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Title:   Author  item
                                            McClure, Matthewitem
                                            Kim, Eui-Sooitem
                                            Bickhart, Derekitem
                                            Null, Danielitem
                                            Cooper, Tabathaitem
                                            Cole, Johnitem
                                            Wiggans, Georgeitem
                                            MARSAN, PAOLO - Catholic University Of The Sacred Heart Italyitem
                                            COLLI, LICIA - Catholic University Of The Sacred Heart Italyitem
                                            SANTUS, ENRICO - European Brown Swiss Federationitem
                                            Liu, Ge

                                                         - *George*item
                                            Schroeder, Steven

                                                         - *Steve*item
                                            MATUKUMALLI, LAKSHMI - National Institute Of Food And Agriculture (NIFA)item
                                            Van Tassell, Curtis

                                                         - *Curt*item
                                            Sonstegard, Tad
  Submitted to: PLOS ONE
                                    Publication Type: Peer Reviewed Journal
                                    Publication Acceptance Date: 2/13/2013
                                    Publication  Date: 3/20/2013
                                    Citation: Mcclure, M.C., Kim, E., Bickhart, D.M., Null, D.J., Cooper, T.A., Cole, J.B., Wiggans, G.R., Marsan, P.A., Colli, L., Santus, E., Liu, G., Schroeder, S.G., Matukumalli, L., Van Tassell, C.P., Sonstegard, T.S. 2013. Fine mapping for Weaver Syndrome in the Brown Swiss breed with the identification of possible casual mutations across NRCAM, PNPLA8, and CTTNBP2 and Developement of a diagnostic SNP haplotype. PLoS One. 8(3):e59251.Interpretive Summary: The recessive disease Bovine Progressive Degenerative Myeloencephalopathy (Weaver Syndrome) causes financial harm to producers as affected cattle are identified after 6-18 months of age and they are unuseable for milk production due to the effect of the disease.  While previous genetic research had identified microsatellite markers that could be used to identify carrier animals, the accuracy of genetic tests based upon them has decreased over time to the point that they are no longer used in the USA.  As the disease allele is still present in the Brown Swiss population, this study was performed to identify possible genetic changes causing the disease and provide the basis for a diagnostic test for presence of the conditition. The result will allow producers world wide that use purebred Brown Swiss or crosses to identify Weaver carrier animals and, therefore, properly manage them.
                                Technical Abstract: Bovine Progressive Degenerative Myeloencephalopathy (Weaver Syndrome) is a recessive neurological disease that has been observed in the Brown Swiss cattle breed since the 1970’s in North America and Europe.  Bilateral hind leg weakness and ataxia appear in afflicted animals at 6 to 18 months of age, and slowly progresses to total loss of hind limb control by 4 years of age.  While Weaver has previously been mapped to bovine BTA 4 and a diagnostic test based on the TGLA116 microsatellite is commercially available, neither the causative gene nor mutation has been identified; therefore misdiagnosis can occur due to recombination between the commercial marker and causative mutation.  Analysis of 34,980 SNP on BTA 4 from the Illumina BovineHD BeadChip in 20 Weaver Brown Swiss carriers and 49 homozygous normal Brown Swiss bulls revealed a reduced Weaver locus (48-53 Mb), upstream of TGLA116 (58.2 Mb).  Genotyping of 153 SNP, identified from whole genome sequencing of 10 normal and 10 carrier Brown Swiss animals, across a validation set of 841 animals resulted in the identification of 41 diagnostic SNP that are concordant with the disease.  Of these, 37 are adjacent to NRCAM, one non-synonymous (serine to asparagine) in PNPLA8, one synonymous and one non-synonymous (lysine to glutamic acid) in CTTNBP2, and one is intergenic.  Haplotype analysis of 7,458 Brown Swiss animals with Illumina BovineSNP50 data and imputed 41 diagnostic SNP resulted in 1 haplotype that was concordant with the Weaver phenotype.  Use of this haplotype and the diagnostic SNP can be quickly implemented to identify Weaver carriers both in the Brown Swiss breed and any breed influenced by Brown Swiss genomics.


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