ABSTRACT
Animal trypanosomiasis (Nagana), a protozoan disease, is the source of huge productivity losses to small scale farmers in sub-Saharan Africa. Nagana affects wild animals, sheep, goats, camels and cattle reducing their productivity or causing death in severe cases. Several interventions for the disease have been developed and applied including vector control using insecticides and the use of trypanocides. However, these control measures have been ineffective with the trypanosomes developing resistance to the existing trypanocides. Ineffective interventions to Nagana necessitate the need to advance a better disease control strategy. The use of the trypanotolerance trait that is expressed by some West African cattle breeds is promising because infected cattle don’t develop the severe form of the disease that reduces productivity. Trypanotolerance trait can be introduced to cattle breeds that show no tolerance through breeding. This study sought to understand trypanotolerance trait by identifying the key genes involved in the trypanotolerance trait. The sample size used was n=1199 cattle from 44 cattle breeds which were organized into 4 case-control groups of African indigenous and hybrid cattle. A GWAS was performed on each of the four groups to identify the significant SNPs after quality control. A total of 36 genes were found to contain the significant SNPs in all the case-control groups. All cases groups (Sheko, N’Dama, Boran and N’DamaXBoran) were compared to the same set of controls, n=993 cattle. This control group consisted of 3 cattle breeds from Africa (n=108), 31 cattle breeds from Europe (n=693), 2 cattle breeds from South America (n=27), 2 cattle breeds from Asia (n=49), 1 cattle breed from North America (n=105) and 1 cattle breed from Australia (n=11). Separate comparison of the case groups to the same control set highlighted 6, 4, 9 and 17 genes in the Sheko, N’Dama, Boran and N’DamaXBoran comparisons respectively. The roles of some of these genes in several pathways have also been individually described in previous studies. This study suggests that the key genes responsible for the trypanotolerance trait are SUSD1, DPF3, COL19A1 and SLC19A3 among others that are found in the N’Dama and Sheko cattle breeds that are mainly involved in the molecular mechanism that may lead to reduced parasitemia.
TABLE OF CONTENTS
Declaration i
Dedication ii
Acknowledgement iii
Table of contents iv
List of tables vi
List of figures vii
List of appendices viii
List of abbreviations ix
Abstract x
CHAPTER ONE
1.0 INTRODUCTION
1.1 Background 1
1.2 Research question 1
1.3 Objectives 2
1.4 Specific objectives 2
1.5 Null hypotheses 2
1.6 Justification 2
CHAPTER TWO
2.0 LITERATURE REVIEW
2.1 The cause of African animal trypanosomiasis 3
2.2 Geographical distribution of animal trypanosome species 3
2.3 The lifecycle of Trypanosomes 4
2.4 Clinical presentation of animal African trypanosomiasis in cattle 5
2.5 Cattle breeds and trypanotolerance 6
2.6 Control of trypanosomiasis 8
2.7 Trypanotolerance mechanism 9
2.8 Genome wide association studies 10
CHAPTER THREE
3.0 MATERIALS AND METHODS
3.1 Description of data 11
3.2 Performing genome wide association studies 13
3.3 Quality control 14
3.4 Overlapping SNPs 14
CHAPTER FOUR
4.0 RESULTS
4.1 Sheko significant SNPs 15
4.2 N’Dama significant SNPs 20
4.3 Boran significant SNPs 23
4.4 N’Dama X Boran significant SNPs 25
CHAPTER FIVE
5.0 DISCUSSION
5.1 Genes identified in trypanotolerant cattle breeds 32
5.2 Genetic variants identified in non trypanotolerant breed 41
5.3 Genes identified in hybrid cattle 42
CHAPTER SIX
6.0 CONCLUSION AND RECOMMENDATIONS
6.1 Conclusion 45
6.2 Recommendations 46
REFERENCES 47
APPENDICES 82
LIST OF TABLES
Table 3.1: The inclusion threshold parameters used to filter SNPs in Plink before GWAS analysis 14
Table 4.1: List of significant SNPs for the Sheko case-control group 16
Table 4.2: List of significant SNPs for the N’Dama case-control group. 21
Table 4.3: List of significant SNPs for the Boran case-control group 24
Table 4.4: List of significant SNPs for the N’Dama X Boran case-control group. 26
LIST OF FIGURES
Figure 2.1: The global distribution of common livestock trypanosomes T. congolense, T. vivax and T. b. evansi 4
Figure 2.2: Trypanosome developmental stages in the mammalian host and the insect vector 5
Figure 3.1: The global distribution of taurine and indicine cattle breeds used as cases and controls in the study 12
Figure 3.2: The number of samples of the African breeds.The N’Dama and Sheko are trypanotolerant, Boran is susceptible to trypanosomiasis and the N’Dama X Boran is a hybrid with intermediate tolerance 13
Figure 4.1: Sheko cases vs controls 28
Figure 4.2: Ndama cases vs controls 29
Figure 4.3: Boran cases vs controls 30
Figure 4.4: NdamaXboran cases vs controls 31
LIST OF APPENDICES
Appendix 1: The distribution of samples according to the cattle breed and its continent of origin (sample size n=1199 from 44 breeds) 82
LIST OF ABBREVIATIONS
AAT – African animal trypanosomiasis
GWAS – Genome wide association studies
SNP – Single nucleotide polymorphism
QTL – Quantitative trait locus
TICAM1 - Toll like receptor adaptor molecule 1
ARHGAP15 - RHO GTPase-activating protein 15
RBMS3 - RNA binding motif single stranded interacting protein 3
GRID1 - Glutamate ionotropic receptor delta type subunit 1
UTR – Untranslated region
RNA – Ribonucleic acid
DNA – Deoxyribonucleic acid
RBP – RNA binding protein
MYC - Master regulator of cell cycle entry and proliferation
MSSP - MYC gene single-strand binding protein
ARE - AU rich elements
CPE - Cytoplasmic polyadenylation element
mRNA – Messenger ribonucleic acid
Chapter 1
INTRODUCTION
1.1 Background
Trypanosoma congolense, the most prevalent and widespread pathogenic trypanosome species, infects cattle (Bos taurus/ Bos indicus) in most of sub-Saharan Africa resulting in life- threatening Animal African Trypanosomiasis (AAT) (Muhanguzi et al., 2017). Trypanosomes are transmitted by tsetse flies, and are injected into the cattle as metacyclic forms, which transform to the bloodstream forms found in circulation (Peacock et al., 2012). Nagana causes serious productivity losses amounting to approximately US$ 900 million per year within sub- Saharan economies (Mamoudou et al., 2016).
Indigenous cattle breeds like Baoule and N’Dama (Bos taurus) have been shown to be tolerant to the trypanosome infection (Noyes et al., 2011). Baoule breed in West Africa which are found in the trypanosomiasis-endemic southern part of Burkina Faso, have evolved tolerance to trypanosome infections (Albert et al., 2019). Pure-bred Zebu (Bos indicus) cattle are susceptible to trypanosomiasis but they are preferred by the farmers due to their large body sizes and more meat or milk production. Farmers often cross-bred Zebu and Baoule resulting in offsprings with improved trypanotolerance and size (Hanotte, 2002). The ancestry of the Zebu cattle breed is prominent in the large-sized admixed cattle. However, Zebu genome sections that may be associated with trypanotolerance can be expected to have higher extents of Baoule ancestry (Oleksyk et al., 2010).
Chromosome 22 (between 51.20 - 51.40Mb) has been suggested in previous studies to have genes that are involved in trypanotolerance (O’Gorman et al., 2009). The N’Dama that are trypanotolerant show a distinct and rapid transcriptional response to trypanosome infection and hence the genes involved in such immune responses can be upregulated or downregulated. Genetic variations in TICAM1 and ARHGAP15 genes are thought to confer structural and functional changes in the proteins they encode, and they have been associated with the trypanotolerance trait mechanism (Noyes et al., 2011).
1.2 Research question
Is there an association between mutations in the cattle genomes and trypanotolerance trait?
1.3 Objectives
1.3.1 General objective
To investigate the genetic variations associated with trypanotolerance trait in cattle.
1.4 Specific objectives
I. To identify genetic variants associated with trypanotolerance in Bos taurus, Bos indicus and hybrids.
II. To identify the genes and gene functions that may be disrupted or enhanced by variations.
1.5 Null hypotheses
There are no genetic variants associated with the trypanotolerance trait in cattle.
1.6 Justification
Both the indigenous and exotic cattle breeds produce meat, milk and manure at different efficiencies but the indigenous cattle breeds are often used for draft purposes in sub-Saharan Africa. Indicine cattle breeds are susceptible to trypanosomiasis, tick and other vector borne diseases but the trypanotolerant breeds can withstand these diseases benefiting from the trait (Noyes et al., 2011). It is, therefore, important to harness these trait and use it to control trypanosomiasis because trypanosomes have developed resistance to the available drugs leaving farmers with almost no options in the fight against the disease (Solomon & Workineh, 2018).
It is important to elucidate and measure the genetic variability between the trypanotolerant and susceptible cattle breeds for purposes of artificial selection in cattle. This analysis will enable the improvement of cattle productivity especially in sub-Saharan Africa, where trypanosomiasis has resulted in huge economic losses. AAT challenge is worse because of the absence of a vaccine and drug resistance that has resulted in poor cattle productivity. AAT can also be managed through improved cattle breeding for the introgression of trypanotolerance trait, which is associated with tolerance to other common diseases like tick borne diseases and helminthiasis.
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