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NC1010: Interpreting Cattle Genomic Data: Biology, Applications and Outreach (NC-209)

Statement of Issues and Justification

The tremendous efforts of animal genomics researchers involved in the ongoing National Research Support Project-8 (NRSP-8) and past Multistate Research Projects (NC-209, NC-210/220, NC 168, NE-60) have resulted in the extremely successful species genome projects. These projects have provided chromosomal sequence data, physical and linkage maps, and molecular genetic markers of production, health, and product quality traits in cattle (dairy and beef), sheep, pigs, poultry, and more recently horses. However, the full value and applications of the species genome projects will be realized only when the actual genes and gene products (proteins) that coordinate and regulate important animal traits are known and understood. The time has come to harvest the value of species genome projects by linking chromosomal DNA information to expression profiles, phenotypes, and functions of specific genes and proteins in relevant models of animal husbandry. In cattle, for example, knowledge of the genes involved in nutrient partitioning, mammary development, and muscle growth will enable researchers to develop accurate genetic selection strategies using biologically relevant molecular markers for milk and meat production/quality. In addition, knowledge of the genes involved in digestion and nutrient absorption will allow researchers to develop optimal nutritional regimes for cattle of particular genetic backgrounds reared in a variety of environments. Similarly, a better understanding of the genes that regulate female reproduction will enable researchers to find real solutions to the problem of poor conception rates in high producing dairy cows. Finally, knowing what genes come into play when cattle are stressed by the environment, or challenged by infectious pathogens and the continued metabolic demands required to support high production, will enable researchers to develop novel management and breeding strategies and therapeutic drugs that promote animal health, well being, and food safety.

A major unifying feature of health, reproduction, production, and product quality traits that are important to the sustainability of US dairy and beef industries is their complex physiology, which involves intricate coordination of multiple gene expression events in a large variety of tissues at different stages of an animals productive lifetime. Traits such as these have mostly proven refractory to in-depth molecular analysis by traditional methodologies, but are excellent candidates for functional genomics and proteomics studies. These complex traits also form a unifying backbone of the research proposed under this new Multistate Research Project. Participants of the Project will use a variety of genomics and proteomics techniques to determine the location, structure, function, effect, and expression of genes affecting health, reproduction, production, and product quality in dairy and beef cattle. Identified genes and proteins will be shared amongst participants for contribution to ongoing SNP (single nucleotide polymorphism) analyses, mapping efforts, and for analyses of statistical associations with the economically important health, reproduction, production, and product quality traits recorded in the numerous resource populations contributed to the Project by various participants (see below).

Importantly, recent development of mixed and tissue-specific bovine complementary DNA (cDNA) libraries have allowed bovine genome researchers to obtain large numbers of expressed gene sequences (known as expressed sequence tags, or ESTs), which can be used to link chromosomal DNA sequences to specific cellular functions and phenotypes (Beckmann et al., 1997; Duggan et al., 1999). Thus, ESTs are critical tools for bovine functional genomics efforts and the ultimate development of transcript maps that are helping researchers decipher the independent and interconnected functions and variations of cellular proteins that result in particular phenotypes. Bovine ESTs that are sequenced, mapped, and compared to known genes and full-length cDNAs recorded in public databases are already being used by Project participants to develop bovine-specific microarray interrogation systems capable of monitoring thousands of gene expression changes in a variety of comparative experiments (e.g., Yao et al., 2001; Burton et al., 2001). Therefore, when combined with cDNA microarray technologies, existing bovine EST collections are powerful tools for discovering genes in livestock that associate with outcomes of various husbandry practices, genetic selection schemes, environmental extremes, nutritional regimes, reproductive status, and infection scenarios. These EST libraries and cDNA microarray technologies will be available to the proposed Project through its participants (see below).

However, if the activity or yield of gene transcription is not proportional to the functional activity of the encoded proteins, then knowledge about gene transcription events gained through functional genomics studies can be limited with regard to which proteins are actually responsible for altering a given trait (Matthews et al., 1998; 1999). This limitation is compounded if a given functional activity results from and (or) is regulated by multiple gene products (Lin et al., 2001; Jackson et al., 2001). Another limitation of stand-alone functional genomics approaches is that relatively little information is gathered about whether expressed proteins undergo post-translational modifications or where functional activity is localized. These limitations can be especially critical if achievement or alteration of a given trait results from expression of multiple proteins. Consequently, to fully understand the metabolic and regulatory status of many cells and tissues resulting in particular phenotypes, the ability to simultaneously identify and analyze the expression patterns of multiple proteins is required (Jensen et al., 1999). Current methods for separation and identification of proteins by 2-dimensional (2-D) electrophoresis, paralleled by development of mass spectrometric techniques sensitive enough to be applied to biological systems, have given rise to protein-based gene expression analysis (proteomics). As antibodies to these proteins are developed, microarray technology can be used for even more rapid screening of expressed proteins. When coupled with information from functional genomics analyses, proteomics contributes to a very comprehensive understanding of how and why particular phenotypes occur. Proteomics approaches to identifying and studying the structure, function, and expression of candidate genes affecting health, reproduction, production, and product quality in cattle will be used in the proposed Project (see below). Where appropriate, gene function studies will be supported using transgenesis and cloning technologies already in use by Project participants (see for example, Kerr et al., 2001).

Because of the far-reaching nature of the proposed gene discovery efforts that link actual genes to relevant chromosomal locations and protein variants that determine the health, reproduction, production, and product quality phenotypes of interest (Objectives 1 and 2 below), the proposed Project requires connected efforts of researchers from multiple disciplines and geographical locations. Multistate Research Projects are the perfect and necessary forums to foster such research efforts. The current proposal was developed in collaboration with ongoing efforts of participants from NC-209, NE-112, NCR-199, NRSP-8, and several members of the National Bovine Functional Genomics Consortium (see below), as well as several new investigators from AZ, KY, IL, MI, PA, and VT with keen interest in joining the Project (refer to Appendix E). Therefore, this proposal was developed from multistate and multidisciplinary perspectives and will require the support and connections that are fostered through Multistate Research Project activities. As with any large genomics/proteomics efforts, it will be increasingly important to communicate new information from this type of work to other interested animal researchers, industry representatives, government agencies, and the public at large. Objective 3 (see below) of the proposed Project will ensure that this is accomplished.

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