Investigating host genetics and the role of selection for increased resistance to bovine tuberculosis in dairy cattle
The significant social and economic losses as a result of bovine tuberculosis (bTB) present a continuous challenge to cattle industries in the United Kingdom (UK) and worldwide. Furthermore, as a zoonotic disease, bTB may pose a threat to humans. The potential transmission of bTB in cattle, estimated by the basic reproductive ratio (R0) was found to range between 1.0 and 1.9 in previous studies. In the UK, there has been an overall increase in bTB incidence in the last two decades despite national control and eradication programmes spanning over five decades. Such programmes mainly consist of surveillance based on the administration of skin tests and culling of animals reacting positive to these tests. Animal mobility restrictions are implemented in this case. At the same time, several studies have demonstrated that there is significant host genetic variation in individual cattle susceptibility to bTB, making the disease amenable to improvement with genetic or genomic selection. In addition, genomic analyses enhance the understanding of genetic mechanisms underlying the disease and its dynamics. The overall aim of this PhD thesis was to address existing scientific research gaps on the genetics of bTB resistance in dairy cattle. The following specific objectives were set: 1) to identify genomic regions underlying susceptibility to bTB using novel trait definitions, 2) to quantify the impact of long-term genetic selection for increased resistance to bTB on disease prevalence and dynamics and 3) to determine the consequences of genetically selecting for increased resistance to bTB on other economically important traits in dairy cattle. Genome-wide association studies (GWAS), regional heritability mapping (RHM) and chromosomal association analyses were applied in order to identify genomic regions associated with bTB (objective 1). Phenotypes comprised de-regressed estimated breeding values of 804 Holstein-Friesian sires obtain from the UK national genetic evaluation for bTB. Phenotypes pertained to three bTB trait definitions: i) positive reactors to the skin test with positive post-mortem examination results (phenotype 1); ii) positive reactors to the skin test regardless of post-mortem examination results (phenotype 2) and iii) as in (ii) plus non-reactors and inconclusive reactors to the skin test with positive post-mortem examination results (phenotype 3). In all cases, non-reactors without a subsequent positive post-mortem were considered to be healthy animals with regards to bTB. Genotypes based on a 50K SNP DNA array were available and a total of 34,874 SNPs remained after quality control. The estimated polygenic heritability for susceptibility to bTB was 0.26, 0.37 and 0.34 for phenotypes 1, 2 and 3, respectively. GWAS identified a putative SNP on Bos taurus autosomes (BTA) 2 associated with phenotype 1, and another on BTA 23 associated with phenotype 2. Genomic regions encompassing these SNPs were found to harbour potentially relevant annotated genes. RHM confirmed the effect of these genomic regions and identified new regions on BTA 18 for phenotype 1 and BTA 3 for phenotypes 2 and 3. Heritabilities of the genomic regions ranged between 0.05 and 0.08 across the three phenotypes. Chromosome association analysis indicated a major role of BTA 23 on susceptibility to bTB. A stochastic genetic epidemiological model based on four main disease states, namely susceptible (S), exposed (E), infectious (I) and test-sensitive (T), was developed to address objective 2. Effects of selection for increased resistance to bTB were investigated in a closed, genetically heterogeneous simulated population whose structure reflected the UK national dairy herd. Disease dynamics reflected real bTB data from the UK national genetic evaluation. The proposed genetic epidemiological model was implemented to simulate breakdowns under both absence and presence of selection. Genetic selection was simulated over 20 generations in 50 replicates, while exploring various selection intensities reflecting selection of the 10, 25, 50, 70 and 100% (no selection scenario) most resistant sires. Results indicated that selection significantly reduced the average underlying susceptibility across generations. The risk of breakdown was reduced by half after 4 and 6 generations for high selection intensities (10 or 25% of sires selected) and after 9 and 15 generations for low selection intensities (50 or 70% of sires selected). The average percentage of secondary cases was reduced to less than 1% in 4 and 5 generations for high selection intensities, and in 7 and 11 generations for low selection intensities. The reduction in the number of secondary cases across generations could also be indicative of the possible impact of genetic selection on the basic reproductive ratio (R0) which is defined as the number of secondary cases that results from an infectious individual in a naive population. Genetic selection also reduced severity and duration of breakdowns across generations. Finally, with regards to objective 3, a stochastic simulation was used to investigate the long-term effects of selection for resistance to bTB on other economically important traits in the UK dairy selection programme. Selection was simulated in a genetically heterogeneous population across 10 generations in 50 replicates. Animal genetic values for bTB and other traits were simulated based on variance and genetic correlation estimates obtained from literature. Independent culling levels selection of sires was applied in every generation whereby selection was first based on increasing resistance to bTB, then improving either an overall index, milk fat yield (FY) or milk protein yield (PY). This mimics real life practices regarding the newly released national genetic evaluations for bTB resistance. The overall index comprised several traits of interest such as milk yield (MY), FY, PY, feet and legs (FL), mammary (MAM), milk somatic cell count (SCC), calving interval (CI), non-return to service at 56 days (NR56) and lifespan (LS). A fertility index (FI) consisting of CI and NR56 was also considered in the analyses. Regarding bTB, different levels of selection intensities were explored corresponding to selection of the 10, 25, 50, 70 and 100% (no selection) most resistant sires. Two levels of selection intensity on the overall index, FY or PY were considered corresponding to selecting the best 5 and 10% of sires that were left after first selecting for bTB resistance. Results indicated that selection for increased bTB resistance would generally not have far-reaching consequences on other important traits. As expected, susceptibility to bTB declined with time and increasing selection intensity. Trends for all production traits (MY, FY and PY) in the present study were affected by selection for increased bTB resistance because of their significant genetic correlations with bTB. However, body conformation traits (FL and MAM) were not affected by selection for increased bTB resistance due to zero correlation assumed between these traits and bTB in the present study. Selection on bTB hampered improvement of SCC but enhanced LS because it was correlated unfavourably with SCC but favourably with LS. In all selection scenarios, the overall index improved and was generally not affected by selection for bTB resistance. Similarly, the FI was not affected by selection on bTB in all cases. However, secondary selection on production traits only (FY or PY) led to a decline in FI. Results presented in this thesis add insight into the genetic architecture of bTB and offer a prediction of potential effects of genetic selection for increased resistance to bTB in dairy cattle. The genomic regions and candidate genes identified to be associated with susceptibility to bTB will assist to further elucidate pathways critical to cattle susceptibility to bTB. Consistent with previous studies of other populations and trait definitions, results from genomic association analyses suggest that susceptibility of cattle to bTB is heritable and likely a polygenic trait, amenable to improvement by genetic and/or genomic selection. Embarking on routine selection for resistance to bTB will reduce future bTB prevalence and severity of breakdowns across selection generations, as manifested by results of this thesis. The results also highlight the importance of considering selection as a complementary strategy to existing interventions. This has the potential to accelerate control and ultimate eradication of bTB. This strategy could assist the UK to achieve the national goal of being officially bTB free by 2038. Furthermore, as indicated by results of this thesis, selection against bTB in the national breeding programme will not adversely affect other economically important traits. Assimilation of bTB into the overall index will better manage possible antagonistic correlations between bTB susceptibility and some of the other traits.