The East African Shorthorn Zebu (EASZ) cattle are ancient hybrid between Asian zebu × African taurine cattle preferred by local farmers due to their adaptability to the African environment. The genetic controls of these adaptabilities are not clearly understood yet. Here, we genotyped 92 EASZ samples from Kenya (KEASZ) with more than 770,000 SNPs and sequenced the genome of a pool of 10 KEASZ. We observe an even admixed autosomal zebu × taurine genomic structure in the population. A total of 101 and 165 candidate regions of positive selection, based on genome-wide SNP analyses (meta-SS, Rsb, iHS, and ΔAF) and pooled heterozygosity (Hp) full genome sequence analysis, are identified, in which 35 regions are shared between them. A total of 142 functional variants, one novel, have been detected within these regions, in which 30 and 26 were classified as of zebu and African taurine origins, respectively. High density genome-wide SNP analysis of zebu × taurine admixed cattle populations from Uganda and Nigeria show that 25 of these regions are shared between KEASZ and Uganda cattle, and seven regions are shared across the KEASZ, Uganda, and Nigeria cattle. The identification of common candidate regions allows us to fine map 18 regions. These regions intersect with genes and QTL associated with reproduction and environmental stress (e.g., immunity and heat stress) suggesting that the genome of the zebu × taurine admixed cattle has been uniquely selected to maximize hybrid fitness both in terms of reproduction and survivability.

East Coast fever (ECF) is a fatal sickness affecting cattle populations of eastern, central, and southern Africa. The disease is transmitted by the tick Rhipicephalus appendiculatus, and caused by the protozoan Theileria parva parva, which invades host lymphocytes and promotes their clonal expansion. Importantly, indigenous cattle show tolerance to infection in ECF-endemically stable areas. Here, the putative genetic bases underlying ECF-tolerance were investigated using molecular data and epidemiological information from 823 indigenous cattle from Uganda. Vector distribution and host infection risk were estimated over the study area and subsequently tested as triggers of local adaptation by means of landscape genomics analysis. We identified 41 and seven candidate adaptive loci for tick resistance and infection tolerance, respectively. Among the genes associated with the candidate adaptive loci are PRKG1 and SLA2. PRKG1 was already described as associated with tick resistance in indigenous South African cattle, due to its role into inflammatory response. SLA2 is part of the regulatory pathways involved into lymphocytes' proliferation. Additionally, local ancestry analysis suggested the zebuine origin of the genomic region candidate for tick resistance.

63East Coast fever (ECF) is a fatal sickness affecting cattle populations of eastern, central, 64and southern Africa. The disease is transmitted by the tick Rhipicephalus appendiculatus, and 65 caused by the protozoan Theileria parva parva, which invades host lymphocytes and promotes 66 their clonal expansion. Importantly, indigenous cattle show tolerance to infection in ECF-67 endemically stable areas. Here, the putative genetic bases underlying ECF-tolerance were 68 investigated using molecular data and epidemiological information from 823 indigenous cattle 69 from Uganda. Vector distribution and host infection risk were estimated over the study area and 70 subsequently tested as triggers of local adaptation by means of landscape genomics analysis. We 71 identified 41 and seven candidate adaptive loci for tick resistance and infection tolerance, 72 respectively. Among the genes associated with the candidate adaptive loci are PRKG1 and SLA2. 73 PRKG1 was already described as associated with tick resistance in indigenous South African 74 cattle, due to its role into inflammatory response. SLA2 is part of the regulatory pathways 75 involved into lymphocytes' proliferation. Additionally, local ancestry analysis suggested the 76 zebuine origin of the genomic region candidate for tick resistance. 77 Author summary 78The tick-borne parasite Theileria parva parva infects cattle populations of eastern, central 79 and southern Africa, by causing a highly fatal pathology called "East Coast fever". The disease is 80 especially severe for the exotic breeds imported to Africa, as well as outside the endemic areas of 81 East Africa. In these regions, indigenous cattle populations can survive to infection, and this 82 5 tolerance might result from unique adaptations evolved to fight the disease. We investigated this 83 hypothesis by using a method named "landscape genomics", with which we compared the genetic 84 characteristics of indigenous Ugandan cattle coming from areas at different infection risk, and 85 located genomic sites potentially attributable to tolerance. In particular, the method pinpointed 86 two genes, one (PRKG1) involved into inflammatory response and potentially affecting East 87Coast fever vector attachment, the other (SLA2) involved into lymphocytes proliferation, a 88 process activated by T. parva parva infection. Our findings can orientate future research on the 89 genetic basis of East Coast fever-tolerance, and derive from a general method that can be applied 90 to investigate adaptation in analogous host-vector-parasite systems. Characterization of the 91 genetic factors underlying East Coast-fever-tolerance represents an essential step towards 92 enhancing sustainability and productivity of local agroecosystems. 93