Identification of candidate signature genes and key regulators associated with trypanotolerance in the Sheko breed
by Yonatan Ayalew Mekonnen
Date of Examination:2020-01-31
Date of issue:2020-05-19
Advisor:Prof. Dr. Armin Schmitt
Referee:Prof. Dr. Olivier Hanotte
Referee:Prof. Dr. Henner Simianer
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Abstract
English
African Animal Trypanosomiasis (AAT) is caused by a protozoan parasite that affects the health of livestock. Livestock production in Ethiopia is severely hampered by AAT and various controlling measures were not successful to eradicate the disease. AAT affects the indigenous breeds in varying degrees. However, the Sheko breed shows better trypanotolerance than other breeds. The tolerance attributes of Sheko are believed to be associated with its taurine genetic background but the genetic controls of these tolerance attributes of Sheko are not well understood. In order to investigate the level of taurine background in the genome, the genome of Sheko is compared with that of 11 other African breeds. The result shows that Sheko has an admixed genome composed of taurine and indicine ancestries. To identify selective sweeps in the Sheko genome, three methods were applied: (i) The integrated haplotype score (iHS), (ii) the standardized log ratio of integrated site specific extended haplotype homozygosity (EHH) between populations (Rsb), and (iii) the composite likelihood ratio (CLR) method. The combined results of these methods reveal 99 genomic regions harboring 364 signature genes in Sheko. Out of the signature genes, 15 genes are selected based on their biological importance described in the literature. In addition, 13 overrepresented pathways and 10 master regulators are identified in Sheko using the TRANSPATH database in the geneXplain platform. Most of the pathways are related to oxidative stress responses indicating a possible selection response against the induction of oxidative stress following trypanosomiasis infection in Sheko. Moreover, the trypanotolerance tendencies of the Nuer, Benshangul, and Gindeberet breeds are assessed by comparing the candidate genomic regions, genes, hub genes, overrepresented pathways, and master regulators identified in each breed with Sheko and among themselves. In addition, the identified genes and genomic regions are compared with the trypanotolerant QTL regions in N’Dama, and genes as well as genomic regions of Muturu. The common genomic regions and genes in Nuer, Benshangul, and Gindeberet that are shared in common with Sheko, N’Dama, and Muturu are identified. Furthermore, the hub genes, overrepresented pathways, and master regulators in Nuer, Benshangul, and Gindeberet breeds which are in common with Sheko are identified. These results indicate that the Nuer, Benshangul, and Gindeberet breeds have undergone similar evolutionary responses against trypanosomiasis. The findings reported in this thesis show that the master regulator Caspase which is identified in Sheko, Nuer, and Benshangul is a key protease that plays a major role in the emergence of adaptive immunity in harmony with the other master regulators. In this thesis, I present for the first time the importance of master regulators involved in trypanotolerance not only for the breeds included in this thesis but also in the context of cattle genomics. These results suggest that designing and implementing genetic intervention strategies is necessary to improve the performance of susceptible animals. Moreover, the identification of master regulator Caspase suggests potential candidate therapeutic targets for the development of new drugs for trypanosomiasis treatment.
Keywords: trypanosomiasis, trypanotolerant, selection signature, candidate signature genes, master regulators, overrepresented pathways