

Notably, the sample analyses data revealed that a certain mutation was always present in the carrier animals but not present in non-carrier animals. As researchers continued to rule out certain markers on the carrier-animal haplotype, the location quickly became evident. It was now possible to know with 100 percent accuracy the carrier status of heterozygous calves.

With this information confirmed, a genomic test for HCD was developed by the University in Liège – Belgium and by another genetics group in Switzerland who also participated in the research.

This latest test not only is able to identify heterozygous calves that carry the mutation but also eliminates the chance of a false positive from occurring – neither of which the earlier test was able to conclude or provide. Farmers now had the means to make sound, certain decisions concerning a calf and the future of their herd.

Test the quality of bull semen

As in the case of Storm, looks can be deceiving. With recent advances in genetic discovery, genomic tests such as the test developed to identify HCD will continue to pave a more profitable and efficient path by giving farmers the ability to make strategic herd management decisions with confidence.

With the HCD test now available, A.I. companies can test their line-up of Holstein bulls to eliminate any chance of producing calves that carry the HCD mutation. Moreover, farmers who have already experienced calf mortality due to cholesterol deficiency now have a valuable tool to begin eliminating HCD from their herd once and for all.

“We have already begun testing bulls that have indicated ‘positive’ by the haplotype,” says Erik Mullaart, senior researcher at CRV in Amsterdam, The Netherlands.

“The ability to identify the bulls that are definite carriers from bulls that merely imply the haplotype will deepen and strengthen our sire offering without limiting the functional traits that keep our customers thriving.”

Ultimately, as more genetic discoveries are made within a given cattle population, and through early and routine genomic testing, a herd has the potential to be shaped and molded to meet each farmer’s specific operational goals through sire selection, calf retention, disease prevention and trait improvement, helping meet the demands of an ever-changing dairy market and a growing, global population.  PD

David Wilson is a breeding program manager with CRV USA. Email David Wilson.

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