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Genetic mutation from one bull caused loss of 500,000 calves

Holly Drankhan for Progressive Dairyman Published on 24 February 2017
Holstein bull Pawnee Farm Arlinda Chief

Pawnee Farm Arlinda Chief, or Chief for short, is responsible for 14 percent of the current Holstein genome in the U.S.

While many of Chief’s genes have benefited the breed, a recent study in the Journal of Dairy Science identified one dangerous mutation hidden among his DNA that is responsible for more than 500,000 spontaneous abortions worldwide.

The search for the mutation began when Paul VanRaden and his fellow researchers at the USDA Agriculture Research Service Animal Genomic and Improvement Laboratory adopted techniques used to confirm the inheritance of brachyspina, a congenital lethal defect discovered in Europe.

The team was unable to find any cows with two copies of several haplotypes – or sequences of genes inherited from a single parent. These haplotypes included Holstein Haplotype 1, or HH1, on chromosome 5.

Homozygous individuals – or those with two copies of HH1 – were expected to compose a much higher percentage of the population based on prediction equations, VanRaden and colleagues outlined in the December 2011 issue of Journal of Dairy Science.

An absence of homozygous individuals indicates the presence of a recessive mutation that is lethal if inherited from both parents.

In other words, animals with two copies of the mutated HH1 never entered the population sampled by the USDA due to early death, explained Heather Adams, author of the 2016 Journal of Dairy Science study and genomic research specialist for Corporate Resources International’s International Center for Biotechnology.

HH1 was subsequently linked to decreased conception rates and increased stillbirths. Through pedigree analysis, VanRaden traced the source of the haplotype to Chief.

Born in 1962, the bull’s desirable traits and the advent of A.I. made him highly prolific. His offspring include more than 16,000 daughters, 500,000 granddaughters, and 2 million great-granddaughters, as well as several sons that became popular sires.

The recent Journal of Dairy Science article estimates Chief’s economic contributions to be about $30 billion in increased milk yield.

“It was surprising that it was found in Chief because he had been one of the primary foundation bulls of the Holstein breed from the 1960s, and so that meant that this bad mutation had been there in high frequency for many decades, and nobody had ever reported it,” VanRaden said.

In the past, abortions were most likely blamed on the cow rather than the bull, Adams said. This could partially explain why the deleterious mutation in Chief’s DNA was overlooked for so long.

“Now with genomics, we can more accurately find the root of the problem – maybe the cow, maybe the bull,” Adams said.

Two of Chief’s sons, Mark and Ivanhoe Chief, were also determined to be carriers of HH1. Cumulatively, they sired more than 70,000 daughters.

The USDA approached Harris Lewin, a professor and former vice chancellor for research at UC – Davis, who had already sequenced Chief’s DNA for an unrelated project. Adams, then a postdoctoral researcher in Lewin’s lab at the University of Illinois at Urbana –Champaign, joined him on the quest to uncover more about the mutation.

“All of the legwork [the USDA] did make our part extremely easy – they gave us information on where to look and what we were looking for, and Chief’s sequencing data unveiled the rest,” Adams said.

In less than 24 hours, researchers pinpointed the mutation’s location to the apoptosis peptide activating factor 1 gene, or APAF1 for short. Apoptosis, or programed cell death, is a key component of early development.

Previous papers documented that most laboratory mice with inactive APAF1 genes die in utero. Authors therefore concluded that the mutated gene in Chief’s genome was most likely responsible for the prenatal fatalities in his offspring.

This conclusion was supported by the fact that among more than 246,000 genotyped Holsteins, the authors didn’t find a single APAF1 homozygote.

The mutation was responsible for approximately 525,000 abortions worldwide and 140,000 in the U.S. during a 35-year period, with an estimated economic loss of $425 million, according to the article.

“Had the mutation been discovered early on, the loss would not have been so significant, and the mutation could have been removed or controlled through selective breeding,” Adams said.

To discover mutations like APAF1 in a timely and accurate manner, researchers need a large pool of genotyped animals, Adams continued. Therefore, the availability of affordable DNA sequencing methods is crucial.

Since 2009, the dairy industry has genotyped more than 1.5 million Holsteins using single-nucleotide polymorphism chips that evaluate common genetic variations within individuals, VanRaden said.

Single-nucleotide polymorphism chips help narrow in on the location of genes responsible for certain desirable and undesirable traits.

“So even without seeing the real genetic mutation, the markers are always close by, and that lets us estimate where the genetic effects are and what their sizes are,” VanRaden said.

The information gathered from the chips is maintained in a databank shared by the Council on Dairy Cattle Breeding and the USDA for research to improve genomic predictions. These developments are then shared with breeding companies and producers.

Before the 2013 Supreme Court ruling banning patents on naturally occurring genes, genetic testing was sometimes cost-prohibitive. In the past, producers paid $30 to $40 per animal to evaluate a single defect, VanRaden said.

“That’s a huge amount of new information that especially commercial farmers and most breeders couldn’t afford to get before, and now they get it automatically,” he said.

Not only is the number of animals genotyped growing but so is the number of genetic markers evaluated. This means researchers will have more complete data to investigate, Adams said.

With the APAF1 mutation identified and genomic sequencing more affordable, the carrier frequency of the defect in Holsteins has already been reduced from 8 percent to 2 percent in 2015, according to the article.

“Of course, we need to remember that we can’t throw the baby out with the bathwater,” Adams said.

“If you have a bull with outstanding genetic merit for production traits, but he also carries a deleterious recessive mutation like that in APAF1, you don’t just avoid using him altogether; avoid carrier-to-carrier matings where you have a 25 percent chance of producing the lethal recessive,” she added. “Or if you choose to mate the carriers, know you have a 25 percent chance of the pregnancy ending in abortion.”

Adams said it’s up to farmers to weigh the risks and make the call.  end mark

PHOTO: Widely used Holstein bull Pawnee Farm Arlinda Chief made a mark on the breed by transmitting desirable traits like milk production, but it was discovered last year that he also passed on an undesirable trait that caused thousands of stillbirths and abortions. Photo courtesy of Danny Weaver and Agri-Graphics Ltd.

Holly Drankhan
  • Holly Drankhan

  • Student
  • Michigan State University College of Veterinary Medicine

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