Study on genetic factors controlling liver copper concentration in sheep
Veterinary Medical Science
Final Report Abstract
Due to a limited ability to excrete unneeded copper (Cu) from the liver, sheep are more susceptible to copper poisoning than other farm animals. On the other hand, an undersupply of copper is also frequently observed in sheep farming. Therefore, adequate nutritive Cu supply in sheep can be difficult to achieve. Interestingly, susceptibility to both Cu intoxication and Cu deficiency varies between sheep breeds. Furthermore, Cu concentration in the liver shows a high heritability and is variable between and within sheep breeds. Therefore, the aim of this study was to identify the molecular genetic regions that exert a significant control on liver Cu concentration in sheep. Genome-wide association analysis using liver samples from Merinoland sheep with high and low Cu concentration reveals promising candidate genes such as DYNC1I2, VPS35, SLC38A9 and CHMP1A. Gene ontology (GO) terms such as lysosomal membrane, mitochondrial inner membrane and sodium proton antiporter activity were significantly enriched. Genes involved in these identified pathways mediate multivesicular body (MVB) fusion with lysosome for degradation and control membrane permeability. Signatures of selection analyses with available SNP data from several sheep breeds known to be Cu tolerant or susceptible revealed genomic regions putatively under selection for that trait. A region under selection on chromosome 11 harbours various genes associated with oxidative stress and apoptosis. Genes identified in this region include SLC25A11, TP53, TNFSF12, TNFSF13, ALOX15, ALOX12, EIF5A and ACADVL. This and findings from some subsequent analyses suggest that variability in response to inflammation and apoptosis may be responsible for breed differences in liver Cu sensitivity resulting in varying hepatic Cu concentration. In a third part of the project, transcriptome analysis for differentially expressed genes was conducted with samples from Polish Merino sheep with high and low liver copper concentration. Differentially expressed genes include MVD, SQLE, DHCR7, FDPS, CYP51 and INSIG1. This and results from GO term analyses indicate that there is a possible link between cholesterol or steroid biosynthesis with hepatic Cu concentration at least in Polish Merino sheep. Taken together, liver Cu concentration seems to be a polygenic trait and within breeds mainly controlled by other genetic factors than between sheep breeds. The promising candidate genes and associated pathways identified should be further investigated for their breeding or nutritional potential to ensure an adequate and sustainable Cu supply to sheep.
Publications
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First look into the genetic architecture influencing liver copper concentration in Merinoland sheep. 39th Conference of the International Society of Animal Genetics (ISAG), July 2-7 2023, Cape Town.
Adeniyi, O. O. & Lühken, G.
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Single-Locus and Multi-Locus Genome-Wide Association Studies Identify Genes Associated with Liver Cu Concentration in Merinoland Sheep. Genes, 14(5), 1053.
Adeniyi, Olusegun O.; Medugorac, Ivica; Grochowska, Ewa; Düring, Rolf-Alexander & Lühken, Gesine
