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Genetic test for the identification of carriers of complex vertebral malformations in cattleRelated Patent Categories: Chemistry: Molecular Biology And Microbiology, Measuring Or Testing Process Involving Enzymes Or Micro-organisms; Composition Or Test Strip Therefore; Processes Of Forming Such Composition Or Test Strip, Involving Nucleic AcidGenetic test for the identification of carriers of complex vertebral malformations in cattle description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20060240471, Genetic test for the identification of carriers of complex vertebral malformations in cattle. Brief Patent Description - Full Patent Description - Patent Application Claims
FIELD OF THE INVENTION [0001] The present invention relates generally to a genetic disease observed in bovines termed Complex Vertebral Malformation (CVM). More particularly, the invention relates to molecular markers for identifying potential bovine carriers of CVM and for identifying the CVM gene locus and mutations thereof responsible for complex vertebral malformation in bovines. BACKGROUND OF THE INVENTION [0002] Complex Vertebral Malformation (CVM) is a congenital vertebral disorder detected in Holstein-Friesian (HF) black and white dairy cattle. The disease has recently been described (Agerholm et al., 2000). In Denmark, all cases diagnosed until today (Oct. 17, 2000) have been genetically related to the former elite US Holstein bull Carlin-M Ivanhoe Bell. According to the present data, CVM appears to be inherited as an autosomal recessive disease. [0003] The disease is characterised by a congenital bilateral symmetric arthrogryposis of the distal joints and malformations of the columna, mainly at the cervico-thoradc junction combined with reduced body weight (Agerholm et al., 1994). [0004] Externally, there are the following major findings: In many cases the cervical and/or the thoracic part of the columna seems to be short. Moderate bilateral symmetric contraction of the carpal joints and severe contraction and supination of the phalango-metacarpal joint (fetlock) are constant findings. Contraction and pronation of the phalango-metatarsal joint and slight extension of the tarsus are also common findings. In most cases an irregular course of the columna around the cervico-thoradc junction is observed. Scollosis may be observed, and lesions may be present in other regions of the columna. The irregular course is often recognised by inspection and palpation of the ventral aspect of the co-lumna. However, lesions may be minimal and restricted to two or few vertebrae. In such cases the columna may be of almost normal length. Therefore, radiological examination of the columna is recommended to exclude vertebral malformations in suspected cases. The spinal cord is of normal size lying with the vertebral canal without obvious compressions. Using radiology, complex vertebral malformations consisting of hemlvertebrae, fused and malshaped vertebrae, scollosis, and anchylosis are found at varying degrees. This is best demonstrated following removal of the arcus vertebrae. In some cases malformations of the heart are present, mostly as a high interventricular septal defect and eccentric hypertrophy of the right ventricle. Malformations of the large vessels may occur. In the lungs fetal atelectasis is present. Serohemorrhagic fluids are most present in the thoracic cavity. A variety of other malformations have been observed, but these are not constant or common findings. Lesions due to dystocia are often found. [0005] Malformations have been observed both in aborted fetuses, prematurely born calves and in stillborn calves born at term. Cases among older calves have not yet been observed. In general the body weight is reduced, and the body weight is lower in premature born calves than in calves born at term. [0006] Additionally, there seems to be an increased frequency of abortions in cows inseminated with semen of carrier bulls. At present the cause of this is unknown. [0007] Presently, the only tool available for CVM diagnosis is patho-anatomical diagnosis based on the above described presence of bilateral symmetric arthrogryposis of the distal joints and malformations of the columna, mainly at the cervico-thoradc junction combined with reduced body weight. However, symmetric contractions of the limbs are common and general findings in vertebral malformations in calves. Therefore, differential diagnostic problems do exist as it is often difficult to differentiate between CVM and other malformations. [0008] The fact that the genetic defect appears to be spread by the bull Carlin-M Ivanhoe Bell which has been used intensively all over the world makes it of significant economic importance to be able to test whether current and potential breeding bulls are carriers of the defect. [0009] In order to obtain an estimate of the frequency of potential CVM carrier animals within the Danish cattle population, the present inventors have extracted pedigree information from the Danish national cattle database. At the time of the extraction (October 2000) there were registered 919,916 pure-bred cows and heifers, and 169,821 pure-bred bulls and male calves. Bell was found 707,915 times in the pedigrees of the cows and heifers and 161,043 times in the male pedigrees. In Tables 1 and 2 below, the number of occurrences of Bell in each generation of the pedigrees is shown. TABLE-US-00001 TABLE 1 Occurrence of Bell in the pedigrees of Danish Holstein cows and helfers Generations Cumulative NR Frequency Percent Frequency 2 21240 3.0 21244 3 202460 28.6 223704 4 321043 45.4 544747 5 133956 18.9 678703 6 27307 3.9 706010 7 1869 0.3 707879 8 36 0.0 707915 [0010] TABLE-US-00002 TABLE 2 Occurrence of Bell in the pedigrees of Danish Holstein bulls Cumulative Generation Frequency Percent Frequency 2 436 0.3 436 3 20144 12.5 20580 4 82394 51.2 102974 5 44545 27.7 147519 6 12455 7.7 159974 7 1040 0.6 161014 8 29 0.0 161043 [0011] Although these numbers also include some double and triple occurrences of Bell in the pedigrees, the data clearly show that a majority of the Danish Holstein cattle are potential carriers of CVM. Clearly, the problem is immense on a global scale. [0012] Thus, there is great demand in the cattle industry for a genetic test that permits the identification of cattle in various breeds that are potential carriers of CVM (e.g. before detectable onset of clinical symptoms). [0013] Prior to the present invention, microsatelilte mapping has not been applied to the gene causing the above complex vertebral malformations which has not been isolated or characterised. Thus, to the inventors' best knowledge, the diagnostic method according to the invention described in further detail in the following has not previously been suggested or disclosed. [0014] Accordingly, the present invention, which comprises mapping of the disease locus for CVM, has provided a DNA test based on microsatellite markers located on bovine chromosome BTA3. The ability of the test to define the carrier status of animals descending from Bell has been confirmed which appears from the examples below. SUMMARY OF THE INVENTION [0015] In its broadest aspect, the present invention provides a method for detecting the presence in a bovine subject of a genetic marker associated with bovine complex vertebral malformation (CVM), comprising the steps of providing a bovine genetic material, and detecting in the genetic material the presence or absence of at least one genetic marker that is linked to a bovine complex vertebral malformation disease trait or a specific nucleotide polymorphism which causes the complex vertebral malformation disease trait. [0016] In a further aspect, the invention pertains to a diagnostic kit for use in detecting the presence in a bovine subject of at least one genetic marker associated with bovine complex vertebral malformation (CVM), comprising at least one oligonucleotide sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15 , SEQ ID NO:16, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37 and SEQ ID NO: 38, and combinations thereof. Furthermore, the invention relates to a diagnostic method including a diagnostic kit for the detection of a G/T polymorphism in the bovine SLC35A3 gene causative and diagnostic for CVM in cattle. DETAILED DESCRIPTION OF THE INVENTION [0017] One primary objective of the present invention is to enable the identification of cattle carrying bovine complex vertebral malformation (CVM). This is achieved by a method which detects the presence of a genetic marker associated with bovine CMV in a bovine subject. More specifically, the genetic marker may be the bovine SLC35A3 gene or even more specifically specific polymorphisms in the bovine SLC35A3 gene. [0018] As used herein, the term a "bovine subject" refers to cattle of any breed. Thus, any of the various cow or ox species, whether male or female, are included in the term, and both adult and new-born animals are intended to be covered. The term does not denote a particular age. One example of a bovine subject is a member of the Holstein-Friesian cattle population. [0019] The term "genetic marker" refers to a variable nucleotide sequence (polymorphic) that is present in bovine genomic DNA on a chromosome and which is identifiable with specific oligonucleotides. Such a variable nucleotide sequence is e.g. distinguishable by nucleic acid amplification and observation of a difference in size or sequence of nucleotides due to the polymorphism. In useful embodiments, such genetic markers may be identified by several techniques known to those skilled in the art, and include typing of microsateliltes or short tandem repeats (STR), restriction fragment length polymorphisms (RFLP), detection of deletion or insertion sites, and random amplified polymorphic DNA (RAPD) as well as the typing of single nucleotide polymorphism (SNP) by methods including restriction-fragment-length polymerase chain reaction, allele-specific oligomer hybridisation, oligomer-specific ligation assays, mini-sequencing, direct sequencing, fluorescence-detected 5'-exonuclease assays, and hybridisation with PNA and LNA probes and others. However, it will be appreciated that other genetic markers and techniques may be applied in accordance with the invention. [0020] As described above, "bovine complex vertebral malformation" (CVM) is a congenital vertebral disorder. Presently, the disease has only been detected in Holstein-Friesian (HF) black and white dairy cattle; however, it is also contemplated that other bovine races may be affected. The disease has recently been described by Agerhoim et al., 2000. Accordingly, in the present context CVM and bovine complex vertebral malformation disease trait are to be understood as a disease resulting in the clinical symptoms previously described herein, and as reported and defined by Agerholm et al., 2000. Continue reading about Genetic test for the identification of carriers of complex vertebral malformations in cattle... 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