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Overview

Aim

Preliminary identification of key genes involved in the regulation of lactation and lactation performance

Overview 2004-05

Project 1.1 provides crucial bioinformatics support for all projects in Program One, enabling analysis of data on genes that might have applications in the dairy industry. The project has been instrumental in creating an integrated map of all cattle chromosomes, incorporating a vast amount of data from world-wide sources. This map will significantly accelerate the process of discovering genes of importance to the dairy industry, including those that control production traits, disease resistance, reproduction and bioactives in milk. The map comprises 11,088 genes and markers across all 31 cattle chromosomes. The public version of these maps can be viewed via http://medvet.angis.org.au/ldb By comparing the CRC’s integrated bovine map with the human sequence map, a virtual bovine genomic map has been created, comprising more than 19,000 genes and more than 17,000 SNPs – ahead of the completion of the international Bovine Genome Project. Of the 17,000 SNPs, 6481 have been identified by CRC researchers.

Following the processing of the first bovine Affymetrix gene expression chips, new powerful methods for statistical analysis of Affymetrix expression data have been developed. Analysis of bovine Affymetrix expression data from the lactation-cycle experiment has revealed 3227 genes of interest, including a high-priority list of 490 genes.

To support Project 1.6 Mining Australian biodiversity, cross-species transcriptome maps have been developed, and are available in a single page. The full series of wallaby lactation microarray experiments have been completed. Annotation of sequence from 9696 seal expressed sequence tags (ESTs) has identified a maximum potential of 4448 genes. A sheep linkage map based on the University of Sydney’s Awassi/Merino backcross flock has been developed for use in the mapping of lactation traits which cannot be readily mapped in cattle. It consists of 201 markers. This will facilitate integration with other sheep maps, including the Australian Sheep Genome Map, and provides links to the closely related bovine map.

Project 1.2 Screening of gene function

Dr Ross Tellam

CSIRO Livestock Industries

Aim

Preliminary definition of the function of genes in the mammary gland

Overview 2005-06

The expected outcome of Project 1.2 is the development of a panel of candidate genes for evaluation of gene function. During the year several large experiments were completed including the use of microarray transcriptional profiling to identify differentially expressed genes as a function of the mouse lactation cycle; mastitis challenges in dairy cattle mammary tissue; and mammary tissue comparisons from the QSI5 strain of mice which are highly fertile and produce large volumes of milk. Considerable efforts are currently directed at processing data, and finalising differentially expressed gene lists and associated bioinformatics information. In addition, assessment of the IP landscape associated with some high-priority candidates is underway.

The major task for Project 1.2a Functional genomics of bovine lactation physiology is the discovery and identification of bovine genes that play a significant role in regulation of lactation in the dairy cow. More specifically the traits of interest include milk composition and persistence of lactation. Most protocols and platforms have been established in the CRC’s laboratories and it is achieving steady progress towards these goals. These strategies and approaches have yielded a significant amount of information in relation to the identification of candidate regulatory genes through the expression profiling of both bovine and mouse mammary tissue as well as the bovine mammosphere model. A panel of lead genes has been taken forward to Project 1.3 for functional analysis in vitro before development of in vivo applications.

The aim of Project 1.2b Mastitis gene screening is to identify genes and proteins that underlie resistance and susceptibility to mastitis in dairy cattle. Modulation of the activities of these genes and proteins by a variety of means will enhance resistance to mastitis, and increase productivity and profitability in the Australian dairy industry. The project has made significant progress this year, generating substantial microarray data and a significant number of high-priority candidate genes. Some of these genes have been taken forward into Project 1.3b where their detailed functions are being determined for specific industry applications such as an early diagnostic for sub-clinical mastitis and mastitis treatments.

Project 1.3 Detailed study of gene function

Associate Professor Peter Williamson

Reprogen, Faculty of Veterinary Science, The University of Sydney

Aim

Generate detailed data on gene function required to ensure a robust degree of IP protection through the patent system

Overview 2004-05

The goal of Project 1.3 is to develop gene products that can be used to enhance dairy cow productivity and health. Activity on the project has increased significantly over the past year in response to increasing data coming out of Project 1.2. The project is divided into two sub-projects and mines the candidate gene database developed for all gene discovery projects across Program One and public domain resources. It is the engine for high-resolution gene functional analysis as a prerequisite for development of gene-derived products such as direct gene markers, exogenous products for health and production, diagnostics and potential vaccines.

Project 1.3a Detailed study of gene function in bovine lactation is capitalising on a gene expression and genetics database that has provided a large number of potential gene candidates. These genes are being analysed for milk protein effects; mammary epithelial cell modulation; and their potential for use in veterinary or human health products. Detailed studies of candidate gene function by regulation of gene expression, analysis of impact on key target traits by way of expression pathways and proteomics using a bovine mammary epithelial cell model (mammosphere model) are underway. This will screen genes before progressing small numbers of successful candidate genes into animal testing. The first of these candidates is now under preparation for analysis.

The aim of Project 1.3b Mastitis and gene function is to identify and modulate the functions of genes and proteins that underlie resistance and susceptibility to mastitis in dairy cattle. Several genes identified in Project 1.2b might be useful as diagnostics for sub-clinical mastitis; therapeutic treatment for mastitis; agents that can modulate the antibody content of milk; and genes that might lead to gene markers associated with milk production traits, including resistance to mastitis. A number of recombinant proteins based on these genes have been produced and purified, and are now being tested for bioactive properties. Some proteins are also being used to raise specific antibodies. The latter will be used as experimental tools, as well as in the development of specific tests to measure the levels of these proteins in milk. The ability to modulate innate immune responses in mammary epithelial cells has been demonstrated

Project 1.4 Identification of genes via positional cloning

Professor Herman Raadsma

Reprogen, Faculty of Veterinary Science, The University of Sydney

Aim

To increase the marker density on the bovine map using known genes and SNPs and fine map specific regions of chromosomes where QTL are known to be segregating

Overview 2004-05

Through this project, a panel of candidate genes for evaluation of gene function will be developed. It aims to deliver a commercially proven system for the application of marker-assisted selection to speed genetic gain in the Australian dairy herd. This project primarily addresses the discovery and exploitation of DNA markers for QTL in Australian dairy cattle. Resources used include semen samples from Genetics Australia and data from the Australian Dairy Herd Improvement Scheme (ADHIS). There are three major components: Project 1.4a Proof of concept for bovDArT within Australian dairy cattle as a bovine platform for low-cost whole-genome analysis; Project 1.4b Mapping and confirmation of QTL in dairy cattle; and Project 1.4c Mapping QTL and gene discovery by transcript profiling for lactation persistency ,energy utilisation and mastitis resistance in ruminant population with extreme lactation performance.

A database with more than 2500 genes has been compiled. The most promising candidate genes are being evaluated in conjunction with Project 1.3 above. New functional candidate genes from all other projects in Program One will also be evaluated as positional functional candidates. Discovery of markers is being accelerated by the use of high-density and high-throughput SNP marker genotyping platforms such as Illumina and ParAllele Bioscience. All prospective candidate genes have been mined for SNP markers and screened for prospective utility and pre-selection of genes for further evaluation by way of association analysis with target traits of interest. Efficient mining strategies of candidate genes for complex traits measured via model organisms (sheep and mouse) or from public domain sources have been implemented. A fully functional integrated gene marker pipeline is now shown to have substantial utility.

Project 1.5 Mouse mutagenesis to identify key genes

Associate Professor Christopher Ormandy

Garvan Institute of Medical Research

Aim

Identification of key genes involved in lactation through the application of a mouse mutagenesis approach 

Overview 2004-05

The research strategy employed in this project has the potential to identify every gene essential for lactation. It is the only ENU screen with the potential to inform the gene discovery effort in cattle. The project is divided into two sub-projects: Project 1.5a Models of augmented or reduced lactation, and Project 1.5b ENU Mutagenesis to discover new genes controlling milk composition and production.

Through Project 1.5a, the CRC aims to identify genes influencing milk composition and production by transcript profiling mouse models of augmented versus compromised lactation. The construction of mouse transgenic models of candidate gene over-expression to examine their functional role in mammary development and lactation has begun.

Through Project 1.5b, the CRC aims to identify genes influencing lactation by screening panels of ENU mutagenised mice for failed lactation. Opening of the Australian Phenomics Facility (a Major National Research Facility) at Australian National University allowed this project to progress in 2005 as it provided access to increased mouse resources.

The data on genes produced in Project 1.5 is given to Project 1.1 to mine for further genes involved in lactation which might be of interest.

Project 1.6: Mining Australian biodiversity to identify bioactives in milk

Dr Kevin Nicholas

University of Melbourne

Aim

Identification of bioactives in the milk and the mammary gland

Overview 2004-05

This project is providing a selective advantage to the Australian dairy industry by investigating the unique aspects of reproduction and lactation of Australian native fauna to identify candidate genes and bioactive molecules of value to achieve improvements in milk yield, milk composition, lactational persistency, to modify growth and development of the young and for biomedical outcomes.

Combining genetic research data from the tammar wallaby and the Australian fur seal, CRC scientists can rapidly identify comparable genes in the dairy cow. Echidna milk was also examined during the year for its unique properties. More than 500 genes from the wallaby and 65 genes from the seal have been identified for further study. Under this project, the Dairy CRC is establishing patent positions on a range of genes and proteins in the first step towards commercialising this research for the dairy industry. The project is co-funded by the CRC and the Geoffrey Gardiner Dairy Foundation.