Hunting for the Weaver Causative Mutation in Brown Swiss Cattle

Bovine Progressive Degenerative Myeloencephalopathy (Weaver Syndrome) is a recessive neurological disease that has been observed in US and international Brown Swiss cattle since the 1920’s.  Bilateral hind leg weakness and ataxia appear in afflicted animals at 6 to 8 months of age.  Total loss of control of the hind limbs occurs 12 to 18 months after initial clinical signs, usually resulting in euthanasia.  While Weaver has been mapped to bovine chromosome 4, neither the causative gene nor mutation has been identified.  Analyzing 35,353 SNP on chromosome 4 from the Illumina BovineHD BeadChip in 20 Weaver Brown Swiss carriers and 49 homozygous normal Brown Swiss bulls, refined the Weaver locus to a 4-Mb region.  Novel variations within the region (N=53,007) identified from whole genome sequencing of 10 carrier and 10 normal Brown Swiss animals.  Filtering for allele frequency, repeat regions, and against genomic variations identified in 8 other breeds resulted in 127 candidate differences.  Forty-four SNP were chosen based upon their proximity to an effect on genes in the region.   These SNP were genotyped in 900 Brown Swiss animals of various disease statuses to determine the most likely causative mutation for Weaver Syndrome.