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• We have recently shown that Factor XI deficiency in Holstein cattle is caused by a mutation that leads to a shortened protein that lacks biological activity.
• We are developing a DNA-based test to genotype normal, carrier and affected animals, in order to examine the frequency and severity of this condition in U. S. Holstein cattle.

Inherited deficiencies of Factor XI, a blood clotting factor, have been documented in humans, dogs, and cattle. The bovine disorder has been known since 1969 when it was discovered in Holstein cattle in Ohio. Characterized by hemophilia-like symptoms, it was later observed in Holstein-Friesians in Canada, England, and Australia. Like DUMPS and BLAD, it is inherited in an autosomal recessive manner. Accordingly, carrier animals (heterozygotes) for the defective gene appear to be outwardly normal, while affected animals (homozygotes) have a bleeding disorder; one quarter of offspring from mating a carrier bull to a carrier cow are expected to be affected with Factor XI deficiency.

Current testing methods do not always distinguish between normal and carrier animals. As a result, little testing for Factor XI has occurred in the U. S., where its frequency could be as high as the 7 percent currently estimated for Canadian Holsteins. In addition, the full consequences of the condition for affected and carrier animals have not been well established. Bovine Factor XI deficiency can result in spontaneous or induced bleeding episodes. Continued bleeding can occur from the umbilical cord at birth and/or upon dehorning or castration. Affected cows can hemorrhage at calving and/or can produce blood-stained milk. While certain episodes can be catastrophic, leading to death of the animal, some affected animals can survive for years with no overt signs. However, evidence suggests that reproductive performance of these animals may be compromised.

We have recently completed sequencing the gene for bovine factor XI and have identified the mutation that causes the deficiency. As indicated in Figure 1, the mutation consists of a 76-base insertion into exon 12, one of the coding regions of the gene. The figure shows that the normal exon 12 consists of 176 bases, while the mutated exon 12 is 76 bases longer. While most of the insertion consists of long strings of adenine (A) bases, part of the insertion codes for a premature “stop” signal that prevents the full length, fully-active protein from being made. As a result, normal blood clotting is compromised in animals with this mutated gene.

This research has been possible because of our collaboration with Canadian researchers who have maintained a herd of Factor XI deficient cattle for over 20 years. They have provided us with samples from affected animals from their herd. We are continuing to examine those samples to make sure that only one mutation is responsible for all the observed cases. We are also developing a DNA-based test for normal, carrier and affected animals. This will permit us to determine the genotype of animals reliably and inexpensively.

Our next step will be to assess the frequency of this condition in U. S. Holstein cattle. We will be starting with a sample of the top 400 AI bulls as of July 1990. We may examine a more contemporary cohort of bulls as well. We will then examine the severity of the condition, by examining the productivity and longevity of daughters of carrier and normal bulls. This will permit us to assess the economic impact of the condition and to propose a cost-effective way to control this condition, if warranted.

Deleterious inherited disorders are one of the trade-offs involved in heavy selection of dairy cattle for increased production. It is estimated that any one animal carries a half dozen of these conditions. With heavy use of any one animal, the frequency of deleterious genes is increased. Accordingly, we should expect these conditions to occur in the contemporary dairy industry. Fortunately, when a condition can be characterized and identified by a reliable and inexpensive test, it can be readily controlled, with little loss of genetic gain, as has been the case with DUMPS and BLAD.