GENETIC RESISTANCE TO DISEASES IN CATTLE

Genetic resistance to diseases

Seminar on GENETIC RESISTANCE TO DISEASES IN CATTLE :Seminar on GENETIC RESISTANCE TO DISEASES IN CATTLE Anjan Dandapat M.V. Sc (GAB) G.B. Pant University of Agriculture & Technology

Introduction :2 Introduction Resistance: Resistance is defined as the host’s ability to moderate the pathogen lifecycle. Tolerance: Tolerance refers to the ability of animals to tolerate infection by the pathogen and withstand the effects of disease. Genetic Resistance Genetic component to resist pathogen infection Genetic architecture of resistance: QTL- trypanosomosis and mastitis resistance in cattle

Genetic Resistance of lndigenous Livestock :3 Genetic Resistance of lndigenous Livestock N’Dama and other West African Shorthorn breeds of cattle- Resistance to trypanosomes (Murraay and Trail, 1982) In India, Desi cattle (Indigenous breeds)-Resistance to diseases

The disease resistance will be broken down into four major areas: :The disease resistance will be broken down into four major areas: Adaptability Protective Mechanisms Immune System Healing Capacity The combined function of all these mechanisms provides cattle with a resistance to disease.

Components of genetic resistance :5 Components of genetic resistance Animal Pathogen Pathogenicity Virulence

Mechanisms of disease resistance :6 Mechanisms of disease resistance A number of candidate genes/ loci associated with disease resistance/ susceptibility have been identified, at least in humans and mice (Hill,2001). In mice, a gene known as Kif1C decreases susceptibility to Anthrax (Dietrich et al., 2001) Epithelial Barrier Innate Immunity Acquired Immunity Genetic basis of Immunity

Slide 7:The Immune System Natural (barriers, secretions, etc.) Innate (born with) Acquired (memory) Cell mediated (immune cells) Humoral (antibodies)

Slide 8:8 Genetic resistance to bacterial pathogens in mice

Genetic resistance to bacterial pathogens of cattle :9 Genetic resistance to bacterial pathogens of cattle Disease Pathogen Gene Brucellosis Brucella abortus NRAMP1 Tuberculosis Mycobacterium bovis NRAMP1 Salmonellosis Salmonella dublin NRAMP1

Slide 10:Mastitis .02 Somatic Cell Score .15 Pinkeye .22 Respiratory .11 to .48 Disease Resistance is Heritable Sources of Genetic Variation Differences between breeds: Dermatophilosis- West African Bos taurus cattle- more resistance than Zebu type populations such as Ghana Sanga, Gudali and Gobra Zebu (Ambros et al.,1999) Differences within breeds: The within breed variation is best described by estimates of Heritability (h). Gene Polymorphisms

: Rarely will all animals exhibit clinical symptoms. Cattle breeds differ for disease related traits Tick borne diseases (Wambura et al., 1998) Pinkeye (Snowder et al., 2005a) Bovine respiratory disease (Snowder et al., 2005b) Justification: Genetic Variation for Disease Resistance

Slide 12:12 Congenital Disorders in Cattle

Slide 13:Chediak–Higashi syndrome Renal tubular dysplasia Bovine chondrodysplastic dwarfism Beta-mannosidosis Inherited disorder (conformation, metabolic, etc.) Approximately 125 known genetic disorders

Slide 14:Clinical screening Pedigree analysis Test matings Biochemical Screening DNA markers Gene therapy Genetic Control of Congenital disorders

:15 Microbial Diseases in cattle

Slide 16:16 Genetic tools to improve mastitis resistance Fine mapping of gene loci Genetic resistance to mastitis: Some marker haplotypes identified on chromosome 9 of the Nordic dairy cattle

Biotechnological DefenseAgainst Mastitis Disease :17 Biotechnological DefenseAgainst Mastitis Disease

Slide 18:18

Slide 19:19 Lysostaphin can protect againstinfection (3 µg/ml is probably enough)•Lysostaphin seems to cause no harm

Slide 20:20 Brucellosis- NRAMP1 gene Genetic resistance to Brucella abortus in the water buffalo (Bubalus bubalis) is associated with Nramp-1 gene. (Giorgia et al.,2006)

Slide 21:21 Bovine tuberculosis- NRAMP1 gene Mycobacterium bovis is genetically influenced by the candidate gene, NRAMP1. Qureshi et al., 1996 Salmonellosis- NRAMP-1 gene NRAMP-1 has been identified and cloned in a number of domestic mammals including cattle (Ables et al., 2002). Friesian calves are more resistance to Salmonella typhimurium infection than Jersey calves (Wray and Sojka, 1978).

Slide 22:22 Nramp1 gene have been found in the genome of bovines (Feng et al.,1996). Nramp1 gene is involved in regulation of major histocompatibility complex (MHC) class-11 genes (Barrera et al., 1997). Nramp2 gene appears to be involved in iron transport, with mutations resulting in microcytic anaemia in mice (Fleming et al.,1997) and rats (Fleming et al.,1998). NRAMP1 SSCA polymorphism is associated with bovine brucellosis resistant and susceptible phenotypes. Nramp1, A Gene controlling Resistance To Intracellular Pathogens

Slide 23:23 Genetic Resistance To Prion Protein Genetic diversity in the PrP gene protects populations from TSEs.

Slide 24:24 Texas A&M Researchers Cloning BSE-Resistant Cattle Cows are indeed useful creatures, supplying milk, beef, leather -- and even producing life-saving drugs in their milk. But bovine spongiform encephalitis (BSE), or "mad cow" disease, poses a constant threat to the cattle industry, spurring Texas A&M University researchers to develop the technology for cloning BSE-resistant cattle.

Slide 25:25 Bovine leukaemia virus Bovine herpesvirus-1 Foot and mouth disease virus Genetic Resistance To Viral Diseases In Cattle

Slide 26:26 The new molecular test for VSV field strains has been used by a USDA-APHIS in South American countries. Antigen Processing Genes as Genetic Markers for Disease Resistance in Dairy Cattle Shalhevet et al.(1998) TAP-1 TAP-2 LMP-2 LMP-7 Vesicular Stomatitis virus-Genome sequencing

Slide 27:27 If calves are sampled on consecutive days, the repeatability of FEC values is approximately 0.6 (Gasbarre et al., 1996); this repeatability decreases dramatically if the time between samples is extended (Stear et al., 1984). Secondly, FEC values decreases with the age of the animal, and change throughout the year based on grazing behaviour of the animals. Thirdly, the sex of animal influences FEC values than cows. Suarez et al. (1990) found that Zebu cattle had higher FEC values than did either Hereford or Hereford x Brahman crosses grazed in Argentina. The heritability of FEC values have ranged from Approx. 0.1-0.8. Gasbarre et al. (1993) found that serum antibody against parasite antigen was strongly influenced by the sire of the calf (heritability 0.7-0.8), but there was no relationship between serum antibody levels and FEC values. Genetic Resistance To Parasitic Diseases Genetics Of Helminth Resistance

Slide 28:28

Slide 29:29 Trypanotolerance Gene in Cattle

Slide 30:30

:31 Dwarf breeds of small ruminants have co-existed in some hot and humid forest environments with tsetse and ticks since 5000 BC. Those breeds are also reputedly trypanotolerant (FAO,1980; Toure et al.,1981; Mawuena, 1986, 1987; Bengaly et al., 1993). Evolution of genetic resistance

Slide 32:32 Theileria annulata T cells stimulated in host kill Cause: Poor Nutrition Unusually heavy challenge infections Genetic Resistance to Tropical Theileriosis Haemonchus placei - Genetic resistance

Slide 33:33 Individual resistance assessment and resistance markers Frish (1994) identified the presence of a major gene for resistance to ticks in the Belmont Adaptaur cattle. Age-related immunity Species resistance Breed resistance Resistance To Ticks and Tick-borne Diseases Breeding For Host Resistance to Ticks Host Resistance To Tick-borne Disease Infection Resilience The host’s ability to maintain a reasonable level of productivity in the face of a parasitic challenge (Albers et al., 1987).

Heritability (h2 x 100) estimates for resistance to Boophilus microplus in cattle :34 Heritability (h2 x 100) estimates for resistance to Boophilus microplus in cattle

: Resistance possibly associated with the MHC complex has been noted in respect of lymphocytosis caused by bovine leukaemia virus (Lewin and Bernoco,1986) and infection-induced high somatic cell counts in milk (Dietz et al.,1997) in cattle. Park et al.(1993) described a chronic progressive neurological disorder, posterior spinal paresis (PSP), in Holstein bulls possessing the A8 BoLA Specificity. Disease association Posterior spinal paresis Mastitis (Mejdell et al.,1994; Mallard et al.,1995) Bovine leucosis Viral and bacterial infection (Lewin, 1989; Andersson and Davies,1994 ) Intracellular parasites and ectoparasites (Lewin et al., 1994; Andersson and Davies,1994 ) Several synthetic antigens Bovine MHC Molecules and Disease Cattle MHC

Slide 36:36 Genetic Selection

Slide 37:37 Marker assisted selection for disease resistance genes DNA markers Multilocus Markers Minisatellite or VNTR RAPD AFLP Single-locus Markers RFLP SNP Microsatellites

Markers on Chromosomes :38 Markers on Chromosomes Markers

Markers on Chromosomes :39 Markers on Chromosomes Markers

Slide 40:40 CURRENT STATUS OF MARKER-ASSISTED SELECTION Weaver disease is associated with increased milk production gene. This disease has a microsatellite (TGLA116) in U13 syntenic (genetic loci that lie in the same order on the same chromosome in different species) group, which has been observed in Brown Swiss cattle. In cattle bovine cardiomyopathy, a genetic disease associated with 5.2 kb DNA fingerprint, it has been found that the gene affecting pre-weaning growth is linked to the B blood group system. RFLP marker establishes the association between BOLA (Bovine Lymphocyte Antigen) complex and infectious diseases like bovine leukaemia virus infection which is also correlated with milk and fat production in dairy cattle.

Slide 41:The simulation models of host-parasite interaction for cattle fever transmitted by Boophilus cattle ticks (Haile et al.,1992; Teel et al., 1996) and East coast fever transmitted by Rhipicephalus appendiculatus ticks (Byrom and Gettinby,1992) A mathematical model of rinderpest infection is described by Tille et al. (1991) Recently a comprehensive mathematical modell describing the BSE epidemic in Great Britain is described by Anderson et al. (1996), Donnelly et al. (1997a) and Ferguson et al. (1997a) Modelling Farm Animal Diseases

Slide 42:42 Genetic correlations between production and disease resistance traits are often antagonistic Milk yield in dairy cattle has antagonistic correlations with metabolic, physiologic, and microbial disease traits (Simianer et al., 1991; van Dorp et al., 1998). Growth rate in mice is genetically associated with over 100 physiologic, metabolic, and microbial susceptible diseases. (nih.gov) In beef cattle, these correlations have not been defined.

Slide 43:43 Immune Response Approach will probably be some sort of Selection Index that will include some combination of: • Base immune measure • Vaccine response • Cell mediated response And some threshold for high responders (titers) to reduce effect on production traits.

Genetic Approaches to Reduce Diseases :44 Genetic Approaches to Reduce Diseases

Slide 45:45 Management Nutrition Physiological State Environment Vaccination What is the genetic component? Largely: Genotype by Environment Interaction

Slide 46:Evaluation of Treatment Records led to Discovery Bovine Success Story Breeding a bull with a natural resistance to brucellosis to normal cows increased resistance to brucellosis in the calves to 59% compared to 20% in a control population. (Templeton et al., 1990) Selection for Host Biological Response: Somatic Cell Score Bovine Success Story Selection for reduced somatic cell count in dairy cattle decreased incidence of mastitis (Shook and Schutz, 1992)

: Modelling studies have played a major role on genetic resistance to disease. Genetic-epidemiological models of nematode infections, for example, have demonstrated that substantial reductions in parasite challenge will arise as a consequence of increasing host resistance (Bishop and Stear, 1997). Recent studies at Roslin Institute the importance of the bovine MHC in determining immune responsiveness to specific peptides (Glass et al., 2000) and in disease resistance (Lewin et al., 1999) has been demonstrated. Non-MHC genes, however, are collectively likely to influence immune responsiveness and disease resistance to a greater extent. Genetic variation in disease resistance in farm animalsRoslin Institute Annual Report 2000-2001

: Identifying pathways that intersect with T.congolense response QTL  Dr Harry Noyes - University of Liverpool, UK They have mapped 5 QTL in mice and 10 in cattle that are associated with response to infection. The challenge is now to identify the genes underlying these QTL. They are using gene expression microarray, tiling array and SNP data. Analysis of the immune system and host-pathogen interactions - providing insight in to disease resistance and treatment Dr P Kaiser- Head of the Avian Genomics group at the Institute for Animal Health - Meetings Chair

:49 They have identified two independent mechanisms by which ticks become resistant to pyrethroids. They've found one strain of resistant Mexican tick possessing a gene that produces a large amount of a specific esterase protein, called CzEst9, which is involved in the breakdown of pyrethroids. New test for pesticide resistance in cattle fever ticks; quarantined cow goes through a tick treatment bath at an APHIS facility in McAllen, Texas Agricultural Research,  July, 2002  by Linda McGraw Quarantined cow goes through a tick treatment bath.

:50 The Bovine Genome Sequencing ProjectDr Ross Tellam Senior Principal Research Scientist CSIRO Livestock Industries Australia Objective: Production of disease resistant animals; improved disease diagnosis; early detection of predisposition to disease; identification of disease susceptible sentinel animals

:51 Objectives YNP and GTNP are genes that endow bison with natural resistance to brucellosis. They propose to test NPS bison herds for variants of the natural resistance associated macrophage protein1 (NRAMP1) gene that has been shown to have a major impact in controlling a natural resistance to brucellosis in bovines. Application of Conservation Genetics to the Long-term Management of Bison in Five National Parks (Badlands, Grand Teton, Theodore Roosevelt, Wind Cave, and Yellowstone National Parks) Research Leader: Peter GoganU.S. Department of the Interior, U.S. Geological SurveyNorthern Rocky Mountain Science Center, BOX 173492, Montana State University, Bozeman, Montana

Quantitative genetic approaches to breeding for genetic resistance to disease in cattle :52 Quantitative genetic approaches to breeding for genetic resistance to disease in cattle Additive genetic variation between breeds Additive genetic variation within breeds Non-additive genetic variation between breeds (heterosis) Non-additive genetic variation within breeds (Inbreeding)

Bovine Success Story :53 Bovine Success Story Mastitis Attention is given to mastitis susceptibility in cattle genetic improvement programmes in Sweden (Lindhe, 1982) and Norway (Solbu et al.,1982). Tick resistance Resistance to ticks has been found to be highly heritable (Utech and Wharton, 1982). After three generation of selection- Resistance 89-99% in Illawara shorthorn herd

Slide 54:54 The Future

Slide 55:55

Slide 56:56

Slide 57:57 IF CHITINASE GENE COULD BE EXPRESSED IN THE SKIN OF CATTLE , IT COULD PROVIDE THEM WITH A NON TOXIC FORM OF NATURAL RESISTANCE TO INSECTS.

Slide 58:58 Future Strategy Using functional genomics and proteomics Disease genetic research strategy Scan the genome for host response loci Caveats Vaccination programme + Inherited natural resistance Better production Animals bred for resistance to one pathogen are also more resistant to another pathogen. Example: Lps and Lsh gene in mice resistance to several unrelated intracellular pathogen

Slide 59:59 THANK YOU THANK YOU