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• Factor XI deficiency is an inherited bleeding disorder observed in Holstein-Friesian cattle worldwide.
• Current testing cannot always distinguish normal from carrier animals for this condition.
• Research is underway to establish the molecular basis for this disorder, so that a DNA-based test can be developed, which would be more reliable and economical.
• In our research to date, 20 percent of the normal gene for bovine Factor XI has been sequenced.

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; 25 percent 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., despite its presence here at a frequency that 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 pink 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.

The development of a DNA-based test for the condition would greatly facilitate our understanding of the incidence, consequences and economic impact of bovine Factor XI deficiency. Such a test depends on knowing the precise mutation (or mutations) in the DNA that give rise to the disorder. This requires determining the exact sequence of nucleotide bases in the DNA that code for normal Factor XI and the change in the sequence that gives rise to the deficiency.

Recall that DNA, the genetic material found in living cells, consists of two strands of nucleotide bases (abbreviated A, T, G and C, for adenine, thymine, guanine and cytosine, respectively) and that the linear order of these bases codes for the linear order of amino acids incorporated into proteins coded by the DNA. Most genes in animals are organized into exons and introns. Exons are the bases that code for the protein product and introns are bases that are interspersed between these exons.

Our work on bovine Factor XI has been facilitated by the fact that the gene for human Factor XI has been previously characterized. The human gene is 23,000 bases long and is organized into 15 exons and 14 introns. Because of genetic similarities between animal species, we would expect the cattle gene to have a similar organization. Using the methods of molecular biology and in collaboration with Australian researchers, we have sequenced about 20 percent of the bovine gene, namely the last three exons and last two introns. These bovine exons are very similar to the human exons, in that they have 86 percent of the very same bases in the same order and that 89 percent of the amino acids coded by these exons are identical. In addition, the two introns are similarly inserted between the exons.

We are proceeding to sequence the rest of the coding elements of the gene for bovine Factor XI. Once completed, we will be ready to start looking for the differences in the DNA of affected animals. For this part of the research, we will be collaborating with Canadian researchers who have maintained a herd of Factor XI cattle for over 20 years. In the case of the human deficiency of Factor XI, which is found in a variety of ethnic groups around the world, at least 15 separate mutations have been identified as causes of the bleeding symptoms. In livestock animals and within a single breed, a single mutation has generally been found to be the cause of any inherited disorder; this is because our contemporary breeds are inbred. However, only time will tell whether one or more mutations cause bovine Factor XI deficiency. Developing a DNA-based test will be greatly simplified if one mutation is responsible for all cases of the disorder.

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 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.