Integrative Population and Functional Genomics of Trypanotolerance in Hybrid African Cattle

Bos taurus (taurine) and Bos indicus (indicine) cattle diverged at least 150,000 years ago and, since that time, substantial genomic differences have accumulated between the two lineages. During the last two millennia, genetic exchange in Africa has resulted in a complex mosaic of taurine-indicine ancestry, with most cattle populations exhibiting varying levels of admixture. Similarly, there are several Southern European cattle populations that also show evidence for historical gene flow from indicine cattle, the highest levels of which are found in the Central Italian White cattle populations. In Chapter 2, I use two different software tools (MOSAIC and ELAI) for local ancestry inference (LAI) with genome-wide high- and low-density SNP array data sets in hybrid African and Italian cattle populations and obtained broadly similar results despite critical differences in the two LAI methodologies used. My analyses identified genomic regions with elevated levels of retained or introgressed ancestry from the African taurine, European taurine, Asian indicine lineages. Functional enrichment of genes underlying these ancestry peaks highlighted biological processes relating to immunobiology and olfaction, some of which may relate to differing susceptibilities to infectious diseases, including bovine tuberculosis, East Coast fever, and tropical theileriosis. Notably, for retained African taurine ancestry in admixed trypanotolerant cattle I observed enrichment of genes associated with haemoglobin and oxygen transport. This may reflect positive selection of genomic variants that enhance control of severe anaemia, a debilitating feature of trypanosomiasis disease, which severely constrains cattle agriculture across much of sub-Saharan Africa. Some African B. taurus populations have an important evolutionary adaptation known as trypanotolerance, a genetically determined tolerance of infection by trypanosome parasites (Trypanosoma spp.). These are transmitted by infected tsetse flies (Glossina spp.) and cause African animal trypanosomiasis (AAT) disease, which is one of the largest constraints to livestock production in sub-Saharan Africa and causes a financial burden of approximately $4.5 billion annually. In Chapter 3, I confirm that trypanotolerant African B. taurus N’Dama and trypanosusceptible B. indicus Boran cattle respond in largely similar ways during trypanosome infection when gene expression is examined using blood, liver, lymph node, and spleen samples with peaks and troughs of gene expression differences following the cyclic pattern of parasitaemia exhibited during trypanosome infection. I found that transcriptomic differences in response to infection between the populations include genes related to the immune system such as those encoding antimicrobial peptides and cytokines. Within the blood samples, differences in genes relating to coagulation and iron homeostasis support the hypothesis that the dual control of both parasitaemia and the anaemia resulting from the innate immune response to trypanosome parasites are key to trypanotolerance. Integrative genomics combines data from different ‘omic sources to link genotypes and phenotypes with the aim of unravelling biological networks and pathways that undergird complex traits, particularly with respect to disease. Integrative genomic techniques are employed to understand the admixture and selection for resistance to infectious diseases the has shaped genomes of domestic cattle. In Chapter 4, I identify putative candidate genes underlying trypanotolerance through the integration of results of local ancestry analysis of high- and low-density genome-wide SNP data for multiple trypanotolerant and trypanosusceptible hybrid cattle populations with gene expression data from some of the same animals in the form of both RNA-seq and gene expression microarray data from time-course trypanosome infection experiments.