Group Leader: John Willams
IDRA is a joint laboratory between PTP and the Istituto Sperimantali Italiana Lazzaro Spallanzani, with a focus on the the creation of new genomic knowledge and its application to understand the biology of disease responses, and physiology of ruminant species, mainly cattle. The work of the laboratory is broadly divided into two activities, the first, investigating genome structure and function and using this information to create the tools necessary for our research and the second, activity applies genomics to answer biologically interesting questions in the area of disease response and fertility.
Description of Activities
Genome mining, and in silico analysis and Genomic Tools
Our group was involved with the international bovine genome sequencing project (Bovine Genome Sequencing and Analysis Consortium et al., 2009) and used in silico comparative mapping methods to investigate the annotation of the assembled sequence. This analysis identified genes that were missed from the cattle genome or that differed between species (Mazza R et al., 2009). We also examined the annotation of micro-RNA, adding many new bovine miRNA to MIRbase (Strozzi F et al., 2009). This information has been used to develop a genome-wide probe set for the examination of gene and miRNA expression.
1. Johnes disease
Johnes disease, or para-tuberculoses is caused by a strain of myco-bacterium related tuberculosis in cattle and man. Johnes disease occurs at high frequency in dairy herds across the world. Following infection animals remain apparently healthy for many years before clinical signs appear, which are wasting and severs loss of productivity. There is no cure for the disease. Our laboratory is the coordinator of a European commission funded project (Macro-Sys) on para-tuberculosis and tuberculosis in cattle. This work is being carried out as several levels, firstly testing genetic associations between candidate genes and disease, secondly carrying out a genome-wide scan for genetic loci involved in disease incidence, and finally setting up in vitro model system to examine host bacterial interaction.Early results have identified a mutation in a candidate immune function gene that is putatively associated with disease in jersey cattle, while a genome-wide scan using high density SNP markers has identified 3 candidate regions on different chromosomes in Holstein cattle.
Masytitis is probably the most important disease of dairy cattle: all farms have cases of mastitis which impacts on production and cow welfare, in extreme cases resulting in death. Mastitis is a bacterial infectious of the udder, but is cause by several different bacterial agents. Risk factors for mastitis include the anatomy and behaviour of the cow and prevalence of the bacteria on the farm and the on-farm management practices.We are examining genetic risk factors for mastitis, in collaboration with the SelMol project (SelMol), the variation of ant-bacterial genes involved in innate immune defense are being tested for an association with disease incidence and a genome-scan is being carried out to compare bulls with high and low breeding values for somatic cell score (a trait correlated with mastitis incidence).
3. Spongiform encephalopathy
BSE is devastating neurodegenerative disease of cattle that most likely is acquired from infected feed. During the BSE outbreak in the UK during the 1990 over 180,000 cattle were found to be iunfected and were destroyed. The aetiological agene responsible for BSE is an infectious “prion” that is believed to be composed only of protein, which is host encoded, and the disease conformer of this protein is able to induce the same conformation chance of the protein in cells, cause in diseasae. There is no cure for BSE and the transmission of BSE to humans, as variant Cruzfeldt Jacob disease has been shown. It Is not known if BSE was naturally occurring in the cattle population in the UK, before the ouitbreak, or was a new disease in cattle, however a related disease, bovine atypical spongiform encephalopathy (BASE) is seen at low frequency and resemble the spontaneous form of CJD in man.We have projects on BASE and BSE in our group. Possible genetic factors for BSE susceptibility are being examined in BSE cases and controls collected in the UK during the 1990s. This work is focussing on the PrP gene, the product of which shows the changed conformation in diseased animals (link to refs) and using a high density of genome-wide SNP markers. Loci putatively associated with disease have been identified and are now being examined in detail (link to refs) We have also examined gene expression profiles in blood of BASE infected animals. Using pathway analysis groups of genes have been found to be significantly associated with disease, and may prove useful as biomarkers for identifying affected animals.
Good fertility is fundamental for sustainable agriculture: production of animals in sufficient numbers efficiently from the smallest number of parents has a major impact on the profit or loss of an enterprise, additionally production of milk is directly linked to the reproductive cycle. Unfortunately, genetic selection for production has impacted negatively on fertility. Genetic selection for improved fertility is hampered by a low overall heritability, as low fertility is not a single trait, but is a result of various physiological factors. We are focussing our attention of early embryonic development that may be related to early embryonic losses. Our experimental system is focussed on early stage embryos from pure and cross bred cattle in which we are examining gene activation and the role of miRNA.