The genetics of Mycobacterium bovis infection in Irish cattle

Abstract

Infection of livestock with Mycobacterium bovis, is the causing agent of bovine tuberculosis and is of major economic and health concern globally, with the cost of livestock loss estimated at ?2 billion globally. In developed nations the majority of the cost involved with bovine tuberculosis is due to controlling the disease, while in developing nations, infection is endemic leading to reduced productivity and loss of livestock. Zoonotic infection of bovine tuberculosis also constitutes a major human health risk in developing nations. In Ireland approximately 15,000-20,000 cattle are infected with bovine tuberculosis each year, with control of bovine tuberculosis in Ireland incurring a cost of ?63 million to the Irish government. While an extensive eradication program has been in place in Ireland since the 1960s, eradication of the disease from the island has remained elusive. This is in part due to the presence of a natural wildlife reservoir for the disease in the form of Eurasian badgers (Melese meles). Ireland has had a successful nation-wide breeding strategy, carried out by the Irish Cattle breeding federation, in place for cattle since the early 2000s. This breeding strategy has been based around developing accurate genetic evaluations for all breeding sires for economically important traits (i.e. milk yield, fertility etc.), using both progeny records and genotype information. This thesis delves into the underlying genetics of Mycobacterium bovis infection in Irish dairy and beef cattle, utilizing a wealth of phenotypic, genetic and pedigree information supplied by national databases operated by Teagasc, the Department of Agriculture, Food and the Marine, the Irish Cattle Breeding Federation and the Centre for Veterinary Epidemiology and Risk Analysis. Variance components and heritability of Mycobacterium bovis susceptibility in Irish Dairy and beef cattle was estimated using a of 105,914 cow, 56,904 heifer and 21,872 steer single intra-dermal comparative tuberculin test records. A heritability of 0.11 was estimated for all animals analyzed (with a variation of 0.08 to 0.19 for each group separately). The genetic correlation between dairy and beef animals (and all groups) were all positive. This work indicated a much higher heritability for Mycobacterium bovis infection than other documented disease traits (~0.03). Moreover the positive genetic correlation between all animal groups and the correlation between increased prevalence of the disease in sire daughters and estimated breeding value, indicates that implementing a national breeding strategy for increased Mycobacterium bovis infection could be possible. As Mycobacterium bovis infection has been documented to be an elusive polygenic traits, several of GWAS methods were implemented in this thesis to elucidate the underlying genes involved in host susceptibility. A total of 841 dairy sire genotypes with estimated breeding values for Mycobacterium bovis susceptibility were available. One quantitative trait locus on chromosome 23 was common to all three genome-wide analyses for association to Mycobacterium bovis susceptibility. Imputation to whole genome sequence of this QTL region revealed the gene FKBP5 which encodes a protein from the immunophillin protein family, a family of proteins often targeted by immunosuppressant drugs. Finally a search for signatures of selection and ancestry mapping was performed on two anciently admixed cattle groups, East African zebu cattle breeds and cattle originating from the Near Eastern Anatolian peninsula. These breeds provide an interesting intersection of the two domestic lines of cattle, Bos indicus and Bos taurus. Moreover mapping signatures of selection and ancestral haplotypes can often have a higher power of analysis that traditional GWAS methods. A number of key identifiers of selection were identified in both breed groups, which East African Zebu breeds having suggestive signatures of selection for innate immunity and signatures of selection in Anatolian breeds indicating selection towards beef and dairy production traits. The work presented in this thesis has helped the development of a national breeding strategy towards improved resistance to Mycobacterium bovis infection in Irish cattle herds which is expected to be implemented within the next two years. Furthermore it has identified a novel QTL region associated with Mycobacterium bovis infection. Infection of livestock with Mycobacterium bovis, is the causing agent of bovine tuberculosis and is of major economic and health concern globally, with the cost of livestock loss estimated at ?2 billion globally. In developed nations the majority of the cost involved with bovine tuberculosis is due to controlling the disease, while in developing nations, infection is endemic leading to reduced productivity and loss of livestock. Zoonotic infection of bovine tuberculosis also constitutes a major human health risk in developing nations. In Ireland approximately 15,000-20,000 cattle are infected with bovine tuberculosis each year, with control of bovine tuberculosis in Ireland incurring a cost of ?63 million to the Irish government. While an extensive eradication program has been in place in Ireland since the 1960s, eradication of the disease from the island has remained elusive. This is in part due to the presence of a natural wildlife reservoir for the disease in the form of Eurasian badgers (Melese meles). Ireland has had a successful nation-wide breeding strategy, carried out by the Irish Cattle breeding federation, in place for cattle since the early 2000s. This breeding strategy has been based around developing accurate genetic evaluations for all breeding sires for economically important traits (i.e. milk yield, fertility etc.), using both progeny records and genotype information. This thesis delves into the underlying genetics of Mycobacterium bovis infection in Irish dairy and beef cattle, utilizing a wealth of phenotypic, genetic and pedigree information supplied by national databases operated by Teagasc, the Department of Agriculture, Food and the Marine, the Irish Cattle Breeding Federation and the Centre for Veterinary Epidemiology and Risk Analysis. Variance components and heritability of Mycobacterium bovis susceptibility in Irish Dairy and beef cattle was estimated using a of 105,914 cow, 56,904 heifer and 21,872 steer single intra-dermal comparative tuberculin test records. A heritability of 0.11 was estimated for all animals analyzed (with a variation of 0.08 to 0.19 for each group separately). The genetic correlation between dairy and beef animals (and all groups) were all positive. This work indicated a much higher heritability for Mycobacterium bovis infection than other documented disease traits (~0.03). Moreover the positive genetic correlation between all animal groups and the correlation between increased prevalence of the disease in sire daughters and estimated breeding value, indicates that implementing a national breeding strategy for increased Mycobacterium bovis infection could be possible. As Mycobacterium bovis infection has been documented to be an elusive polygenic traits, several of GWAS methods were implemented in this thesis to elucidate the underlying genes involved in host susceptibility. A total of 841 dairy sire genotypes with estimated breeding values for Mycobacterium bovis susceptibility were available. One quantitative trait locus on chromosome 23 was common to all three genome-wide analyses for association to Mycobacterium bovis susceptibility. Imputation to whole genome sequence of this QTL region revealed the gene FKBP5 which encodes a protein from the immunophillin protein family, a family of proteins often targeted by immunosuppressant drugs. Finally a search for signatures of selection and ancestry mapping was performed on two anciently admixed cattle groups, East African zebu cattle breeds and cattle originating from the Near Eastern Anatolian peninsula. These breeds provide an interesting intersection of the two domestic lines of cattle, Bos indicus and Bos taurus. Moreover mapping signatures of selection and ancestral haplotypes can often have a higher power of analysis that traditional GWAS methods. A number of key identifiers of selection were identified in both breed groups, which East African Zebu breeds having suggestive signatures of selection for innate immunity and signatures of selection in Anatolian breeds indicating selection towards beef and dairy production traits. The work presented in this thesis has helped the development of a national breeding strategy towards improved resistance to Mycobacterium bovis infection in Irish cattle herds which is expected to be implemented within the next two years. Furthermore it has identified a novel QTL region associated with Mycobacterium bovis infection. ; TARA (Trinity?s Access to Research Archive) has a robust takedown policy. 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