Genetische Analyse des bovinen bilateralen konvergenten Strabismus mit Exophthalmus des Holstein Rindes sowie der equinen hereditären Mikrophthalmie
Genetic analysis of bovine bilateral convergent strabismus with exophthalmos in Holstein cattle and of equine hereditary microphthalmia
by Anke Bögeholz
Date of Examination:2021-01-12
Date of issue:2021-06-24
Advisor:Prof. Dr. Jens Tetens
Referee:Prof. Dr. Jens Tetens
Referee:Prof. Dr. Cord Drögemüller
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Abstract
English
In the context of the present thesis, two different hereditary diseases of the eyes were investigated. Bilateral convergent strabismus with exophthalmos (BCSE) in Holstein cattle and equine microphthalmia. The aim of the studies was to understand the genetic architecture of the diseases as well as the mode of inheritance and to identify possible causal genes. The long-term intention was to develop genetic testing procedures to exclude potential trait carriers from the breeding population and to reduce the frequency of the occurrence of the diseases. In the case of BCSE in Holstein cattle, no definite causal gene responsible for the development of the disease could be found. The results of previous studies on animals of the Brown Swiss breed could not be reproduced by means of a performed GWAS. No genome regions significantly associated with the occurrence of the disease could be found in animals of this breed. A candidate gene analysis of the gene SPG7 on BTA 18 in a sample of animals of the Holstein cattle breed showed no structural changes in the gene, which could indicate involvement of this gene in the development of the disease. However, it should be noted that only the coding regions of the gene were examined. Therefore, an involvement of the regulatory regions of the gene cannot be excluded. The results of the GWAS based on data after imputation in Holstein cattle, showed no SNPs on BTA 18 associated with the occurrence of the disease. Therefore, an involvement of the gene SPG7 seems rather unlikely. The performed GWAS based on the data after imputation showed significantly associated SNPs on BTA 2, 12 and 17. The significantly associated SNPs are located within the gene ABCC4 as well as adjacent to the NCOR2 and DNAJC3 genes. NCOR2 has already been associated with neurodegenerative diseases, further studies of the gene in data derived from affected animals are necessary to investigate a possible involvement in the development of the disease. Histopathological examinations of two affected animals showed that neurodegenerative processes could be a cause for the development of BCSE. However, the neuropathological examination of the respective nerves and brain areas in an affected animal could not reveal any morphological changes. Further histopathological and neuropathological examinations of affected animals are necessary to identify possibly different phenotypes and to be able to classify the disease more precisely, which could impact on the search for underlying hereditary traits. The results of the conducted studies show that the development of BCSE in Holstein cattle is probably a complex genetic event and that the development of the disease is not due to a single causal gene. In the case of an increased occurrence of equine microphthalmia in a half sibling family structure of a stallion of the Holsteiner Verband no definite causal gene could be identified in the present thesis as well. A performed GWAS based on data of 45 horses (11 affected and 34 unaffected) could not detect any genome-wide significantly with the occurrence of the disease associated.SNPs. However, four chromosome-wide significantly with the occurrence of the disease associated SNPs were found on chromosome 8. One of the four significantly associated SNPs is located near the gene CDH2. This gene plays an important role in embryonic and eye development. Based on these findings, a selection of variants in the coding regions of the gene were sequenced and studied. The results did not suggest that these variants are involved in the development of the disease. Further investigations of the gene, also in its regulatory regions, would be advisable in order to exclude or confirm a possible involvement of CDH2. A performed candidate gene analysis of the RAX gene on chromosome 8 could identify two variants that might be associated with the occurrence of the disease. Since the results were not consistent across all animals, it can be assumed that these variants cannot be considered as the only causative factor for the occurrence of the disease. The involvement of multiple genes and also regulatory regions in the genome as well as a low genotype-phenotype correlation seems likely. It is also possible that factors such as incomplete penetrance and variable expressivity complicate the identification of causal gene variants.
Keywords: BCSE; Holstein cattle; eye disorder; GWAS; equine Microphthalmia