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Welcome to the website of the Southdown Sheep Society, the Society represents the interests of Southdown breeders in the UK and provides registration and marketing services to breeders across the country. The Southdown is the oldest of the terminal sire breeds in the UK and as the name suggests originates from the native sheep which have roamed the South Downs in the South of England for many hundreds of years.

These sheep have led us down a Path Less Traveled, a path full of twists, turns, and rich experiences. Their wool inspired us to learn many new crafts; hand processing fiber, dyeing, carding, spinning, knitting, and weaving.

My adventure as a shepherd began in 2005. We had been searching for an organic solution for grass and weed control in our vineyard. Although we started with the sheep for a practical reason, before long they had woven their way into my heart.

Now these little sheep are used for many things. They make excellent pets & companions for the young, elderly & disabled due to their diminutive size & gentle nature. Their fleece is in the class of cashmere & their wool is ideal for hand spinning. They have been used with great success in wine vineyards as well as fruit & berry orchards since they are excellent grazers & they will not harm the fruits, girdle trunks of trees or harm shrubs. They leave the grounds well groomed & fertilize behind themselves as they graze! Because Babydoll Southdowns are an ancient breed, they are not prone to many of the modern sheep problems & are resistant to foot rot, a common ailment with modern sheep.

An easily lambed breed with quick growing, rapidly finished lambs, the Southdown is also the breed of choice for many small flock owners wanting docile, yet active sheep to graze poorer quality pasture.

Amino acid sequence alignment for exon 10 of Slco1b3 for mutant Southdown sheep (sheep with CPH), CPH-unaffected sheep, and 7 other mammalian species. The black arrow indicates the glycine-to-arginine amino acid change caused by the g.193691915C>T mutation in the mutant sheep. Amino acids highlighted in black represent the most common amino acids conserved across species, whereas amino acids highlighted in gray represent an amino acid change within the same chemical class, and those highlighted in white represent an amino acid change to a different chemical class.

CONCLUSIONS AND CLINICAL RELEVANCE Results suggested a nonsynonymous mutation in Slco1b3 causes CPH in Southdown sheep. This disease appears to be similar to Rotor syndrome in humans. Sheep with CPH might be useful animals for Rotor syndrome research.

Over 70 years ago, a disease characterized by CPH was first described in Southdown sheep flocks in New Zealand.1 Results of subsequent breeding trials revealed that the disease was caused by an inherited recessive trait.2 In the 1960s, the disease was observed in Southdown sheep in California.3 Affected sheep had hyperbilirubinemia but no discoloration of the liver and also had delayed clearance of various organic anions. Cornelius4 described this congenital disease as similar to Gilbert syndrome in humans (OMIM No. 143500) because, at the time, it was believed Gilbert syndrome was the result of a defect in hepatic uptake of bilirubin. However, it was subsequently determined that Gilbert syndrome is caused by a defect in the uridine diphosphate-glucuronosyltransferase 1 A1 gene, which is responsible for conjugation of bilirubin to bilirubin glucuronide.5 Dubin-Johnson syndrome (OMIM No. 237500), another disease of humans characterized by hyperbilirubinemia, is caused by a defect in the canalicular multispecific organic anion transporter gene.6 Rotor syndrome (OMIM No. 237450), another disease of humans, is primarily characterized by the presence of conjugated hyperbilirubinemia subsequent to a hepatic uptake and storage defect.7 Rotor syndrome is an autosomal recessive disorder that is similar to Gilbert and Dubin-Johnson syndromes, and all 3 syndromes are categorized as hereditary hyperbilirubinemia diseases.8

In humans, Rotor syndrome is caused by OATP1B1 and OATP1B3 deficiencies.9,10 Results of those studies9,10 indicate that mutations in 2 genes, SLCO1B1 and SLCO1B3, are required for patients to develop Rotor syndrome. In sheep, little research has been conducted on the function or structure of Oatp1b1 and Oatp1b3 or the genes (Slco1b1 and Slco1b3) that encode those proteins. Only 1 gene ortholog for the Oatp1b subfamily of proteins has been found expressed in the livers of dogs11 and mice,12 whereas 2 orthologs for the OATP1B subfamily of proteins are expressed in the livers of humans. Similarly, the ovine genome assembly Oar_v3.1 appears to support the existence of just 1 transporter within the Oatp1b subfamily because gene models for SLCO1B1 and SCLO1B3 from other mammals align to just 1 locus on chromosome 3 in the sheep genome. We refer to this ortholog as Slco1b3 owing to its higher level of sequence identity with SLCO1B3 than SLCO1B1 (72% vs 69% identical on the predicted protein level).

This purpose of the study reported here was to identify the molecular cause for CPH in Southdown sheep and provide genetic evidence that this disease is more similar to Rotor syndrome than Gilbert syndrome. The hypothesis was that 1 or more mutations within the Slco1b3 gene were responsible for CPH in Southdown sheep.

Over the 6-year period from 2011 through 2016, blood samples (approx 10 mL) were obtained by jugular venipuncture from each of 73 sheep within the research flock. Blood samples collected into blood collection tubes that contained potassium EDTA as an anticoagulant were used for genomic DNA extraction, whereas blood samples collected into blood collection tubes that contained heparin as an anticoagulant were used to obtain plasma for measurement of bilirubin concentrations.

Blood samples from 72 of the 73 sheep were submitted to the Cornell University Animal Health Diagnostic Center in Ithaca, New York, for determination of plasma direct and indirect bilirubin concentrations by means of the Jendrassik-Grof procedure as described.13 Direct bilirubin concentration was used as a measurement of conjugated bilirubin, and indirect bilirubin concentration was used as a measurement of unconjugated bilirubin. Plasma total bilirubin concentration represented the summation of conjugated (direct) and unconjugated (indirect) bilirubin concentrations and was used to classify sheep as mutants and controls.

A phenotypically normal (unaffected) offspring that resulted from mating a homozygous mutant ram with a carrier ewe was chosen for genome sequencing. That sheep was determined to be a heterozygote for CPH on the basis of principles of Mendelian inheritance. A DNA sample from that sheep was submitted to the Biological Resource Center at Cornell University to create a PCR assay-based sequence library with a median insert size of 165 bp, which was whole-genome sequenced by use of paired-end, 100-bp reads.b This resulted in 215,134,336 read pairs. Those pairs were aligned to the Oar_v3.1 genome assembly by use of an alignment algorithm of a commercial software packagec as described14; up to 3 mismatches were allowed per read. The alignment was locally realigned, and variants were called and filtered by use of genome analysis softwared as described.15 Variants were calledd with the following thresholds: a minimum Phred-scaled confidence calling threshold of 40.0 and minimum Phred-scaled confidence emitting threshold of 20.0. Variants were filtered outd with the following thresholds: > 10% of reads with a mapping quality of 0, quality score normalized by allele depth of < 5, and variants adjacent to homopolymer runs > 4 bp long. The final filtered read coverage averaged 138X. Heterozygous variants within Slco1b3 coding exons were identified to focus fine-mapping efforts. That sequence was uploaded to the National Center for Biotechnology Information's Sequence Read Archive (accession No. SRR5749462). Polymerase chain reaction assay primers (Appendix) were designed to amplify exons that contained candidate SNPs for Sanger sequencing by use of web-based softwaree as described.16 Primers were designed on the basis of homology of the human SLCO1B3 gene with the ovine genome assembly because a Slco1b3 mRNA reference sequence for sheep was unavailable.

Eleven sheep (3 mutants, 2 phenotypically normal noncarriers, 5 phenotypically normal carriers, and 1 unknown) were selected for initial sequencing of Slco1b3. For each of those sheep, the genotypes for 7 SNPs located in or near Slco1b3 coding regions were determined by Sanger sequencingf at the Cornell Biological Resource Center. The PCR protocol was as follows: 3 minutes at 95C; 35 cycles of 95C for 30 seconds, 58C for 30 seconds, and 72C for 1 minute; and then a 3-minute extension at 72C. An additional 63 sheep from the research flock that were sampled between 2011 and 2016 were genotyped at the nonsynonymous SNP (OAR3 g.19369115C>T) by Sanger sequencing at the Cornell Biological Resource Center. Another flock of 18 Southdown and Southdown-crossbred sheep that were unrelated to sheep in the research flock were also sampled and genotyped at the nonsynonymous SNP. None of these sheep had signs of photosensitivity before or at the time of sampling, and they were treated as controls. An additional 30 sheep (5 sheep from each of 6 breeds other than Southdown) were likewise sampled and genotyped at the nonsynonymous SNP. Congenital photosensitivity and hyperbilirubinemia had never been described in sheep of those 6 breeds, and those 30 sheep were used to validate that the proposed causative allele did not occur in other breeds. All sequences were analyzed with sequence analysis software.g The 30 non-Southdown sheep were purposely selected to ensure that there was no first-degree relationship between individuals in an effort to minimize potential familial bias. 59ce067264


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