Study on genetic factors controlling liver copper concentration in sheep

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Sheep are known to be impaired regarding their ability to excrete excess copper (Cu) from the liver and therefore to be more susceptible to Cu intoxication than other farm animals. On the other hand, Cu deficiency is also a known problem in sheep husbandry. In consequence, there is little scope for adequate Cu supplementation in the sheep diet. Interestingly, the susceptibility for Cu deficiency as well as for Cu intoxication varies between sheep breeds. Moreover, liver copper concentration seems to be highly heritable and variable between and within sheep breeds. Hence, it is the aim of this study to identify the molecular genetic factors which significantly control the liver copper concentration in sheep. In the first part of this project, Cu concentration will be measured in already collected liver samples from performance tested slaughter lambs of the Merinoland sheep breed. Applying an SNP chip, DNA from 96 of these samples will be genotyped for about 600,000 genetic variants distributed in the sheep genome. Resulting phenotyping and genotyping data will be used for a genome wide association study (GWAS). Subsequently, genome regions which showed to be associated with liver Cu concentration will be screened for genetic variants which could directly control liver copper concentration. For this step, an appropriate next generation sequencing method will be employed. Finally, the most promising among those genetic variants will be tested for their effect on liver copper concentration in additionally collected and phenotyped samples from five more sheep breeds, which are of importance in sheep production and/or known to differ in their susceptibility to Cu intoxication or deficiency. The results of this project will enhance the knowledge on the genetic control of liver Cu metabolism and can help to develop new concepts for therapy and prevention of Cu intoxication and deficiency in sheep.